How the persistence of researchers is finally paying off

With two novel approved and many more in the pipeline, is it time to announce that a new treatment modality has emerged?

class of therapy that has directly attacking tumours, control - system to fight cancer have com - long held promise for ling factors that allow tumour manded sporadic interest but only treating cancer patients growth, using to prevent limited success, a flood of recent may finally have come of but also to treat cancers, helping research findings have earned age. Immunotherapy, or repair damage from other treatments, their place in top journals and biological therapy to give the broad - and more. Now, after more than a ASCO presentations, with promising est term, can use the body’s immune century in which the tantalising pos - trial results and a big pipeline of system in a wide variety of ways, by sibilities for harnessing the immune new agents.

14 Investment analysts, never slow to Harnessing the immune system. Far left: T cells home spot trends, suggest we might be in on a cancer cell. Left: like this approaching a tipping point – the one were the focus of much of the early number of ASCO abstracts on this immunotherapy research, but trials are topic more than doubled over the now ongoing for a range of cancers last two years, reaching more than 300 this year. Researchers now There are two reasons why talk of the ‘end game’ being in immunotherapy has now gained sight for immunotherapy, though such traction, says Christian there is still a long way to go. Ottensmeier, professor of experi - The excitement that is building mental cancer medicine at the was triggered in no small part by University of Southampton in the the approval in 2010 by the US UK. “We’ve had a poor understand - regulatory body, the FDA, of the ing of how the immune system works first therapy, sipuleucel T – but that is changing rapidly with (Provenge) for advanced prostate work on chronic infectious diseases cancer, followed last year by ipili - such as malaria, TB and HIV, as well mumab (Yervoy) for metastatic as cancer – they are cross-fertilising , which is an ‘immune-tar - that Groopman describes in detail, as it and similar questions are being asked. geted’, or stimulatory, antibody agent. led to the development of Yervoy. Second, our tools are much better – Meanwhile the wider public are The breakthrough moment came we had quite rudimentary ways of being primed about the possibility of when Jim Allison, head of tumour looking at immune response, but in a major breakthrough. This April, immunology at Memorial Sloan Ket - the past 10 years there has been an The New Yorker , a literary magazine, tering, and colleagues, spotted that explosion in what we can deliver for carried a story titled ‘The T-cell army’, the mechanism worked in the oppo - measuring immunity. Being able to in which writer Jerome Groopman site way to what had been believed – measure in more detail the different traces the early history of immuno- CTLA-4 had to be blocked, not stim - facets of the immune system, and in therapy back to William Coley, a sur - ulated. It then took a while before ways that others can reproduce, is a geon in New York, who stumbled on they finally persuaded a drug com - major contributor to the field.” a case where a streptococcal infec - pany to take up the approach. As a result, he adds, we are now tion seemed to help a sarcoma Drug companies could be forgiven in a better position to study one of patient eliminate his cancer, and for being cautious, given the long the least explored approaches that then tried to replicate it. history of difficulties. Interleukin-2 have the potential to improve out - T cells – a type of lymphocyte, or (IL-2) and interferon- α – the main - comes for cancer patients. “There is white blood cell, found in the blood and stays of attempts at improving immune also a rapidly accumulating body of other parts of the body – work mainly by responses introduced in the 1980s – evidence to indicate that immune

producing proteins which allow both have significant toxicity and lim - attack on cancer is critical, and look - Y R A immune system cells to communicate ited evidence for overall survival. The ing at it just numerically in the tissue R B I with each other, and which can also past few years have also seen high- is a very powerful tool for predicting L O T attack foreign or cancerous cells. It is profile failures of companies such as outcomes – so there is a strong argu - O H P

the discovery of one type of T cell that CancerVax and Cell Genesys. But this ment that improving outcomes can E C produces a protein called cytotoxic unpromising picture has changed dra - be achieved through improving N E I C

T-lymphocyte antigen-4, or CTLA-4, matically over the last two years. immune responses. And there is a S “In the past 10 years there has been an explosion in what we can deliver for measuring immunity”

