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Cancer Immunotherapies from Magic Bullets to Super T Cells

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Cancer Immunotherapies from Magic Bullets to Super T Cells / SPRING 2018 Cancer Immunotherapies From Magic Bullets to Super T Cells WHAT'S INSIDE » COLEY PHENOMENON 2 / MAGIC BULLETS 2 / BASIC LEUKEMIA RESEARCH LEADS THE WAY 3 CELLULAR WARRIORS AND WEAPONS 5 / BRAKES ON AN IMMUNE RESPONSE 6 / CHECKPOINT BLOCKERS 8 THE PERFECT THERAPEUTIC STORM 9 / SUPER T CELLS TO THE RESCUE 10 BREAKTHROUGHS IN BIOSCIENCE/ ADVISORY COMMITTEE CANCER IMMUNOTHERAPIES: FROM MAGIC BULLETS TO SUPER T CELLS CHAIR» Paula H. Stern, PhD AUTHOR» Northwestern University Feinberg School of Medicine Margie Patlak writes about biomedical research and health COMMITTEE MEMBERS» from the Philadelphia region. She has written for Discover, Marcas M. Bamman, PhD Glamour, Physician’s Weekly, Consumer Reports on Health, University of Alabama at Birmingham The Washington Post, Los Angeles Times, Dallas Morning Aditi Bhargava, PhD News, and numerous other publications. She frequently University of California, San Francisco writes for the National Institutes of Health and the National Academy of Sciences and currently works with a number of David B. Burr, PhD Indiana University School of Medicine trade journals, such as Endocrine News and the Journal of the National Cancer Institute. This is her eleventh article in the Blanche Capel, PhD Breakthroughs in Bioscience series. Duke University Medical Center Deborah A. Cory-Slechta, PhD SCIENTIFIC ADVISOR» University of Rochester Medical Center Jeffrey Sosman, MD, is an experienced clinical investigator whose career has been vested in the immune-based and Rao L. Divi, PhD targeted therapy of melanoma and renal cell carcinoma. He National Cancer Institute, National Institutes of Health has played a significant role in the clinical development of Marnie E. Halpern, PhD the immune checkpoint inhibitors, both Ipilimumab (anti-CT- Carnegie Institution for Science LA-4) and Nivolumab (anti-PD-1). In addition, Dr. Sosman has Loraine A. Oman-Ganes, MD, FRCP(C), CCMG, FACMG lead early trials demonstrating efficacy of BRAF inhibitors in Sun Life Financial patients with melanoma. He has been involved in efforts to R. Brooks Robey, MD, FASN, FAHA identify mechanisms of resistance to checkpoint inhibitors White River Junction VA Medical Center and and approaches to overcome de novo and acquired resistance. Geisel School of Medicine at Dartmouth At the Robert H. Lurie Comprehensive Cancer Center of Scott I. Simon, PhD Northwestern University, he is a Professor of Medicine and University of California, Davis co-leads the Translational Research in Solid Tumors program in the Cancer Center. He is also the first Mary Hendrickson- Deborah J. Veis, MD, PhD Johnson Melanoma American Cancer Society Research Washington University School of Medicine in St. Louis Professor since 2008 for his long term achievements in Katherine A. Wilkinson, PhD melanoma clinical research. San José State University SCIENTIFIC REVIEWER» AD HOC COMMITTEE MEMBER» Tonya J. Webb, PhD Chrystal Paulos, PhD University of Maryland School of Medicine Medical University of South Carolina ON THE COVER» FASEB OFFICE OF PUBLIC AFFAIRS Color enhanced scanning electron microscope image of a FASEB MANAGING EDITOR» CAR-T lymphocyte (pink) attacking a leukemia cell (yellow). Anne M. Deschamps, PhD Image credit: Eye of Science/Science Source Associate Director of Science Policy This article was developed The Breakthroughs in Bioscience series is a collection in collaboration with of illustrated articles that explain recent developments The American Association in basic biomedical research and how they are important of Immunologists. to society. Electronic versions of the articles are available on the Breakthroughs in Bioscience website: www.faseb.org/breakthroughs FOR REPRINTS OR OTHER INFORMATION» Federation of American Societies for Experimental Biology Office of Public Affairs 9650 Rockville Pike, Bethesda, MD 20814 © Copyright 2018, FASEB, All rights reserved. Cancer Immunotherapies From Magic Bullets to Super T Cells SANDRA WAS ONLY 22 YEARS OLD, but she was already running out of time. A cancer cell (gray) being attacked by two cytotoxic Shortly after Sandra got engaged, doctors discovered the nagging cough she had been ex- T cells (gold). Image credit: periencing was due to metastatic melanoma. A deadly cancer had grown from a malignant National Cancer Institute mole she hadn’t noticed, spreading to her lungs and brain. Chemotherapy and radiation treatments slowed, but could not stop its relentless reach. Fortunately, Sandra’s doctor was able to offer her a new experimental treatment that was designed to unleash the power of her immune system so it could more effectively fight off her tumors. Within three months of Sandra’s treatment with this innovative treatment, called immunotherapy, her doctors were surprised to see that every trace of melanoma had disappeared on her CT scan. This marked the beginning of a remission that has lasted more than ten years, and has let Sandra enjoy a high quality of life. Since her recovery, she has even had two children. Sandra can count herself as one of the tens of thou- cancers—with response and survival rates that far out- sands of cancer patients who have benefited from cut- perform traditional treatments. Immunotherapy is differ- ting-edge immunotherapies that have provided new ent from conventional cancer treatment strategies, such therapeutic options. These therapies have proven ef- as chemotherapy and radiation, which directly battle tu- fective in treating advanced skin, kidney, lung, bladder, mor cells. Instead, immunotherapies work by strength- head and neck cancers, and certain types of colorectal ening patients’ own natural arsenals for fighting cancer. 