THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTE R AT JOHNS HOPKINS

SPECIAL ISSUE BLOOMBERG~KIMMEL INSTITUTE for CANCER IMMUNOTHERAPY “Immune therapy is a game changer. We need more research to take us the rest of the distance, but we don’t think there is a single cancer that the patient’s own immune system ultimately can’t beat .”

–Cancer Immunologist Drew Pardoll , M.D., Ph.D.

2016/2017 2 PROMISE & PROGRESS

JOHN RYAN IS AMONG THE MANY PATIENTS WHO HAVE BENEFITTED FROM A PROMISING NEW IMMUNE THERAPY CALLED ANTI-PD1. THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 3

The Final Frontier? Immune Therapies Break Through Cancer’s Protective Barriers

Immune therapy is recognizably different from all conventional cancer therapies. Imagine a cancer treatment that works without making patients sick or causing their hair to fall out. Doctors and nurses agree it is unlike anything they have ever witnessed in the world of cance r medicine. Gone are the iconic bald heads that immediately identified a person—inside or outside of the hospital—as a cancer patient. Like no other disease, cancer has traumatized the human population with its lethality and toxic treatments. That’s all changing now, as therapies that empower the body’s own natural defenses are at last becoming a reality and providing unparalleled, long-lasting responses across many cancer types, and even in the most advanced and treatment-resistant cancers.

PATIENTS ARE SAYING they don’t feel cells. Researchers and clinicians at the and others unleash the commands that like they have cancer. Knowing what Kimmel Cancer Center have worked send the immune cells to work against it. cancer treatment is “supposed” to be together with experts throughout Johns These types of immune therapies have like—many having already experienced Hopkins, using science to follow the had success alone, but perhaps their it—they worry that they feel too well. Man y clues and bring the world what may be greatest power will come in combining ask: “If I feel this healthy, could the treat - a universal treatment for cancer. Cancer them and, through precision medicine, ment really be working?” immunology and melanoma expert using the biological clues within each pa - The answer, experts say, is a resound - Suzanne Topalian calls immunotherapy tient’s cancer to guide treatment. ing “yes,” and the Kimmel Cancer Center “the common denominator.” Leading the way are scientists, like is leading the way with its unprecedent ed Drew Pardoll and Elizabeth Jaffee , findings echoing through the laboratorie s who have been at work for more than 30 and waiting rooms of medical instituti ons, years de ciphering the mechanisms of the community hospitals, and cancer clinics im mune system, how it works and why it all over the world. all too often does not work against can - “This is oncology of the future,” says cer. As students of the immune system, William Nelson , Kimmel Cancer Cente r Pardo ll, Jaffee, and others understood Director, “and the future is now.” that the characteristics of the immune system should make it the perfect anti - A Game Changer cancer weapon, but if the cancer cell was

As long as cancer has been a recognized DREW PARDOLL AND ELIZABETH JAFFEE , CIRCA 1989. complex in its molecular construction, disease, doctors have believed the power the intricacies of the immune system to eliminate it existed within the immune were equally complicated. system, but attempt after attempt to Immune-based therapies reflect a dif - Unlike viruses and bacteria that are unlock this potential has largely failed. feren t approach to treatment. Instead of easi ly recognized by our immune system The potential always existed, but the key targeting cancer cells, the new therapies becaus e they are so different, cancer orig - information needed to turn this promise target immune cells in and around cance rs. inates from our own cells. As a result, it into real treatments was locked away Some treatments increase the number of has all of the cellular mechanisms that inside the DNA of tumor and immune immune cells summoned to the tumor, are used by normal cells at its disposal. 4 PROMISE & PROGRESS RESEARCHERS AND CLINICIANS AT THE KIMMEL CANCER CENTER HAVE WORKED TOGETHER WITH EXPERTS THROUGHOUT JOHNS HOPKINS, USING SCIENCE TO FOLLOW THE CLUES AND BRING THE WORLD WHAT MAY BE A UNIVERSAL TREATMENT FOR CANCER. CANCER IMMUNOLOGY AND MELANOMA EXPERT SUZANNE TOPALIAN CALLS IMMUNOTHERAPY “THE COMMON DENOMINATOR.”

Cancer co-opts them selectively, using ability to dodge an immune attack are Immune Checkpoint them like superpowers to grow, spread, being revealed, and the results, though and cloak themselves from the immune admittedly early, are like nothing that has Blockades More than 8000 practicing oncologists system. ever been seen in cancer medicine. Utter and clinical cancer scientists from all It took time for the technology to destruction of the most resistant, lethal over the world filled the lecture hall at catch up with the scientific ideas, but the tumors is occurring across many cancer the 2015 annual meeting of the American invincible cancer cell may have finally types and with few side effects. Patients Society of Clinical Oncology (ASCO). met its match. This Kimmel Cancer who were months, even weeks, from It’s not the first time a standing-room- Center team of multispecialty collabora - dying are alive and well, some five years only crowd has come there to hear a tors—seasoned investigators and young or more after treatment. Kimmel Cancer Center cancer expert clinician-scientists—has figured out ho w It was what Pardoll and Jaffee imag - discuss one of the most promising new to reset the cellular controls hijacked by ined three decades ago when they first cancer therapies in decades—immune the cancer cell and restore power to the began studying the immune system— checkpoint blockade. This time, cancer immune system. In a convergence of perhaps even better. immunology expert Suzanne Topalian wa s immunology, genetic, and epigenetic there as the David A. Karnofsky Memoria l findings, the secrets of the cancer cell’s The secrets of the cancer cell’s ability to dodge an immune attack are being revealed, and the results, though admittedly ear ly, are like nothing that has ever been seen in cancer medicine . THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 5

“Cancer cells take control of a valuable immune response regulator and turn it on its head. The anti-PD-1 therapy allows us to seize that power back. ” Award and Lecture recipient for “out - types of therapy, oncologists wanted to ongoing after many years,” says Pardoll. standing contributions to the research, know more. Scholarly journals and the These long-lasting responses that contin - diagnosis, and treatment of cancer.” In news media alike were reporting on ued even after therapy was stopped and 2012, Thoracic Oncology Program Direc - drugs that caused lethal melanoma skin caused few side effects are the reason tor Julie Brahmer presented findings on cancers, kidney cancers, and lung can - the auditorium was filled to capacity an immune checkpoint blockade study in cers to melt away and stay away. with doctors anxious to learn how and lung cancer. It marks a changing tide in The therapies are so new—first teste d when they could get this new therapy for clinical cancer research. Immunology in patients in 2006—that the Kimmel their patients. studies had never before received this Cancer Center immunology team readily The source of the excitement is an level of attention at ASCO meetings. admits there is much left to learn. “We immune target called PD-1 and a related With remarkable and lasting results don’t know yet what the ultimate survival partner protein on tumor cells called in about 20 to 40 percent of patients with benefit will be, but for some patients in PD-L1. PD-1 is what immunology experts advanced cancers that resisted all other these first trials, the responses are still call an immune checkpoint. Par doll stops short of calling it an immune system

AMONG NORMAL CELLS, PD-1 IS NOT A BAD ACTOR, EXPLAINS BLOOD AND BONE MARROW CANCER EXPERT AND IMMUNOLOG Y master switch, but the results in labora - COLLABORATOR JONATHAN POWELL . “IT’S ACTUALLY A GOOD THING. IT’S THE MEANS BY WHICH THE IMMUNE SYSTEM REGULATES ITSELF. IT MAKES SURE THE IMMUNE SYSTEM DOESN’T OVERDO ITS JOB.” tory research and these early clinical trials point to it as one of the strongest influ - encers of an immune response to cancer identified so far. It—and likely some othe r similar proteins—is responsible for can - cer’s ability to avert an immune attack. There are two main actions at play in an immune reaction. The first is a “go” signal. “Our cells are constantly present - ing our own proteins to our own immune system,” explains pathologist Bob Anders . One can think of DNA as the blueprint of a cell, and the proteins its genes encode are its building blocks. A protein from a mutated gene looks different than its normal counterpart. In the same way it recognizes bacteria and viruses, the pa - trolling immune system can recognize abnormal cells that don’t belong. “When immune cells come upon something that shouldn’t be there, they generate an im - mune reaction,” says Anders. This is the

BOB ANDERS 6 PROMISE & PROGRESS

Lessons from the RICHARD JONES EPHRAIM FUCHS, LEO LUZNIK First Immune Therapy

SOME OF THE earliest research at the Kimmel Cancer Center that focused on the immune system was in blood and bone marrow cancers and bone marrow transplantation. Cancers of the blood and bone marrow, such as leukemia, lymphoma, and multiple myeloma, pro - vided a unique perspective of normal immune cells, malignant ones, and the magnitude of the immune system’s power system, usually found in a brother or almost all parents, siblings, and children In most cancers, the goal is to engag e sister. A large national registry matched of patients—and sometimes even aunts the immune system, but in bone marrow some of these patients with unrelated and uncles, nieces and nephews, half- transplant, where the patient’s cancer- donors, but most grew sicker and many siblings, and grandparents or grandchil - filled bone marrow is replaced with died waiting for a match to be found. As dren—can safely serve as donors. Now, healthy marrow from a donor, the goal is a result, only about one-half of patients almost every patient who needs a bone to disengage—well, at least a little. The were candidates for the potentially marrow transplant can find a matching reason is a serious complication of bone curative therapy. Minorities suffered donor. Since developing the treatment marrow transplant known as graft versus the most. African-American patients more than a decade ago, Kimmel Cancer host disease (GVHD), a destructive im - who did not have a match in their family Center experts have performed more than mune attack against the patient’s orga ns had less than a 10 percent chance of 600 half-matched transplants for adult and tissue. The transplanted marrow finding a donor in the unrelated registry. and pediatric leukemia and lymphoma. sees its new host as foreign and wages an Pioneering discoveries led by These clinical studies have proven assault that can be as lethal as cancer. Kimmel Cancer Center investigators so successful, with safety and toxicity Veteran cancer immunology leader Richard Jones , Ephraim Fuchs and comparable to matched transplants, that Drew Pardoll first observed its wrath Leo Luznik have now made it possible the therapy is now used to treat chronic as an oncology trainee treating a young for almost any patient to receive a trans - but debilitating noncancerous diseases girl dying from severe GVHD. It plant. The research that led to this break - of the blood in adults and children, such was a defining moment for the young through focused on immune cells known as sickle cell disease and severe autoim - physician-scientist. “I realized that the as T cells and technologies to remove mune disorders . immune system was probably the most these cells from the donor marrow. Clini - More recently, a revolutionary study powerful anticancer weapon we have,” cal studies showed that when the T cells using half-matched transplants to improve says Pardoll. “If we learned how it worked were removed, patients did not get GVHD the effectiveness and safety of solid orga n and could focus it more precisely against but their cancers sometimes came back. transplants with living donors has beg un. cancer, I believe it could be more power - It was one of the first observations of the Kimmel Cancer Center research ers are ful than any drug.” immune system’s ability to kill cancer cell s. collaborating with transplant surgeons Pardoll decided to focus on deci - The challenge was to remove a precise to begin a combined kidney/half-identic al phering how the immune system worke d, amount of T cells—small enough to avoid bone marrow transplant. Since the while Kimmel Cancer Center bone mar - the most severe cases of GVHD, yet a larg e patient and donor would have the same row transplant experts began solving enough number to allow the immune immune system, it could essentially the problem of GVHD in what could system to keep the cancer from returning. eliminate organ rejec tion and a lifetime be considered one of the first immune It turns out that the same drug used of antirejection dru gs. success stories in cancer treatment. to treat patients before bone marrow If successful, this important work transplant could be given post-transplant will conquer the transplantation barrier— to limit GVHD without hampering the rejection—and what is learned could be Making Bone Marrow T cells’ ability to mop up any surviving applied to all solid organ transplants. It Transplant Safe and cancer cells. This discovery led Kimmel also facilitates the research being done Available to All Cancer Center experts to develop a new in regenerative medicine, where work to FOR DECADES GVHD prevented bone type of bone marrow transplant, known a s grow transplantable tissue and organs marrow transplants from being performed a haploidentical or ha lf-identical trans plant. would ultimately be of no clinical use on patients who did not have a donor wit h In this breakthrough approach without the means to successfully and a nearly identically matching immune developed at the Kimmel Cancer Center, safely transplant them into humans. THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 7