1 CANCER IMMUNOTHERAPIES » FROM MAGIC BULLETS TO SUPER T CELLS Immunotherapy encompasses multiple approaches, GLOSSARY including harnessing or enhancing immune cells, hor- ADOPTIVE CELL mones, and other weapons of the immune system to THERAPY (ACT): an destroy tumor cells, as well as releasing the brakes on immunotherapy in which the immune response that tumors trigger. These inno- T cells are removed from vative therapies are ushering in a promising new era a patient, grown, and in cancer treatment that would not have been possi- sometimes modified in ble without the strong foundation of basic research in the laboratory, and then immunology and tumor cell biology built by scientists re-injected into the patient for more than a century. These researchers pursued : a protein ANTIBODY answers to basic questions such as, “how does a vi- produced by B cells that rus cause leukemia in mice,” “why are tumors able to latches onto an antigen evade an immune response despite many immune as part of an immune response to the antigen cells surrounding them,” and “what causes white blood cells to multiply?” Without answers to these key ques- ANTIGEN: a foreign or tions, Sandra would not be raising a family or be count- abnormal substance in ed among the many patients who have benefited from the body that provokes an immune response cancer immunotherapies. B CELL: a white blood 1890s | COLEY PHENOMENON cell that matures in One of the earliest hints that the body’s immune re- FIGURE 1 / DR. WILLIAM COLEY » Dr. William Coley the bone marrow and sponse could combat cancer came from the work of the (center) and colleagues at the Hospital for the Ruptured and produces antibodies Crippled. Image credit: National Library of Medicine. New York City surgeon Dr. William Coley in the 1890s (continued on page 4) (Figure 1). A pioneer in immunotherapy at a time when very little was known about the immune system, Coley fever, which Coley believed was needed for an anti- was intrigued by reports that a few patients with incur- tumor response. At the time, doctors were starting to able advanced cancers experienced remissions, if not use radiation therapy to treat cancer with more consis- cures, after battling deadly bacterial infections. Frus- tently effective results. This caused many of them to trated by the futility of surgery for treating his patients disregard or be skeptical of Coley’s findings, especially with advanced malignancies, Coley injected them with since he couldn’t fully explain them. As noted by immu- heat-killed bacteria, later referred to as “Coley’s toxins,” nologist Dr. Lloyd Old at a research symposium, “Sci- hoping to induce a similar response that would rid their ence had to catch up with the Coley phenomenon, and bodies of cancer. the cellular and molecular language of inflammation Coley claimed that in nearly half of the 93 cancer pa- and immunity had to be understood before the forces tients that he treated with his “toxins,” the tumors that Coley unleashed could be predictably translated shrank or disappeared altogether. When attending into tumor cell destruction.” medical conferences, Coley would sometimes bring 1900s | MAGIC BULLETS along one of his former patients. This young man had Fortunately, scientific explanations for Coley’s find- once been bedridden by a large, inoperable abdominal ings began to emerge over the next century, thanks tumor. After Coley injected the patient with his “toxins,” to the contributions of numerous researchers in basic the man developed a raging fever. But within a short biological science. In 1890, the German scientist Emil period of time after the fever subsided, the cancer mass Behring discovered that if he injected one guinea pig disappeared. The patient went on to live another 26 with the serum of a second guinea pig that had recent- years until he died of a heart attack. ly recovered from diphtheria, the first animal would be Unfortunately, other investigators were not able to du- protected from deadly diphtheria toxins. This led his plicate Coley’s findings, perhaps because their tox- colleague, chemist Paul Ehrlich, to suggest in 1900 ins did not match the immune-stimulating capacity of that there must be “magic bullets” in the blood that those used by Coley. Or perhaps they discontinued seek out and destroy specific toxins. Behring termed the toxin injections before the patient had developed a these agents antibodies (Figure 2). Ehrlich imagined 2 Ehrlich proposed in 1909 that the immune system could counter or eliminate cancers in the same way it does for infections.
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