go signal. When the job is done and marrow cancer expert and immunology the invading cells are taken care of, the col laborator Jonathan Powell . “It’s immune system issues a “stop” signal. actual ly a good thing. It’s the means by These stop signals are controlled by which the immune system regulates itsel f. immune checkpoints like PD-1. In can cer, It makes sure the immune system doesn’t malignant cells hijack the “stop” signal overdo its job,” he says. It’s the cancer to maintain their own survival. They sen d cell that once again assumes the role of a deceptive message to cancer-killing villain. PD-1 is an immune mechanism immune cells that there is no problem. that has been usurped by the cancer cell. Immune cells arrive at the tumor, but “Cancer cells take control of a valuable they are duped with a false message that immune response regulator and turn it everything is OK. “Essentially, they’re on its hea d,” he says. “Anti-PD-1 therapy told to go home. There is nothing to see allows us to seize that power back .” here,” says pathologist Janis Taube . PATHOLOGIST JANIS TAUBE SAYS THERE ARE BIOMARKERS THAT CAN BE USED TO PREDICT RESPONSE TO IMMUNE Taube and Anders describe a sce - Unbelievable Patient THERAPY WITH ANTI-PD-1 CHECKPOINT INHIBITORS. TUMOR CELLS THAT EXPRESS PD-L1, HAVE MANY GENE nario in which a tumor is spreading, and Responses MUTATIONS, AND ALREADY HAVE KILLER IMMUNE CELLS John Ryan is among the many patients PRESENT ARE MOST LIKELY TO RESPOND. THE CANCER as immune cells come in to try to remove IMMUNOLOGY TEAM IS WORKING TO IDENTIFY OTHER the cancer, the cancer turns up the volum e who have benefited from the anti-PD-1 CHARACTERISTICS, LIKE MISMATCH REPAIR ALTERATIONS, THAT WILL MAKE CANCER CELLS MORE VULNERABLE TO on PD-1, a signal that turns the immune therapy being discussed at ASCO. IMMUNE THERAPY. cells off. “The tumor cells use our own Ryan, 71, began experiencing symp - physiology against us,” says Anders. toms in 2013 when he coughed up a small For a time the chemotherapy work ed, The “volume” of the PD-1 stop signal amount of blood. The husband and fathe r but the treatment came at great physical is controlled in the cancer cell by the of eight thought it was strange, but with cost, and these side effects were worsen - expression of one or both of two partner no pain or other symptoms he was stunne d ing. The simplest tasks became difficult. proteins called PD-L1 and PD-L2. In to learn he had the most advanced stage His body was weakening, and worse, solid tumors, like melanoma and lung of a common form of lung cancer known he learned his cancer was no longer cancer, PD-L1 has received the most as non-small cell lung cancer. The cancer responding. Genetic testing of his tumor attention today, but PD-L2 appears to had already spread to a rib. did not reveal any mutations that would play an important role in cancers that There are few diagnoses worse than make him a candidate for targeted thera - start in the blood and lymph late stage lung cancer. The pies. It seemed he was out of options nodes, such as leukemia and JANIS TAUBE cancer kills more people until his doctor suggested he go to the lymphoma. “We see PD-L1 than any other type of Kimmel Cancer Center and meet with frequently in melanoma,” says cancer , and few patients lung cancer expert Julie Brahmer . Taube. “PD-L1 is expressed survive once it has spre ad. Brahmer was one of the lead investi - on the surface of the tumor At this stage, the cancer gators on an experimental clinical study cell. When you see it through is treatment resistant, of the anti-PD-1 therapy in a variety of the microscope, it looks like responding for a brief advanced cancers. Ryan’s form of lung someone outlined the cells time to chemotherapy cancer was among the cancers that with a marker. It forms an or cancer-gene-targeted showed unprecedented responses. armor that protects the therapies, but almost “Before I began treatment, I strug - cancer cell from the immune system.” always resurging even stronger. gled to sit at my kitchen table. After just Giving patients a drug, known as an Medically speaking, Ryan’s diagnosis four treatments, the tumor shrunk by 65 anti-PD-1 checkpoint blocker, for its abil - was Stage 4 non small cell adenocarcino ma percent, and I felt like a human being ity to interrupt PD-1 signaling as well as of the lung. “One of my sons was graduat - again,” says Ryan. A few more treatments the communication between PD-1 and ing from college, and my daughte r was an d Ryan’s rapidly growing lung cancer PD-L1 and PD-L2, removes the stop sig - about to leave for a study abroad. I was nearly gone, and the cancer that nal and re-engages the immune system. wondered if I would live long enough to spread to his rib was eliminated. His only Among normal cells, PD-1 is not a see my son graduate or to welcome my side effect was some minor skin irritations bad actor, explains blood and bone daughter back home,” Ryan recalls. he compared to a mosquito bite.

Anti-PD-1 is not the first checkpoint blockade therapy, but it is the first to work beyond melanoma in as many as 14 other cancer types, and that’s the pivotal difference that has excited the cancer world . 8 PROMISE & PROGRESS

Ryan is not an isolated case. Topali an cancer patients. Lung cancer had never human body—even without help from and Brahmer say about one-quarter of before responded to an immune therapy, immunol ogists—has an immune response the lung cancer patients in their studies and the remarkable activity of anti-PD-1 to cancer . The problem is that the respons e responded to the treatment. The num - in a small number of lung cancer patients is being blocked. That concept, and the bers are even higher for melanoma and proved what Pardoll and other cancer fact that i t is true in people, is exceedingly kidney cancer patients. immunologists long believed—if under - important.” Anti-PD-1 is not the first checkpoint stood, the immune system could be used “This is yet more evidence that blockade therapy, but it is the first to wor k to fight any cancer. “Anti-PD-1 has be - well-thought-out, consistent and collab - beyond melanoma in as many as 14 other come a cancer juggernaut,” says Pardoll. orative research pays off,” says William cancer types, and that’s the pivotal differ - Pardoll first became interested in Nelson, the Kimmel Cancer Center ence that has excited the cancer world. the protein in 2000, when he came upon Director. “Anti-PD-1 is a triumph of team PD-1’s second partner, PD-L2. Lieping science.” It is this willingness to follow The Lung Cancer Chen, a collaborator of Pardoll’s at the leads and seek out other experts that Difference Kimmel Cancer Center who is now at can inform the process that continues The first clinical reports of checkpoint Yale, had just discovered PD-L1 and to position Johns Hopkins as a leader inhibitors in melanoma were exciting showed that it’s expression in human in transitioning laboratory science into and peaked interest, but excitement was lung cancer cells was highly elevated pioneering cancer therapies, he says. tempered because the few successes in compared to normal cells. Although “We developed this one from scratch immune therapy over the last three lung cancers had not responded to other at the Kimmel Cancer Center,” says Pard oll. decades had also been primarily in past immune therapy attempts, this As soon as the components of the PD-1 melanoma and kidney cancer. There discovery provided new evidence that pathway were discovered in 2000, Pardol l, have been documented cases of these it had the potential to work and was the Topalian, Brahmer, and immunology and cancers occasionally going into sponta - reason the Kimmel Cancer Center team genitourinary cancer expert Chuck neous remission, so experts long main - included lung cancer patients in the first Drake saw the potential of blocking it. tained that, by nature, these types of anti-PD-1 trial. They began working with the small cancers had a way of engaging the Powell is excited about the success biotech company Medarex to develop immune system. No other type of cancer of PD-1 in patients, but he is also enthusi - the first anti-PD-1 antibody in the labora - was considered to be responsive to astic about what he sees as a triumph of tory and took it to patients. They too immune interventions. The new therapy science. “What we have learned is so found strong responses in melanoma, but was greeted with guarded optimism. encouraging,” he says. “The mere fact it was Brahmer’s lung cancer patients that That all changed in 2012 when the that we can block a checkpoint and make were game chang ers. Kimmel Cancer Center group published a tumor go away is an incredibly impor - This was the moment Pardoll and the results of anti-PD-1 therapy in lung tant finding because it tells us that the Topalian, who are not only research part - ners but also husband and wife, were

JULIE BRAHMER WAS ONE OF THE LEAD INVESTIGATORS ON AN EXPERIMENTAL CLINICAL waiting for. It was a belief Pardoll had STUDY OF THE ANTI-PD-1 THERAPY IN A VARIETY OF ADVANCED CANCERS. staked his career on, and one that caused Topalian to change course from a career as surgical oncologist to immunology. Sh e worked as a National Cancer Institute scientist alongside cancer immunology pioneer Steven Rosenberg for 20 years before coming to the Kimmel Cancer Center. Rosenberg’s research of interferons and interleukins, cellular messengers critical to immune responses, garnered similar excitement in the 1980s as a po - tential broad-based immune treatment for cancer. The cover of Time magazine boasted the headline “Interferon: The Cure for Cancer.” When the celebrated treatment failed to live up to expectations —most of which had been generated by an eager news media desperately waiting for the grand-slam victory that had been THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 9

Personalized Cell Therapy

IVAN BORRELLO serious side effects to the therapy. “This was a small trial, but we learned that large numbers of activated MILs can selectively target and kill myeloma cells,” says Borello. There is currently an ongoing clinica l trial targeting myeloma patients with high risk features. Borrello and team ho pe to determine if the approach can impact patients where standard approaches are ineffective. The trial will soon be extended to other cancer centers. Borrello and collaborator Kimberly Noonan, a research associate in the school of medicine, say the studies shed light on better ways to grown MILs. “In most of these trials, you see that the more cells you get, the better response you get in patients. Learning how to improve cell growth may improve the Kimmel Cancer Center immunology and bone marrow transplant outcomes of therapy,” says Noonan. expert Ivan Borrello has developed a novel personalized cancer The research indicates that MILs treatment approach called adoptive T cell therapy using the could also be beneficial in the treatment patients’ own immune cells to fight their cancer. This approach of a variety of other cancers, so Borrello has involved a team of heavy hitters to uses cells from the bone marrow known as marrow infiltrating help advance the science and clinical lymphocytes, or MILs. reach beyond myeloma. Other plans include administering MILs in patients T CELLS ARE THE foot soldiers of the im - myeloma. In a first-of-its-kind clinical that have relapsed following an allogene ic mune system, and MILs are a type of trial of the therapy, 22 patients with bone marrow transplant, using MILs tumor-specific T cell, a small subset of newly diagnosed or recurrent multiple from the patient grown and expanded in immune cells that recognize cancer myeloma received the therapy. Following the laboratory, rather than immune cells cells. In cancers of the blood, MILs are standard treatment for multiple myeloma from the bone marrow donor. MILs are found in the bone marrow where the —high-dose chemotherapy to destroy the being developed to treat lung, esophage al, cancer originates. In this new approach, diseased bone marrow—and a stem cell gastric, and prostate cancer in adults and our scientists retrieve patients’ own transplant to repopulate the marrow neuroblastoma and Ewing’s sarcoma in MILs from their bone marrow, expand with normal blood and immune cells, pediatric patients. The team includes of their numbers and coat the cells with patients were given their own MILs. some of the Kimmel Cancer Center’s immune- activating antibodies in a spe - One year after MILs therapy, 13 pa - leading experts in immunology, blood cial Cell Therapy Lab at Johns Hopkins, tients had at least a 50 percent reduction and bone marrow cancer, and experts in and then infuse them back into the in their cancer. Their cancer remained specific cancers, including Drew Pardo ll, patient’s bloodstream where they seek stable for nearly a year, and overall Carol Ann Huff, Leo Luznik, William out and destroy cancer cells. survival was close to three years. Seven Matsui, Jonathan Powell, Ephraim Borrello is using MILs therapy to patients saw a 90 percent reduction, and Fuchs, Richard Ambinder, Richard treat patients with an incurable cancer of their cancer has remained in check for Jones, Ronan Kelly, Nate Brennan , the blood plasma cells known as multiple more than six years. There were no and Brian Ladle . 10 PROMISE & PROGRESS

“Pancreatic cancer is notorious for being in areas outside of the pancreas, and the vaccine allows us to get ahead of the dis - ease and get microscopic cancer cells that surgery might miss.” promised when the “war against cancer” The promise of immune therapy is worked only in a small subset of patients was announced in 1971—the field of can - changing the way new therapies are were once deemed failures. Now, in an er a cer immunology was nearly crush ed. To studied and evaluated. Chemotherapy of precision medicine that uses molecul ar be fair, interleukin-2 treatment, while a poisons cells dividing quickly, including markers to identify the right treatment fo r difficult treatment for patients, continues immune cells. This toxic effect is the each patient, the options are much broade r to be used occasionally today and is cause of the common side effects, like and the outlook is significantly brighter. highly effective in some patients with hair loss, nausea, and infection risk due melanoma and kidney cancer. However, to a compromised immune system. First, There Were instead of being the blockbuster immune Immune therapies appear to work more therapy people had hoped for, it was a slowly over time, and it’s looking now Cancer Vaccines Cancer vaccines were one of the first start. “It was the first evidence that a drug like they work better for longer. Some of immune treatments studied by Kimmel that acted only through the immune this was learned almost serendipitously, Cancer Center investigators. Early system could fight very advanced cancer,” as cancers that initially looked like they research on cancer vaccines by immunol - says Topalian. “Tha t was impor tant were not responding to immune treat - ogist and pancreatic cancer expert because it told us we wer e on the right ments, with more time, began to shrink. Elizabeth Jaffee proved the ability to track with immunotherapy and needed “The immune system has been living successfully recruit immune cells to to keep working on this.” with cancer for years. To make it not be tumors, and even had some therapeutic In fact, many outside the field of so happy living with the cancer takes benefit. All too often, however, the cancer immunology had begun to doubt some time,” says Drake. immune cells—called to the tumor by the promise of immune treatments in Eventually, it all rested upon what the vaccine in large numbers—did not cancer. Immunotherapy discussions at was learned with science and technology— fully attack the cancer. the large national cancer meetings were powerful new ways to look inside the Vaccines can peak the immune re - sparsely attended, and research funding DNA of cancer cells and computerized sponse in days, calling immune cells to was hard to come by. The Kimmel Cancer data mining that measures and quantifies the tumor site. To reverse tolerance of Center immunology team remained the subtlest of changes and differences the cancer—characterized by immune undeterred. They knew the power of the among seemingly similar cancers. cells flooding to the tumor site but not immune system and their convictions wer e The mechanisms that make therapy taking action—can take time. It may also cemented in this truth. The challenge was work in one patient and not in another are require additional kinds of immune thera - channeling this power into real therapies. now being teased out. Treatments that pies. Some patients’ immune systems are on the edge, requiring just a vaccine to make them respond. Others need more. Jaffee and Daniel Laheru, co-direc - tors of the Skip Viragh Center for Pancre as Cancer Clinical Research and Patient Care , are leading the way in cancer vaccine therapy, and their target is one of the deadliest of cancers. Jaffee began working on a pancreati c cancer vaccine more than two decades ago . To make vaccine therapy a reality, sh e became an expert in FDA regulations a nd vaccine manufacturing, and she opened a GMP (good manufacturing practices) facility at the Kimmel Cancer Center to make vaccines for clinical studies. Jaffee, Laheru, and young investiga - tors Dung Le, Lei Zheng, Erik Lutz

IMMUNOLOGY AND GENITOURINARY CANCER EXPERT CHUCK DRAKE HELPED DEVELOP THE FIRST ANTI-PD1 ANTIBODY IN THE LABORATORY. THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 11

EARLY RESEARCH ON CANCER VACCINES BY IMMUNOLOGIST AND PANCREATIC CANCER EXPERT ELIZABETH JAFFEE PROVED THE ABILITY TO SUCCESSFULLY RECRUIT IMMUNE CELLS TO TUMORS AND EVEN HAD SOME THERAPEUTIC BENEFIT.

and others are testing various versions of attracted worldwide attention. Clinic atic cancer is notorious for being in areas the vaccine. It is built from pancreatic coordinator and research nurse Barbara outside of the pancreas, and the vaccine cancer cells that have been rendered Biedrzycki receives more than 60 calls allows us to get ahead of the disease and dormant with radiation and engineered per month from patients who want to get get microscopic cancer cells that surgery to recruit immune cells to track and the vaccine. Once after an appearance by might miss,” says Laheru. attack malignant cells anywhere in the Jaffee on The Dr. Oz Show , the clinic was Other variations include combined body and to continue to do it indefinitely. flooded with more than 1,000 inquiries treatments. In some patients, giving the In some patients, the original itera - from patients all over the country. “The re immune-modulating drug cyclophos- tion of the vaccine has worked remark - is no other cancer center doing this kind phamide before the vaccine causes im - ably. Patients like nearly 20-year survivor of work,” say Zheng. mune structures to form inside tumors Kathleen Dowell, 12-year survivor Donna With funding from the Skip Viragh that help regulate immune cell activation . Bender, and eight-year survivor Nancy Foundation, Laheru, Zheng, Lutz, and Le “These organized immune structures do Amato were given months to live when are working with Jaffee to optimize the not naturally appear in pancreatic cancers, ” their pancreatic cancers persisted after effects of her pioneering vaccine. They says Zheng. “This suggests that there has surgery, chemotherapy, and radiation are making tweaks in timing of vaccinatio n been significant reprogramming of im - therapy. Jaffee’s vaccine continues to and changes to its composition and deliv - mune cells within the tumor.” There is keep their cancers in check. ery that they hope will boost its cancer- evidence that adding a checkpoint block - Because it is perhaps one of the only killing capabilities and make the vaccine ade like anti-PD-1 treatment to the mix treatments that make any real difference a treatment option for many more patien ts. could further enhance immune activity. in long-term survival for this most One of their new approaches is to Another combined approach adds aggressive of cancers, the vaccine has give the vaccine before surgery. “Pancre - a second kind of vaccine, a weakened 12 PROMISE & PROGRESS

DANIEL LAHERU , CO-DIRECTOR OF THE SKIP VIRAGH CENTER FOR PANCREAS CANCER CLINICAL RESEARCH AND PATIENT CARE, IS HELPING LEAD THE WAY IN CANCER VACCINE THERAPY. HIS TARGET IS ONE OF THE DEADLIEST OF CANCERS.

IMMUNOLOGY EXPERT LEISHA EMENS IS STUDYING VACCINES FOR BREAST CANCER AND OVARIAN CANCER.

at a cancer clinic near his home, Greco says he felt worse than he ever had his life . He told himself it was worth it because, as bad as he felt, his doctors told him it was causing his pancreatic cancer to shrink enough that it could be cut out with surgery. As a physician, Greco knew of Johns Hopkins expertise in the Whipple proce - dure, the primary surgical treatment for pancreatic cancer. Johns Hopkins sur - geons perfected the procedure, perform more of them, and train more new sur - geons how do the procedure than any other institution in the world. With this in mind, Greco scheduled a consultation at the Kimmel Cancer Center’s Skip Viragh Center. At his consultation, he learned the chemotherapy hadn’t worked. In fact, his version of the bacterium listeria. The cancers, including about one-half of lung cancer was quite advanced, and a Whip - listeria is genetically modified to be safe cancers, mesotheliomas, ovarian cancers, ple procedure would not help him. “I’m for hu mans but stimulates an immune and stomach cancers. As a result, the vac - so thankful I came to Johns Hopkins,” respons e against the protein mesothelin. cine is now being tested in lung cancer says Greco. “If I had listened to the doc - Ralph Hruban , pathologist and Director and mesothelioma, and Kimmel Cancer tors in Florida and went ahead with the of the Sol Goldman Pancreatic Cancer Center immunology expert Leisha Emens surgery, I’m certain I would have died.” Researc h Center, found mesothelin in will lead a trial testing it in ovarian cance r. Greco continued to do his research. high levels on the surface of pancreatic He was familiar with immune therapy cancer cells, and Jaffee and Le believe Patient Perspective and went to the National Cancer Insti - the protein helps pancreatic cancer cells Sarasota internist Jonathan Greco, 58, is tute’s clinicaltrials.gov website to search to grow and spread. “The combination among 90 patients enrolled in a clinical for experimental treatments and infor - essentially trains the body to recognize trial to test the effectiveness of a mation. “Johns Hopkins clearly had the and attack pancreatic tumors,” says Le. cyclophosphamide, GVAX, listeria, and most immunotherapy experience. It was Ongoing research has revealed that anti-PD-1 quadruple combination. evident they had been doing this longer mesothelin is over-expressed in many After nine weeks of chemotherapy than anybody,” says Greco. THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 13

He enrolled in a clinical trial designed and led by Elizabeth Jaffee and Immune Therapy Shows Dung Le that is the centerpiece of a Promise for Breast Cancer Stand Up To Cancer pancreatic cancer dream team directed by Jaffee. It combines treatments with the vaccine- enhancing drug cyclophosphamide, the immune-activating GVAX vaccine, mesothelin-targeting listeria, and the immune checkpoint blockade with anti-PD-1. The pancreatic cancer GVAX vaccine was developed by Jaffee with Viragh funding and is manufactured at a GMP facility in the Kimmel Cancer Center that she opened and directs. The combined therapy represents a culmination of immunology laboratory and clinical science, joining the strength of several immune-targeted therapies in an attempt to topple one of the most lethal cancers. Jaffee and Le hope the combination will pack the immune PRELIMINARY results of an early, multi - ROISIN CONNOLLY, M.B.B.CH ., WAS AWARDED A YOUNG punch needed to break the resistance of INVESTIGATOR AWARD FROM THE NATIONAL COMPREHEN - center study showed an experimental SIVE CANCER NETWORK TO INVESTIGATE WHETHER THE pancreatic cancer. IMMUNE SYSTEM CAN BE HARNESSED IN THE TREATMENT immune therapy drug was safe in patien ts OF TRIPLE-NEGATIVE BREAST CANCER. TUMOR BIOPSIES “I feel fortunate to be one of the with metastatic, triple-negative breast AND BLOOD SAMPLES OBTAINED FROM PATIENTS WILL 90 patients participating in this trial,” BE USED TO LEARN MORE ABOUT HOW THE IMMUNE cancer. These early findings offer new SYSTEM ACTS IN PATIENTS WITH TRIPLE-NEGATIVE BREAST says Greco. Le says it’s too early in his CANCER AND TO IDENTIFY BIOMARKERS THAT WILL HELP hope in the fight against this particularly DISTINGUISH PATIENTS WHO WILL RESPOND BEST TO treatment to measure the effect the aggressive and difficult-to-treat disease. THESE TREATMENTS. treatment is having on his cancer or to The study involved 54 patients with were evaluated to assess the impact of know what the long-term impact will be . advanced triple-negative breast cancer the drug. Six patients survived at least After his experience with chemotherapy , from the Kimmel Cancer Center and 24 weeks without disease progression, Greco says he is grateful for a treatment other cancer centers. The patients an unusual result among patients with that doesn’t make him sick. “I feel like received an experimental drug, known this type of advanced and resistant myself again. I feel great. I swim every - as a PD-1 blockade, designed to disrupt a cancer. Two patients saw their cancers day, and I’m still seeing patients. I feel pathway that hides tumor cells from the disappear, and tumors shrunk in another like I’m cured.” immune system. two patients. “Early data in this trial show that Next steps include testing the drug’s Then Came PD-1 the drug is generally safe and well-toler - benefit in groups of patients and compar - The first patients were treated with anti- ated, and it appears to be able to control ing it with standard treatments to deter - PD-1 in 2006 as part of a small clinical disease in some of these patients,” says mine its therapeutic value. A large global trial led by Brahmer and funded by study leader Leisha Emens, M.D., Ph.D. study to evaluate it as a possible standard Medarex, now part of pharmaceutical “Now we’ll need to test it further in more therapy is underway. giant Bristol- Myers Squibb. The scien - patients and compare it with standard “Engaging the immune system to tific studies to better understand how therapies to establish its therapeutic fight breast cancer is a game changer,” anti-PD-1 was working were supported value.” says Emens. “This is especially true for by the Melanoma Research Alliance, the The drug binds to an immune-regu - triple-negative breast cancer, for which National Cancer Institute, and faculty lating protein known as PD-L1, disruptin g chemotherapy is currently the only stan - support Susan Topalian received from an interaction between it and a related dard treatment option outside of a clini - the Kimmel Cancer Center and the protein known as PD-1, enabling an im - cal trial. Identifying a way to predict Department of Surgery when she came mune response against the cancer cells. ahead of treatment which patients are to Johns Hopkins. The researchers determined that 37 of more likely to respond is critically impor - Fast forward to 2015, and people the 54 patients expressed the PD-L1 tant, and there are ongoing efforts to were getting very excited again about protein in some immune cells within identify biomarkers for patients who are immunotherapy when the attention of their tumors, and 21 of these patients more likely to respond to this therapy.” JONATHAN GRECO IS ONE OF 90 PANCREATIC CANCER PATIENTS PARTICIPATING IN A CLINICAL STUDY OF A VACCIN E/ ANTI-PD-1 COMBINATION. THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 15

NURSE ANGELA VAN TASSEL ADMINIS - TERS THE SECOND OF NINE VACCINA - TIONS TO PANCREATIC CANCER PATIENT JONATHAN GRECO.

the cancer world—some 30,000 people who wanted to learn about our work long process,” she says. “Today, it’s cele - attending the ASCO meeting—was fixed were signs that immune therapy was brated, but over the last 30 years there on the findings from the Kimmel Cancer now part of mainstream oncology,” have been many things that looked great Center cancer immunology team as says Topalian. in the laboratory that did not translate Topalian explained this immune check - Topalian, who has been there into patients.” Although cancer im - point that could be reset with a drug. In through many of the ups and downs in munology experts had held steadfast to addition to igniting an immune response cancer immunology, prefers to call it an their convictions that they could figure against cancer, the anti-PD-1 drug could evolution. To the public and even scien - out a way to make the immune system be given in the outpatient clinic and tists outside of cancer immunology, it work against cancer, outside of the field caused very few side effects. The media, may seem like an overnight sensation. there were whispers of defeat. “In 2012, including Science , one of the world’s In reality, it was the product of research with our publication in the New England leading scientific journals, dubbed it a that occurred over decades with many Journal of Medicine on a 300-patient breakthrough. “The attention it was contributors, when all but the immunol - clinical trial of anti-PD-1, everything cam e receiving and the number of people ogy diehards weren’t looking. “It’s been a together. It was our moment,” she says. “The notion of doing clinical trials with experimental drug combinations, even where none of the drugs have FDA approval, is becoming the norm. These drugs are turning clinical therapeutic s on its head. This is a game changer. ” 16 PROMISE & PROGRESS

Immune Therapy for Childhood Cancers

BRIAN LADLE CHRISTOPHER GAMPER

WITH THEIR LOW toxicities, immune say there is emerging evidence that im - that surround the DNA that help signal it therapies seem tailor-made for pediatric mune therapies may be more effective to remain dormant or go into action. As a cancer patients where long-term effects against chemotherapy-resistant cancer. result, Ladle and Gamper are decipherin g caused by conventional therapies are of They offer new hope for pediatric pa - the normal epigenetic activity of immune great concern. Childhood cancer patients tients with cancers that currently cannot T cells and exploring whether existing can suffer the consequences of be cured with standard treatments. epigenetic-targeted treatments might be chemotherapy throughout their lifetime, Ladle is excited about this less toxic able to improve immune responses to including fertility issues, cardiac toxici - approach to destroying cancers. “It’s a cancer. ties, learning impairment and more. In privilege to be able to cure kids of cancer, Ladle and Gamper believe epige - fact, many cancer immunology experts but right now, what we have to put them netic drugs may augment the effective - believe immune therapies may be a para - through to get them there is unaccept - ness of other immune treatments, such digm changer, eventually replacing able,” he says. “We have to do better for as cancer vaccines and immune check - chemotherapy as the first-line treatment them.” point blockers. They are also looking for in many pediatric cancers because of While he doesn’t think immune other proteins expressed by tumor cells its ability to spare patients from these therapy will completely replace the need that work like PD-1 to shut down an dangerous toxicities. for surgery and chemotherapy, he immune response to cancer. In addition, Take, for example, Hodgkin’s lym - believes it has great potential to reduce new pediatric oncology physician-scien - phoma. It is a common childhood cancer the amount and duration of treatment. tist Nico Llosa is working on ways to use that responds well to chemotherapy, but More importantly, since immune cells PD-1 blockade and other similar immune treatment is long and toxic, and the can travel anywhere throughout the agents to fight pediatric cancers. growing brains and bodies of children body—inside bones and to organs and While there have been significant and adolescents are particularly tissue—they have a unique ability to find advances in cancer immune therapies in susceptible to the damaging effects of and destroy lingering cancer cells that adults over the last few years, translating chemotherapy. New research shows often result in the recurrence and spread these findings to pediatric cancers lags Hodgkin’s lymphoma may be one of the of cancers. far behind. “This is the main reason I best responders so far to anti-PD-1 im - Ladle and Gamper are discovering wanted to work in pediatric oncology,” mune checkpoint blockade therapy, with crucial links between T cell behavior, says Ladle. “There is so much promise. respons e rates approaching 90 percent. the main cells activated in an immune We know that children’s immune system s There have been excellent respo nses and response, and the epigenetic or chemical are much more responsive than adults’.” low toxicities even in patients whose environment of T cell DNA. Although What Ladle envisions are treatments that cancer resisted standard drug treatment. the DNA code of a T cell that has never harness and deploy the body’s own natu - Researchers like pediatric oncolo - been activated is identical to that of T ral ability to fight cancer and decrease gists and cancer immunology experts cells engaged in an immune attack, sig - the need for invasive surgeries and toxic, Brian Ladle and Christopher Gamper nificant changes occur in the chemicals cell-poisoning drugs. THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 17

collaborators are working to better un - talked to him about a clinical trial testing Pioneering Patients derstand how to encourage the immune the benefits of giving a pancreatic cancer system to attack only tumors and leave vaccine before surgery. THOMAS KOTULA (LEFT) other parts of the body alone. The pancreatic vaccine, developed AND EVAN LIPSON “He’s living his life,” says cancer by Elizabeth Jaffee, supercharged the immunology nurse Trish Brothers . immune system, drawing cancer-attackin g “Im mune therapy has offered real hope to killer T cells to pancreatic tumors. Jaffee Mr. Kotula, both in terms of combating his had laboratory evidence that giving the cancer and allowing him to avoid some of vaccine before surgery gave the immune the debilitating side effects often associate d system a step up on the cancer and might with traditional cancer treatments.” help it get at microscopic cancer cells “I’m so glad I came here. I can’t say that could cause the cancer to spread. enough about these doctors and nurses. She was working with two young clinical “I Don’t Feel Like I Have They are like family,” says Kotula. “What investigators, Dung Le and Lei Zheng, Cancer” a difference from a year ago. I don’t even to explore whether earlier use of the vac - Thomas Kotula, a patient with melanom a feel like I have cancer.” cine would provide a clinical advantage. being treated by Evan Lipson , is receivin g Ogle was well aware of the high rate a combination of two immune checkpoint GENE OGLE of pancreatic cancer spread and recur - inhibitors, anti-PD-1 and anti-CTLA -4. rence. As an engineer, he is a numbers He comes to the Kimmel Cancer Center guy. He recalled a survival chart he saw every two weeks for the hourlong infusion. around the time of his surgery. “It peaked “He was in pretty rough shape the at one year and went down after that. first time I saw him,” says Lipson. Kotul a’s Less than 5 percent of people survived melanoma had spread, including a soft - past five years.” says Ogle. ball-size tumor in his thigh that made it “Enrolling in the vaccine trial was difficult to walk. By his third treatmen t, an easy decision for me,” says Ogle. “I the tumors began to get smaller. A year still had no hope that I would survive, later they have shrunk by more than half. “I Beat Pancreatic Cancer” but I thought if I participated in the The clinical trial he is on, headed by When Gene Ogle’s doctor told him he vaccine study, I might be able to help melanoma expert William Sharfman , had pancreatic cancer, his first question doctors move that survival curve far calls for two years of treatment. was: “How long do I have to live?” Ogle beyond five percent.” “A major focus of our research in - was just 54 years old when he got the new s, That was nearly six years go, and volves understanding how to safely and and his thoughts immediately turned to contrary to the statistics and his own per - effectively use these new immune-based his father, who died of the same disease sonal predictions, Ogle is alive and doing medications in as many patients as possi - 30 years earlier at 63. Although many well. It’s been almost four years since his ble,” says Lipson. “One of the potential years had passed, his memory was clear. final vaccination. His cancer isn’t gone, advantages of immune therapy is that onc e “My father died two months after he was but it’s not growing. With the boost from the immune system is activated, it can keep diagnosed. My knowledge was that it the vaccine, his immune system appears cancer at bay for long periods of time.” was incurable and killed quickly.” to be keeping it in check. “I’m still here, Kotula, a husband, father of six, and Ogle’s doctor told him that there had and I want to be a message of hope to grandfather of nine, says he came to the been many advances since his father’s others,” he says. Kimmel Cancer Center for a second diagnosis, and specifically referred to Ogle fully expected to become a opinion at the encouragement of his chil - discoveries at the Johns Hopkins Kimm el pancreatic statistic, but not a positive dren. His doctor at a community hospital Cancer Center. He decided to make an one. “My perspective is changing,” he near his home recommended surgery. appointment at its Skip Viragh Center for says. He is certain the wonderful care he Lipson had to deliver the bad news to Pancreas Cancer Clinical Research and received, including surgery, chemotherap y, Kotula that surgery would be of little Patient Care. radiation therapy, and particularly the value because the cancer had spread, but Despite the diagnosis, there was pancreatic cancer vaccine, allowed him he offered him an opportunity to partici - some good news. His cancer was not as to beat the odds. “I’m so proud to be a pate in Sharfman’s immune therapy trial. advanced as his father’s, and he was a part of these studies. It’s a huge honor,” Kotula has experienced relatively candidate for a Whipple procedure, a says Ogle. “Everyone who took care of mild side effects from treatment, includ - complex pancreatic cancer surgery per - me—from the receptionist to the nurses ing a rash and some thyroid issues, says fected at Johns Hopkins. At the appoint - and doctors—was top-notch. They all Lipson. He and his cancer immunology ment research nurse Carol Judkins also had so much compassion.” 18 PROMISE & PROGRESS

A Milestone in continue to do well. Such responses are tant events in their lives that he honestly virtually unheard of in advanced cancers. might not have otherwise lived to see,” Cancer Medicine “We don’t know yet what the ultimate says Drake. Remarkable responses were occurring in survival benefit will be, but for these earl y On the other hand, there are can - a significant number of patients, putting trials and these patients, the responses cers, including prostate and pancreatic the framework for a potentially broad- are lasting a long time,” says Pardoll. cancers, that remain largely resistant. based treatment for cancer in place. This “We don’t have to intervene anymore “We need to address that on the research glimmer quickly ignited into a spark and with therapy. The patients’ own immune side,” says Topalian. Drake does not get continues to gain momentum as collabo - systems have taken over the battle.” a good response in all bladder cancer pa - rations across many specialties at Johns “It is a cyclical process,” says Topalia n. tients either. “In some patients, it works Hopkins are expanding its benefit to “We need to continue working between quite well, but in others, the cancer con - other cancers. the laboratory and the clinic to advance tinues to grow,” he says. Understanding This success revealed that the im - the science and understand mor e about why some tumors do not respond is as mune system could be employed against responses, how long the drugs need to important as learning why others do, he cancers beyond melanoma and kidney be given, and how to make the treatment says. “If we can figure out when it works cancer. As important, it provided defini - work in more patients.” To hel p gather and how it works—what kinds of cells are tive proof that there was a common force these answers, she is turning to patholo - involved and what is happening from an at work to shut down an immune respo nse gists Anders, Taube, and Ed Gabrielson, immunological standpoint—maybe we to cancer. who are uncovering the biomarkers, the can take non-responders and make them The most recent clinical study pro - unique cellular characteristics and signals responders,” Drake says. vides clear evidence that for lung cancer that differentiate cancers tha t re spond to There are currently about eight dif - patients whose immune cells express anti-PD-1 from those that do not. ferent types of antibodies that block PD-1 PD-1 or whose tumor cells express PD-L1 , The list of responding cancers con - or PD-L1 on the market. The treatment is immune therapy works better than the tinues to grow. Bladder cancer, Hodgkin ’s now FDA-approved for melanoma and best chemotherapy drugs and with far lym phoma and a few difficult-to-treat lung cancers, and Pardoll says approvals fewer side effects. In addition, patie nts cancers, like tripl e-negative breast cancer for kidney cancer, bladder cancer, and with late-stage lung cancers frequently and mesothelioma, are on it, with others, Hodgkin’s lymphoma are anticipated by become resistant to chemotherapy, but like certain ovarian, endometrial, colon, the end of 2015 or early 2016. They aren’t Brahmer says that patients who respond head and neck, stomach, liver, and cheap, costing about $100,000 or more to immune therapy tend to continue esophageal cancers, expected to soon per year for each patient treated. responding. “In my 20 years in practice, I be added. Although there have been many new s have never seen anything like this. We’re Drake tells of a patient referred to reports about the pricing of the drugs, reporting three-year and more survival him from fellow Greenberg Bladder immunology research nurse Alice Pons rates in lung cancer patients who hones tly Cancer Institute physician-scientist and colleagues say pa - would not typically be around,” says Trinity Bivalacqua . The patient was tients have not seemed Brahmer. “This is truly a milestone in getting chemotherapy to shrink the size concerned about the cancer medicine.” of his bladder cancer so that it could be cost. That could be be - As for how long patients will removed with surgery. When Bivalacqua cause some insurance continue to respond off treatment and operated, he found the cancer had alread y companies are covering whether there are any long-term effects spread. Surgery would not cure him, so them even before final FDA approval. of this type of immune therapy, it’s too he left his bladder intact and referred the Nurse practitioner and immunology soon to know. Pardoll, Topalian and col - patient to Drake. expert Barbara Biedrzyck i says other in - laborators are working to answer these The patient had lost his hair and was surance compa nies may resist approving questions. They also want to make sense underweight from the chemotherapy, and immune ther apy, requiring patients to firs t of the varied responses. In some patients, now it was no longer working. “He was try less expensive drug therapies. To help tumors were held in check, neither not looking well when he came to see me ease the cost burden, the pharmaceutical growing nor shrinking. Other patients, in 2013,” says Drake. He recommended companies making anti-PD-1 drugs say like Ryan, experienced huge reductions immune therapy with anti-PD- 1. Almost they have programs to provide free drugs in the size of their tumors, but they didn ’t immediately, the patient regained his for patients who cannot afford them. go away completely. Pardoll and Topalian appetite and put some weight back on Immune therapies are outpatient have gone back to the laboratory to better and reported just generally feeling better. treatments, and although there have understand the biology of these respons es. Over time, his cancer shrank by 80 been some serious side effects, in most In virtually all patients, however, the re - percent. His only side effect was a small, patients they have so far proven to be sponses appear to be long lasting. Some itchy rash on his shoulder. “He has three very safe. When hospitalizations, patients from the original clinical studies children and was able to witness impor - management of side effects, and the THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 19 cost of drugs, are taken into consideratio n, will play a leading role. The first anti-PD-1 Expanding Responses Biedrzycki suspects the costs of trials were open to all patients with One of the ways cancer immunology chemotherapy and immune therapy advanced cancers that were resistant to experts are improving response is by will become much more comparable. standard treatments, but as our scientists combining immune drugs. “The notion With improved responses and lower learn more about what cancers respond of doing clinical trials with experimental toxicities, which are clearly documented and what cancers do not, they can begin drug combinations, even where none of in common cancers, such as non small to use biomarkers to identify the cancers the drugs have FDA approval, is becom - cell lung cancer, withholding immune and patients most likely to benefit from ing the norm,” says Pardoll. “These drugs therapies from patients could intensify immune therapy. Pharmaceutical compa - are turning clinical therapeutics on its public ire aimed at the already battered nies have already begun developing bio - head,” he says. “This is a game changer.” reputations of the pharmaceutical and marker tests for PD-L1 based on the wor k One of these combinations is anti- insurance industries. of Anders and Taube that demonstrated LAG-3 and anti-PD-1. LAG-3 was shown “This research has completely PD-L1 expression was the best predictor by Drake, Powell and others to shut dow n changed the slow, conservative approval of response to anti-PD-1 treatment. immune responses to cancer cells, simila r to PD-1. Unlike PD-1, however, inhibiting process for drugs,” says Pardoll. “Typically “PD-L1 on tumor cells is the cloak that LAG-3 did not create the same robust you would have phase I and II clini cal shields cancer from the immune system,” response that occurred with anti-PD-1 trials and then a big phase III trial, an d if says Anders. “If the tumor is not express - therapies. However, Drake found that a drug makes it all the way through, it ing PD-L1, it is not likely to respond to combining two drugs—one that targets gets approval.” Some of the anti-PD-1 anti-PD-1 therapy.” Some clinical trials PD-1 and another targeting LAG-3—work s drugs are getting approved right out of already require the biomarker test for in synergy to boost the immune response the gate in phase I trials. “They have PD-L1 before treatment, says Topalian. against cancers. Combined approaches such remarkable therapeutic effects and At the same time, the cancer using another checkpoint inhibitor know n little toxicity that we don’t need phase immunology team continues to work as anti-CTLA-4 and anti-PD-1 drugs III studies. There is an obligation to get in the laboratory to find other immune also have been studied, and Drake believes the therapy to patients quickly,” he says. “stop” signals and learn how to transfor m tha t as more immune regulatory genes Nelson says this is where Johns Hop - immune therapy-resistant cancers into are identified, more combinations will kins leadership in precision medicine responsive cancers. be revealed.

CANCER IMMUNOLOGY NURSING TEAM (LEFT TO RIGHT), BARB BIEDRZYCKI, ANGELA SCARDINA, BETH ONNERS, HOLLY KEMBERLING, MAUREEN BERG, SUSAN SARTORIUS-MERGENTHALER, KATRINA PURTELL, TIANNA DAUSES, ANGIE VAN TASSEL, DENISE GALLAGHER, GALINA MELANCON, KATHY ELZA-BROWN 20 PROMISE & PROGRESS

What happens in that tissue and cells system responds to biofilms as well as Micromanaging right under the biofilm, are the same the gene expression of these bacterial Colon Cancer processes we see in cancer.” Another communities and how they interact mystery was related to the location of with other bacteria inside of the biofilm,” the biofilms. In her team’s study of 178 she says. THERE IS A microscopic society living surgery or colonoscopy patients treated Biofilms are a new discovery, and within us. Our bodies are home to more at either The Johns Hopkins Hospital or Sears and team are the first to systemati - than 100 trillion microorganisms, more the University of Malaya Medical Centre cally explore them in colon cancer. than 10 times the number of human cells in Malaysia, the vast majority of biofilms Patients with an inherited form of in the body. Many of them reside in our were located in the right colon. “It’s colon cancer, known as familial adeno - gut. Most of the time, this microsociety— virtually a universal feature of tumors matous polyposis (FAP), may provide which includes hundreds of species of that appear in that section of the colon, some early answers. The disease is char - bacteria—and its human host coexist har - although we don’t understand why,” acterized by large numbers of polyps in moniously. The “bugs” we live with aid says Sears. the colon. Sears says FAP sufferers also in digestion, metabolism and immunity. To help answer some of these develop many biofilms, but instead of With such an overwhelming number s questions, Sears is working with cancer being made up of many types of microor - advantage, it may only take the activity of prevention and control expert Elizabeth ganisms, they primarily consist of two a single organism to shift this harmoni ous Platz , cancer immunology expert Drew types of bacteria. “This is the best relationship in a way that can promote Pardoll , and gastroenterologist Francis evidence so far that particular organisms cancer, says infectious disease expert Giardiello to establish a large multicent er may be relevant, and it may help us zero Cynthia Sears . colonoscopy study to define the natural in on the bacteria that could be pushing Of the trillions of possibilities, Sears history of biofilms and their association this process,” says Sears. has zeroed in on a population that appear s to changes in tissue. “When we detect Among her long-term goals, Sears to be related to colon cancer development. biofilms, where are they? How long do hopes to use her findings to develop a non - The entire colon is lined with a thic k they last, and what do they do? This is invasive test to detect biofilms and predict protective layer of mucus, and, under what we want to figure out,” says Sears. a person’s risk of developing cancer. “Most normal conditions, bacteria are excluded. The study will also establish a large colon cancers are known to develop slowly In some colon cancers, however, Sears, bank of biofilm samples to integrate ove r time,” she say. “It’s a disease that’s researcher Christine Dejea , and team complex microbial and immune analyses. curable if diagnosed early, and maybe have found biofilms made up of a subset “We want to understand how the immun e biofilms are an early warning sign.” of bacteria that has managed to invade the mucus. “They invade the layer of mucus that protects the epithelial cells lining the colon and upend the whole biology of the system,” says Sears. With so many different forms of bacteria colonized within the human body, it is a difficult task differentiating those that keep us healthy from those that contribute to disease. In this case, the association seems clear. The risk of colon cancer may be as much as five time s greater in patients who have biofilms in their colons compared to those who have none. Sears doesn’t yet know how these biofilms develop, but she has a hunch about their link to cancer. She speculates that they cause inflammation in the col on, which spurs genetic mutations that lead to cancer. “When we look at people who undergo screening colonoscopy, we find CYNTHIA SEARS a subset of people who have biofilms. THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 21

SUZANNE TOPALIAN

“We know there are more check - by providing amino acids, glucose, and these nutrients slows the growth of points and that, in some cancers, we lipid s that nourish tumor cells can have cancer cells without harming normal might have to block more than one,” says an antitumor effect. cells. Adding a checkpoint blocker like Powell. “Maybe in some patients, PD-1 is “We think tumor cell metabolism anti- PD-1 allows the immune system to not the relevant checkpoint, and we’ll can be considered a kind of immune swee p in and finish the job on the weak - have to find the one that is. In other can - checkpoint because it creates an environ - ened cancer cells. cers, we may have to block more than on e ment that turns off the immune respons e,” Powell is also studying a group of checkpoint because both are relevant.” says Powell. Surprisingly, blocking these failed Parkinson’s disease drugs that Powell and colleagues are also havin g nutrients is cancer specific. All cells need target a pathway known as adenosine success using anti-PD-1 in combination nutrients, but normal cells don’t require that acts as an on/off switch for immune with a drug that interferes with metabo - the extraordinarily high levels demanded T cells. Studies in Powell’s laboratory lism of cancer cells. Tumors kill by grow - by rapidly dividing cancer cells. “To be a found that the drugs were remarkably ing, and they require nutrients—lots of really good cancer cell, it needs a huge proficient at instigating an immune them—to sustain this growth. Blocking amount of these nu trients,” he says. response against cancer cells. The drugs cell pathways that enable this growth Cutting off the biological s upply line of have already been studied in patients

“I have never seen anything like this. We’re reporting three-year and more survival rates in lung cancer patients who honestly would not typically be aroun d. This is truly a milestone in cancer medicine. ” 22 PROMISE & PROGRESS with Parkinson’s disease and proved safe, so with funding, he hopes to be able to bring them to clinical trials for patients with cancer in less than a year. These new combinations will not be limited to immune agents. Animal research by radiation oncology fellow Andrew Sharabi and Drake found that focused radiation treatment, like that used in radiosurgery, stimulates an immune response against the cancer. Sharabi says cell damage caused by radia - tion deploys immune cells to the tumor site, and combining anti-PD-1 with radio - surgery unleashes an immune assault on the cancer. “Radiation opens the door, THE ROAD TO CANCER IMMUNITY “IF A CAR IS SITTING AT THE TOP OF A HILL WITH THE FRONT POINTING DOWNHILL, IT and anti-PD-1 therapy allows the immune MAY ONLY NEED THE PARKING BRAKE RELEASED TO START MOVING. ANOTHER CAR SITTING ON A FLAT ROAD MAY NEED THE BRAKE RELEASED AND A PUSH TO GET GOING. A CAR SITTING AT THE BOTTOM OF A HILL AND FACING UPHILL WILL cells to get to work,” says Sharabi. NEED THE BRAKE RELEASED AND A LOT OF GAS TO GET MOVING,” SAYS DREW PARDOLL . Radiation oncologist Joseph Herman , Anders, and Taube find evidence that Pardoll and Topalian are hopeful cells. These are the situations where radiosurgery may be activating immune that combination therapies may be the adding anti-PD-1 has the potential to cells in pancreatic cancer as well, a cancer key to converting currently nonrespond - cause a synergistic immune response. that currently does not respo nd well to ing cancers like prostate cancer into She and others are compiling this labora - anti-PD-1 treatment. Combining radio - responders. Similar to Sharabi and tory evidence. This component is critical, surgery with the right immune-targeted Drake’s work, Topalian believes that she says. “There are endless possibilities drugs may increase responses in a variety giving another kind of therapy up front, of potential treatment combinations. of cancers. Anders is examining tumors including radiation, chemotherapy or We can’t test them all, and we can’t that are traditionally treated with radia - targeted therapies, and following with simply do combinations of convenience,” tion, including head and neck cancers anti-PD-1 could provoke an immune says Topalian. “We have to let the and esophageal cancers to look for response in currently resistant cancers. research lead us, and then move to the expression of PD-L1 in tumor cells, an She is working in her laboratory to clinic only with combinations supported indicator that they might respond to an see what therapies incite an inflammato ry by scientific evidence.” anti-PD-1 checkpoint blockade/radiation response in the tumor, because inflam - Some cancers will respond to anti- therapy combination. mation draws the attention of immune PD-1, but others will need more to get the immune system working. Pardoll is confident that working together over JOSEPH HERMAN time Johns Hopkins experts will be able to figure out the right combinations to get the immune therapy moving against almost any cancer.

The Learning Curve With Ryan’s cancer stable—no longer shrinking, but not growing either— Brahmer has decided to stop anti-PD-1 treatment. “We think that over time the immune system creates a memory. The T-cell remembers how to attack the cancer and stop the cancer from shielding itself from the immune cells. We think the immune system can keep the cancer under control now, even without treatment,” says Brahmer. THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 23

If Ryan’s cancer begins to grow, she will start therapy again. Other patients JOHN RYAN whose tumors began to grow again after anti-PD-1 treatment was stopped have responded with treatment that was reinitiated. It’s all part of the learning curve. Ryan continues his regular trips from his home near Middleburg, Virginia, to the Kimmel Cancer Center to have his cancer monitored. He also par ticipates in a Stand Up To Cancer- fun ded study providing blood samples that hel p researchers understand more about ho w immune checkpoint blockad e therapy works against cancer. Not ever y patient whose immune cells express PD-1 or whose tumor cells express PD-L1 respond to immune therapy. Patients like Ryan are helping investi - gators solve those mysteries and leadin g them to ways to help more patients. “I feel like this is about more than just me,” says Ryan. “Immune therapy saved my life, and I want to bring this message of hope to others. I know how fortunate I was to have this wonderful team of doctors and nurses at Johns Hopkins. They are my heroes,” he says. “Two years ago, in a very short period of time, I went fro m feeling fine to being in serious tr ouble. I thought I might have only months to live and that I would miss so many important mome nts Pardoll sees the therapy as a true Another Road in my children’s lives. Time was critica l, breakthrough in cancer medicine. This Leads to PD-1 and I was fortunate to get in the right is not just hyperbole; he actually did the math. With 14 different cancer types Forty years ago as efforts to decipher the hands quickly.” responding at rates of between 15 and causes and cures for cancer intensified, Today, Ryan says, he feels better tha n 40 percent, early studies in Hodgkin’s many began looking to the laboratories he has in years. He recently provided lymphoma reporting response rates of of the fledgling cancer center at Johns around-the-clock logistical support as a nearly 90 percent, and enduring cancer Hopkins. From the beginning, the crew chief to his son as he participated remissions, immune checkpoint block - National Cancer Institute had named it in a grueling 100-mile ultra-marathon ade therapy has distinguished itself from a center of excellence. Among the main through the Vermont mountains. “My chemotherapy and gene-targeted thera - areas of research were laboratories friends and family were worried when I pies. “By a factor of 30,” he says, “anti- focused on immunology, genetics, and told them I planned to do this. They were PD-1 is the most powerful single agent epigenetics. One of them, experts hoped, shocked by how much energy I had.” in the history of cancer therapeutics.” would lead to a discovery that would “I feel like this is about more than just me. Immune therapy saved my life, and I want to bring this message of hope to others. I know how fortunate I was to have this wonderful team of doctors and nurses at Johns Hopkins. They are my heroes .” 24 PROMISE & PROGRESS

TOP: IN 1977, BERT VOGELSTEIN, (RIGHT) A YOUNG SCIENTIST CONCENTRATING ON THE NEARLY IMPOSSIBLE TASK OF DREW PARDOLL CRACKING CANCER’S GENETIC CODE, AND DREW PARDOLL , (CENTER) HIS GRADUATE STUDENT AT THE TIME, MET MONTHLY WITH SENIOR CANCER RESEARCHER DONALD COFFEY (LEFT) TO TOSS AROUND IDEAS ABOUT HOW TO CURE CANCER. BOTTOM: SOME 35 YEARS LATER, THE RESEARCH TRIO IS STILL COLLABORATING.

conquer cancer. No one, including Pardo ll, developed a model for cancer initiation ever imagined the interconnection of and progression that became the paradigm these three areas of research or that it for much of modern cancer research. would result in some of the most signifi - Pardoll continued to pursue cancer cant cancer discoveries of our time. immunology, in part inspired by the In 1977, Bert Vogelstein , a young monthly meetings with Coffey. With his scientist concentrating on the nearly im - and Vogelstein’s encouragement, he soon could be used to turn the tide of striking ly possible task of cracking cancer’s genetic joined the faculty and started his own poor responses for that disease. “We were code, and Pardoll, his graduate student at cancer immunology laboratory. But that happy to share any of our research that the time, met monthly with senior cancer was not the end of the Vogelstein/ could help,” says Vogelstein. “It’s all done researcher Donald Coffey to toss around Pardoll collaboration. As Vogelstein in the service of patients. There is no ideas about how to cure cancer. Ideas focused on the cancer genome, Pardoll discussion of the usual academic kinds of were about all anyone had at that time. began to explore the genetic mechanisms things. We don’t do that in the Kimmel Coffey remains an iconic figure at the of immune cells. Neither anticipated an Cancer Center.” Kimmel Cancer Center. The consummate intersection of the two laboratories that teacher with an enthralling Southern would lead to an unusual discovery. drawl challenged talented young investi - “This kind of collaboration is what The Mystery of the gators then—as he continues to do today— makes us Hopkins,” says Vogelstein. Single Responder to work together and look for creative “People share their ideas and results here . Cancer is a disease of genetic mistakes, s o solutions to a tough problem. Usually, Drew [Pardoll] and Suzanne [Topalian] for all intents and purposes, the signals they would talk casually over tea. Even showed us what they found and asked sent out by mutated genes should be an then, the immune system was on their for our ideas.” announcement to the immune system short list of ideas. Vogelstein continued Pardoll and Topalian were trying to that they don’t belong. “Ironically, this to pursue genetics, convinced it would figure out why one of the first colon canc er very mechanism that the tumor uses to yield greater insights into the cellular patients ever treated with anti-PD-1 had accelerate its genetic diversity creates an processes that result in cancer. a complete response—with no detectable Achilles heel for immunotherapy,” says Vogelstein, the Clayton Professor of tumor six years later—but another 32 Luis Diaz , investigator in the Kimmel Oncology and co-director of the Kimmel colon cancer patients did not respond. Cancer Center’s Ludwig Center. The Cancer Center’s Ludwig Center, went They hoped that the Vogelstein team’s more mutations that exist in the cancer, on to define cancer as a genetic disease. expertise in colon cancer could shed the louder the signal and the more Starting with colon cancer, he, Kenneth light on what was unique about that likely it is that the immune system will Kinzler, and their Ludwig Center team patient and maybe what they learned take notice. THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 25

Healing Cancer

The first step was to test the ostensi - She says they have only begun to ble cancer fighting potential in her labo - scratch the surface of this new type of ratory. Elisseeff injected her biomaterials therapy and admits there is much they in mice engrafted with human melanoma need to learn. Still, early findings point to skin cancer cells, and it hampered the the therapy she has created as a way to growth of the cancer. “We’ve looked at heal both wounds and disease. A patient the lymph nodes near the injection site undergoing cancer surgery could have and lymph nodes in other parts of the the biologic material injected during the body and have identified immune chang es operation to promote healing of the sur - directly related to the biomaterials,” she gical wound and to simultaneously gen - says. These observations indicated that erate a cancer-fighting immune response. the treatment has the ability to chase down cancer cells that have broken off from the primary tumor and spread to Nanoparticle Therapy other parts of the body. Gene therapy may be an effective treat - BIOMEDICAL ENGINEER Jennifer Just as important, Elisseeff and ment option for the deadly brain cancer Elisseeff was working on a way to pro - team’s findings challenge the common glioma, but getting the right genes to mote healing in trauma patients when perception that regenerative medicine is cancer cells in the brain has proven diffi - a friend of a cancer patient visiting cancer promoting. “This has been a nag - cult. Now, for the first time, Johns Hop - Elisseeff’s lab told her that similar ap - ging concern in our field, but we’ve never kins researchers used biodegradable proaches were reported to fight cancer. actually seen it occur,” she says. “Our nanoparticles filled with genes to turn A few years later, Elisseeff began re - research provides evidence that this may an inactive prodrug into a potent brain search that promised to bridge the fields not be a concern.” cancer cell killer. The nanoparticles, of immunology and biomedical engineer - The promising anticancer activity in encoding a special gene, were injected ing. She called the emerging field regen - animal models occurred using biomateri - into brain tumors in rats and followed erative immunology. It led her to a new als alone. Elisseeff says adding immune by treatment with the drug ganciclovir. use for her trauma-targeted therapy. therapies, such as anti-PD1 blockades, The treatment successfully killed cancer Elisseeff works with biologically en - may make it work even better. To find cells and extended survival in this animal gineered animal and tumor tissues that out she is collaborating with cancer im - model. are implanted locally at the site of an in - munology experts Drew Pardoll and “Our nanoparticles penetrated com - jury. “The immune system is a first re - Jonathan Powell , who have worked pletely throughout the tumor following a sponder when trauma to tissue and cells with her to establish this fledgling field single injection,” says biomedical enginee r occur,” says Elisseeff, the Jules Stein of regenerative immunology. Jordan Green . “When combined with Professor in the Translational Tissue Elisseeff met Pardoll when they systematic administration of ganciclovir, Engineering Center. Her engineered worked together on Johns Hopkins Uni - rats with malignant glioma lived signifi - biologic materials give it an extra nudge. versity President Ronald Daniels’ innova - cantly longer than rats that did not “They trigger immune cells, particularly tion hub committee aimed at promoting receive treatment.” T cells, to direct other immune cells to innovation translation to bring life- Nanoparticles are ultra tiny struc - heal the injury,” she says. changing technologies to market. It led tures that are about 20 times larger than Elisseeff and team are collaborating to the current collaboration focused on a molecule but 100 times smaller than a with the U.S. military to study in people, combined biomaterials/immune therapy cell, so they can be loaded with genes including servicemen and women animal and clinical studies, and Powell is and small molecules, including immune injured in combat, the safety and activity helping decipher the biologic mechanism s. therapies, and guide and deploy these of her biomaterials. The engineered He has provided laboratory models that therapeutics inside cells. These nanopar - materials are made in the Kimmel reveal the specific immune T cells essen - ticles are able to penetrate tumors and Cancer Center’s GMP facility. If human tial to the healing immune response. deliver immune-system-activating drugs studies are successful, it creates a frame - “This is the first therapeutic model,” and antibodies that cause immune cells work for eventually transferring the says Elisseeff. “No one has ever before to specifically attack cancer cells. This technology to an experimental clinical bridged the fields of immune-engineering type of therapy kills cancer cells more trial for cancer patients. and regeneration.” effectively and with far few side effects.

On the Web: READ MORE ABOUT THE KIMMEL CANCER CENTER’S COLLABORATIONS WITH THE ENGINEERING EXPERTS IN OUR SPECIAL ISSUE OF PROMISE & PROGRESS , ENGINEERING CURES 26 PROMISE & PROGRESS

LUIS DIAZ (LEFT ), AND DUNG LE (RIGHT ) ARE TWO OF THE YOUNG RISING STARS OF THE KIMMEL CANCER CENTER. LE IS A VIRAGH SCHOLAR FOCUSED ON IMMUNOLOGY AND PANCREATIC CANCER VACCINES, AND DIAZ IS A GI CANCER AND GENETICS EXPERT AND DIRECTOR OF THE SWIM ACROSS AMERICA LABORATORY.

So it was not surprising when Kimmel Kinzler, and Papadopoulos developed a immune system should work, ignoring Cancer Center investigators, including test for mismatch repair gene mutations, those things that are “self” and noticing Diaz, had an idea. “It’s mutations,” they so that families with a history of Lynch those things that are different. This is suggested, suspecting that the single syndrome could be screened and their called immune recognition; the next step patient who responded to anti- PD-1 colon cancers detected in an early and is action. That’s the role of anti-PD-1, treatment had Lynch Syndrome, an curable stage. which works by shutting down the can - inherited form of colon cancer character - They could have never envisioned cer cell’s ability to send false signals to ized by abnormally large numbers of the clinical application that Diaz and commandeer and divert immune cells mutations. another young immunology investigator, from reacting. With anti-PD-1, the immu ne The research that formed the basis Dung Le , would have for the test. It cells alerted by the high number of gene for their conclusion occurred some 20 would prove instrumental. “What is the mutations were put into action to kill years earlier, remarkably from the same patient’s mismatch repair status?” Diaz cancer cells. Ludwig Center laboratory. In 1993, Vogel - asked Pardoll and Topalian about the “For other treatments, including stein, Kinzler, and Nickolas Papadopoulo s single colon cancer responder. Using the chemotherapy, the changing tumor of the Kimmel Cancer Center and Albert test Vogelstein, Kinzler, and Papadopoulos biology due to accumulating mutations de la Chapelle from The Ohio Stat e developed two decades earlier, they causes treatments to stop working, but it University identified a genetic alteration proved their suspicion was spot on. The seems to make immune therapies work linked to Lynch syndrome, a hereditary patient’s tumor was positive for mis match better,” says Le. It’s likely more about the form of colon cancer that is caused by repair alterations. The large number of quantity of mutations than the specific mistakes in mismatch repair genes. mutations common to mismatch repair type of mutation. The investigators be - The job of mismatch repair is to served as an alert to immune cells becau se lieve the good responses to anti-PD-1 correct copying errors that occur when they make the tumor look much more that occur in a subset of melanoma and DNA replicates and cells divide. People different from normal colon cells that lung cancers are also related to the accu - who inherit a defective copy of the gene don’t have this large number of mutations . mulating gene mutations caused by sun experience high rates of mutations and Imagine a crowd of people in a exposure in melanoma and smoking in are at increased risk of developing colon room. If one person is speaking a lan - lung cancer. “In theory, you only need cancer. Colon cancers in patients with guage different from the rest, it might go one mutation to get the immune system’s mismatch repair deficiency have more unnoticed. If many of them are speaking attention, but larger numbers of mutations, than 1,000 mutations while those without a different language, it will likely garner shift the odds in your favor,” he says. typically have less than 100. Vogelstei n, attention. In principle, this is the way the The only way to prove the hypothe sis THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 27

“Immune therapy is a game changer . We need more research to take us the rest of the distance, but we don’t think there is a single cancer that the patient’s own immune system ultimately can’t beat.” was to test it in pa tients, but these trials straightforwardly about the significance mistakes—including some rare, difficult- are expens ive and a huge undertaking for of their findings. Even before accrual to to-treat cancers—and the treatment young investigators. Diaz and Le were the study was completed, the results worked. “If you have the mismatch undeterred. Merck agreed to donate the were so dramatic that repair signature, you should be treated drug, but it was the generosity of private they were viewed as a with a checkpoint inhibitor,” says Diaz. funders— Swim Across America , the major finding, warrant - “Defects in mismatch repair genes are Lustgarten Foundation, the Skip Vira gh ing publicatio n in the found in a small percentage of many can - Foundation, the Banyan Gate Foundatio n, prestigious New Eng - cer types,” says Le. Vogelstein estimates the Commonwealth Fund, and the Sol land Journal of Medicine that 2 to 4 percent of all cancers have Goldman Pancreatic Cancer Research in 2015, featured at the mismatch repair mistakes, and when that NICO LLOSA Center—that allowed Diaz and Le to make American Society of is calculated across every cancer type, it happen. Clinical Oncology, and setting the stage fo r the potential to help a lot of people is ve ry Le and Diaz are two of the young FDA breakthrough status for anti-PD-1 real. Le believes that similar biomarkers rising stars of the Kimmel Cancer Center. immune therapy in patients with mis - for immunotherapy response could be Le is a Viragh Scholar focused on im - match repair deficiency. applied to cancers with errors in other munology and pancreatic cancer vaccine s, Roughly 60 percent of patients with DNA repair genes. and Diaz is a GI cancer and genetics mismatch repair deficiencies responded “There is a tsunami coming,” says expert and director of the Swim Across to treatment, pointing to the presence of Anders , who believes the mismatch repair America Laboratory. The balance of other checkpoint blockades that work test is the first of many that will be used cancer genetics/cancer immunology similarly to PD-1. This will be the focus to predict response to immune therapy. expertise each brought to the table was of additional laboratory research. As crit - This is what excites Diaz and Le. perfectly suited to this study. ical of a finding, however, was that none They witnessed it firsthand, and Diaz “The success of the Kimmel Cancer of the 25 patients with normal mismatch brims with enthusiasm when he speaks Center is inextricably tied to our ability repair responded to treatment. The particularly of two young patients who to attract the best and brightest talent,” investigators will need to replicate their were part of the clinical study. says Nelson. “This trial is an example of findings in a larger number of patients, bu t Stephanie Joho, who has Lynch syn - the depth of talent we have in our young it provides clear evidence that mismat ch drome, had just graduated from college investigators. Unfortunately, as this repair alterations in tumors predicts when she was diagnosed with colon can - study illustrates, it can be a challeng e for which patients are good candi dates for cer. Surgery and two different types of them to find funding for their science immune therapy with anti-PD-1 . chemotherapy did nothing to avert the because they may not yet have a large Additional laboratory research at aggressive cancer. Out of options and body of work or the notoriety of more the Kimmel Cancer Center has pointed in excruciating pain, Joho searched senior investigators. It is one of the to other immune checkpoints in these desperately for other treatments and greatest shortcomings in research but a tumors, which could be targeted in com - had reached out to Diaz, who until the priority at the Kimmel Cancer Center. bination with anti-PD-1. Frank Housse au mismatch repair discovery had tried It was our benefactor Sidney Kimmel’s and pediatric cancer expert Nico Llosa everything available. Recognizing Joho vision—a vision he brought to life found high expression of LAG-3 in would be a perfect candidate for his new through the Kimmel Scholars Program mismatch repair deficient tumors. study, he called her. She was distraught, —and vitally important to the future of Beyond colon cancer, the clinical sitting in a waiting room at another com - cancer medicine.” study demonstrated that mismatch prehensive cancer center after one more With funding in place and the drug repair deficiency is a universal biomarke r failed search for an experimental therapy, acquired, Le and Diaz began a clinical of response to immune therapy. They when she got Diaz’s call. “Come down trial in 48 patients. Le, the more subdued tested the treatment in a small number of here. We’ll cure you,” he told her. After of the research duo, speaks calmly and other cancers marked by mismatch repair treat ment with anti-PD-1, Joho’s tumor 28 PROMISE & PROGRESS

“Throughout my career as a clinician and scientist and now as cancer center director, I cannot recall another time when so many opportunities were within our grasp.”

—William Nelson, Director Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 29 shran k, and her pain subsided. “I haven’t the ground up, and we’re very fortunate cells in his laboratory, he found that felt this well in four years,” says Joho, to have it here.” some of the genes that were being reacti - now 25. “Dung and I are standing on the vated were connected to immune re - Another patient was weeks from shoulders of many giants,” says Diaz. sponses. Among them was PD-L1 which dying and being encouraged to enter hos - interacts with a key molecule on immune pice care when Diaz and Le learned his The Epigenetic cells, PD-1. tumor was positive for mismatch repair. He was so sick that they had to get a spe - Connection CYNTHIA ZAHNOW A number of the controls that turn the cial exception to get him enrolled in the immune system on and off are epigenetic trial. “Without any doubt, this young in nature. These chemically mediated on man’s lif e was saved by this treatment,” and off switches alter the function of says Diaz. genes without mutating the DNA, usuall y Diaz recalls more patients. “We by adding chemical groups to the signal - could fill this room with people who hav e ing portion of genes or by tightening or benefited, ” says Diaz. The two recognize relaxing how the DNA is packaged withi n their s tudy was small, and in science, the cell. Epigenetic therapies that target numbers matter. Still, they have met Baylin and young investigator these control mechanisms, can reactivate every one of the patients in their study, Cynthia Zahnow, working with him as genes that have been turned off. and they also recognize that medicine is part of the Stand Up To Cancer Epigenetics more than numbers. Behind every statis - Dream Team, shared their findings with STEPHEN BAYLIN tic is a human being. Pardoll. In some lung cancer cells, the “It is rare to get a response in colon PD-L1 gene was already active, and cancer patients who have not responded epigenetic therapy made its signal even to other standard therapies, and most of stronger. Pardoll believed that adding them had just months to live,” says Le. anti-PD-1 therapy in conjunction with She is hopeful this discovery will very epigenetic therapy could activate an im - soon benefit thousands, but nonetheless, mune response right within the tumor. at this moment, they celebrate Joho and Treated with epigenetic drugs, the 20 other lives that were saved. the ability of cancer cells to evade the “One of the things that put us at the immune system is broken and they send forefront of clinical breakthroughs in new signals, beckoning immune cells to cancer immunology is that we never for - come and get them. At the same time, got the science,” says Pardoll. “Having they begin to express PD-L1 to shield the leading epigenetics and genetics Stephen Baylin is one of the world’ s against immune attack. Anti-PD-1 breaks researchers here gives us an edge. At most foremost epigenetics experts. He, Vogel - off that communication, unleashing the institutio ns, the different laboratories stein, and Pardoll have independently in - immune system on the cancer cells. don’t interact at all. At Johns Hopkins, formed some of the most vexing problem s Baylin, Zahnow, and team went interaction among different disciplines of cancer initiation, spread, and treatme nt back to the laboratory to decipher the is the norm, and these types of collabora - resistance. Their combined knowledge immune evasion signature for lung, tions have led to some exciting immunol - is the cancer world’s triple threat. By deci - breast, colon, and ovarian cancers. To ogy advances. There is no other place phering the inter-related complexiti es of do this, they looked at all of the genes in I know of with these deep, intellectual genetics, epigenetics, and immunology, lung, breast, and ovarian cancers that roots in genetics and immunology and they are bringing forth some of the most got turned on in cancer cells with epige - the support of the institution to carry out encouraging cancer treatment strategies netic-targeted therapies. Lots of genes investigator-initiated trials,” says Vogel - of our time. were switched on, they found, but what stein. “You can’t create that environment As Baylin explored the effects of stood out were the 20 percent or so from scratch. It has to be built in from epigenetic-targeted drugs on lung cancer related to immune regulation. These

By deciphering the inter-related complexities of genetics, epigenetics, and immunology, they are bringing forth some of the mo st encouraging cancer treatment strategies of our time . 30 PROMISE & PROGRESS

“Kimmel Cancer Center scientists have made seminal contribu - tions to the basic science, and now what is happening is almost magical as we make the unbelievable transformation to harness the immune system to attack tumors . Our latest findings further decipher the mechanisms that lead to this immune reaction and offer a novel way to potentially boost the success of immune therapies in cancer patients.” genes were studied in depth by post-doc - The viral defense pathway is an an - Aza makes tumor cells think they are toral fellow Kate Chiappinelli and found cient human biological mechanism that infected with a virus and causes them to to be epigenetically programmed to allows cells to recognize when they have sound the alarm to alert the immune evade detection by the immune system. been infected by a virus and helps acti - system. In laboratory experiments where They are now looking at tumor sam - vate an immune response to the viral in - Baylin and Chiappinelli blocked inter - ples from patients receiving combined vader. Our DNA retain a record of our feron in tumor cells, the Aza-induced epigenetic and anti-PD-1 immune viral exposure, creating a history that be - immune response stopped. therapy to see if the epigenetic therapy comes integrated into the genome. This To further test their theory, the two turned on immune genes that would viral record is rendered dormant through collaborated with experts at Memorial cause the cancer cells to respond to anti- epigenetic signaling, but as Baylin and Sloan Kettering Cancer Center in New PD-1 treatment. “Epigenetic therapy Chiappinelli found, it can be reactivated York to examine cancer cells from does not break immune tolerance, but it when epigenetic-targeted therapies are melanoma patients treated with anti- has the potential to sensitize cancers to given. Since it reactivates just a memory CTLA-4, another checkpoint blockade an immune anti-PD-1 checkpoint block - of viruses, it only mimics an infection in immune therapy similar to anti-PD-1. ade treatment,” says Baylin. “We think tumor cells, but fake infection is enough They determined the viral defense it brings in immune cells, so if we follow to generate an immune response. pathw ay expression for each tumor and it with anti-PD-1, we can cause an im - When they examined the DNA of a matched it back to the patients. High viral mune reaction against cancer cells.” This variety of cancer types, including ovarian defense expression matched with all of theo ry is currently being studied in clini - cancer, colon cancer, and melanoma, they the patients who responded to immune cal trials funded by Stand Up To Cancer . found that tumors with high expression of therapy, and low expression matched Baylin continued his research of the viral defense pathway were more with those who did not respond. epigenetic controls of immune response, likely to respond to immune therapy with In a mouse model of melanoma, collaborating with another epigenetics anti-PD-1. Tumors with low viral defense adding an epigenetic drug to cancers that research giant, Peter Jones, director of expression could be coaxed into response were not responding to immune check - research at the Van Andel Institute. if epigenetic-targeted drugs were given point blockade triggered an immune Working together as co-leaders of the before immune therapy. The FDA-ap - response. Baylin says the true test will Stand Up To Cancer Epigenetics Dream proved epigenetic drug 5-azacityidine come from clinical studies, but he is Team, they uncovered a viral defense (Aza) converted low viral defense energized by these laboratory results. mechanism in tumors that mimics a viral expression to high expression. “This is the most exciting time of infection. Epigenetic drugs cause it to “Our research findings are consistent my entire career,” says Baylin. “Kimmel simulate an infection and summon im - with the previous notion that silencing Cancer Center scientists have made sem - mune cells to tumors. viral sequences in the human genome is inal contributions to the basic science, and “Epigenetic drugs upregulate a major function controlled epigeneti - now what is happening is almost magica l as the viral defense pathway, activating cally,” says Baylin. Using drugs like Aza we make the unbelievable transforma tion interferon signaling, and this brings to remove the epigenetic controls that to harness the immune system to attack in immune cells,” says Chiappinelli. silence the noninfectious viral memory tumors. Our latest findings further “When epigenetic therapy is followed by locked away within tumor cells activates decipher the mechanisms that lead to anti-PD-1 checkpoint blockade immune interferon, a signal to the immune sys - this immune reaction and offer a novel therapy, the immune cells go into action tem released by cells when they are in - way to potentially boost the success of against the cancer.” vaded by bacteria or viruses. In essence, immune therapies in cancer patients.” THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER at JOHNS HOPKINS 31

CYNTHIA ZAHNOW AND STEPHEN BAYLIN

Baylin, like all of the Kimmel Cancer technology and in an environment where being at a cancer center that is engaged in Center researchers and clinicians who bench-to-bedside research flourishes, this kind of paradigm-shifting researc h.” held firm to their belief in immune Kimmel Cancer Center experts have Her immunology nursing colleagues con - therapy, is most excited by the safe and solved the puzzle of cancer immune cur. “I’ve worked in oncology for a long durable responses it delivers. resistance, or at least they have identified time. It’s an exciting time to see these new “Many people still view cancer as a many of the pieces. The critical compo - therapies that work in the worst cancers terminal disease, particularly advanced nent—immune resistance, how the can - and don’t cause terrible side effects,” says cancers, and look what we have to put cer cell escapes an immune attack—was research nurse Beth Onners . “One of the patients through to treat them,” says revealed and therapies to undo cancer’s first questions I typically get from patient s Baylin. “Immunotherapy promises to ability to manipulate the immune cells to is, ’Will it make my hair fall out? It’s so change that. It’s already made a huge its own benefit can now be developed. nice to be able to tell them it won’t. ” difference. We have patients now who, “The success we have had so far is The patients who were on chemo- against all odds, are alive and living unlike anything we have ever seen in therapy before treatments like anti-PD-1 well even when we have not completely cancer, and consider that we have only were discovered say they feel like eliminated their cancer. I can only imag - mined about 5 percent of what the im - chemotherapy kept them alive, but ine what the next 10 years will bring. mune system can do in cancer. This is immune therapy gave them their lives You have to be excited about this.” just the beginning,” says Pardoll. “As we back, says Biedrzycki. “It is so exciting learn about other immune signals and to be a part of this,” she says. Whispers of a Cure combined approaches, we think it will After decades of research, it is the These combined approaches are the only start to look better. In 20 years, patients that matter most to the Kimmel newest adaptation of cancer immunology possibly less, immune therapy has the Cancer Center immunology researchers therapies. Pardoll, Topalian, Drake, Jaffe e promise to completely change the face and clinicians. It is not seeing their and their immunology teams are opti - of cancer and make almost all cancers scientific theories proven correct that mistic that the power of immune therapy curable or controllable.” they finds most gratifying. The real sat - and the right combinations will continue Patients, even those who are not isfaction, they say, comes from seeing to expand the numbers of cancer pa - currently on immune therapy, seem to these scientific theories actually help tients who will see their immune systems sense the changing tide, says veteran patients and without the terrible side ef - engaged against their cancers. For the immunology nurse practitioner Tianna fects that have defined cancer treatment first time in the history of cancer, experts Dauses . “Every day, we get calls from for decades. “Immune therapy is a game and patients alike are beginning to see cancer patients who want to come to changer,” says Pardoll. “We need more re - in immune therapy, the potential for a the Kimmel Cancer Center for immune search to take us the rest of the distance, universal cure for cancer. therapy. Current patients, including man y but we don’t think there is a single Through the convergence of a who are on other types of therapies, cancer that the patient’s own immune wealth of expertise, the advancement of express the hopefulness they feel from system ultimately can’t beat.” •