15 “The field has changed in just two years from having little to offer to being a ‘grown up’ treatment” rapidly growing number of ran - a lot of papers in preclinical and trans - immune-targeted agents such as Yervoy, domised phase II and III studies lational research journals – there was a says Lesterhuis. that show this is actually the case. difference in perception about what He outlines some of the key advan - The field has changed in just two immunotherapy can do between clini - tages of immunotherapy. “It can be years from having little to offer to cians and laboratory scientists.”A string very specific – T cells can be directed being a ‘grown up’ treatment.” of high-profile negative trials, in par - against tumour cells, in theory without Joost Lesterhuis, a medical oncolo - ticular with vaccines, has not helped of causing any damage to surrounding gist and researcher at Radboud Uni - course, but there has been steady tissue. The immune system also has a versity Nijmegen Medical Centre, in refinement of animal models and a memory, so if you induce a response, in the Netherlands, says that the basic flow of small human studies that paved general it is long-lasting and can be research community had not lost faith the way for the impact we see now, quite potent – we’ve seen instances in with immunotherapy. “There have been with the standout sector being the novel people with high tumour burden, although people with less tumour tend IMMUNE CHECKPOINT BLOCKADE to respond better. “And immunotherapy is additive – Ipilimumab CTLA4-blocking Melanoma Approved the old idea was that you should go for (Bristol-Myers antibody Prostate cancer Phase III one treatment or another – now we Squibb) and NSCLC are moving in the near future to giving immunotherapy with or on top of Other tumours Phase I–II other therapies.” MDX1106 (Medarex/ PD1-blocking Melanoma, RCC Phase II Bristol-Myers Squibb) antibody and NSCLC Strategies in immunotherapy CT011 (CureTech) PD1-blocking Melanoma and Phase II Immune checkpoint blockade antibody haematological Among the big news stories at ASCO malignancies this year were trials of two agents in the class of immune stimulatory antibodies, VACCINATION STRATEGIES targeting the PD-1 (programmed cell Sipuleucel-T Autologous APC vaccine loaded Prostate cancer Approved death) and PD-L1 (programmed cell (Dendreon) with prostate acid phosphatase death ligand) proteins. The aim is to block pathways that shield cancer cells Dendritic Cell (DC)- Autologous DCs loaded All cancer types Phase I–III based vaccines with tumour antigens from the immune system, and the agents have been trialled not only in MAGE3 ASCI MAGE3 protein NSCLC Phase III melanoma and kidney cancer, which (GlaxoSmithKline) have long been candidates for immuno- PROSTVAC Poxvirus-based Prostate cancer Phase III therapy, but also in non-small-cell lung (Bavarian Nordic) PSA-targeted vaccine cancer (NSCLC), with promising T-VEC () Attenuated herpes simplex Melanoma Phase III results in these hard-to-treat advanced (developed by type 1 virus encoding and HNSCC tumours. Both agents are made by Bris - BioVex as OncoVEX) human GM-CSF tol-Myers Squibb (BMS), which also Source: All tables are adapted from W Joost Lesterhuis and Cornelis J A Punt (2012) makes Yervoy. Harnessing the immune system to combat cancer [poster]. Nature Rev Drug Discov The reason Yervoy has gained so www.nature.com/nrd/posters/cancerimmuno © 2012 Nature Publishing Group much attention is straightforward, says

16 ADOPTIVE CELL TRANSFER Lab-grown T cells Another interesting approach mentioned Adoptive transfer Polyclonal T cells Melanoma Phase III by Lesterhuis is adoptive T cell therapy. with TILs against multiple tumour- While the immune-targeted therapies and associated antigens vaccines aim to induce or boost the body’s Adoptive transfer Monoclonal T cells Melanoma Phase II existing responses to tumours, adoptive with TCR-transduced with high-affinity TCR T cell therapies culture large numbers – T cells against single tumour- potentially billions – of tumour-specific associated antigens T cells in the lab, and infuse these into the patient. This strategy was developed in the Lesterhuis: it is the first drug to show using viruses, proteins, DNA, pep - US (for example in a trial in 2002 with survival benefit in a phase III trial in tides, dendritic cells and so on. Some advanced melanoma, although early work advanced melanoma (although the of these strategies are showing prom - goes back to the 1980s), and has now BRAF inhibitor, vemurafenib, has ise, they say, but most have failed. started to become available for a few competed for attention, and the two One important lesson they highlight melanoma patients in Europe, at centres are being trialled together now). “It from past mistakes is that enough time such as theAmsterdam Cancer Institute, wasn’t that most patients were cured – must be allowed to judge the potential Copenhagen University/Herlev Hospital they weren’t – but it was the first posi - impact of a vaccine in early-stage trials. in Denmark, and the Christie in Man - tive story to tell about melanoma, and Despite the many setbacks, there chester, UK. The T cells can also be there were dramatic responses in a is now a pipeline of candidates in derived from blood or can be genetically minority, and it was the spark that made phase III, such as GlaxoSmithKline’s modified, but in the main melanoma a lot of people enthusiastic again.” DERMA and MAGRIT trials for non- trials they come from the tumour – a This type of immunotherapy is pro - small-cell and melanoma treatment known as TIL (tumour- gressing very rapidly, he adds, because that target the MAGE-A3 antigen, and infiltrating lymphocyte). clinical data are becoming readily avail - Amgen’s talimogene laherparepvec able, and because it is not a patient- (T-VEC), an engineered herpes virus The role of chemotherapy tailored approach. “It’s just an antibody that also targets melanoma. Ottens - The case is now being made that against a surface molecule on T cells.” meier adds that there are at least five immunotherapy deserves to be classed randomised vaccine trials for lung as a distinct treatment modality, to rank Therapeutic vaccines cancer that are well worth watching. alongside chemotherapy, hormonal Ottensmeier points out that there are well-established immune treat - NON-SPECIFIC IMMUNE STIMULATION ments, such as bone marrow and stem cell transplantation in haema - IL2 (Novartis/ Recombinant Melanoma Approved for melanoma Prometheus) human IL2 and RCC in some and for RCC in tological malignancies, but the spec - most countries trum of treatments is opening up widely now. In addition to agents IFN (Schering- Recombinant Melanoma Approved for melanoma Plouαgh/Roche ) human IFN and RCC (adjuvant) and RCC in such as Yervoy, he considers that ther - α several countries apeutic vaccines such as Provenge Denileukin Recombinant IL2– Persistent or Approved in US; orphan are becoming valid treatment options. diftitox (Ontak) diphtheria toxin recurrent cutaneous drug designation in EU His opinion is shared by Lester - (Eisai) conjugate T-cell lymphoma huis, who co-wrote a review paper Other tumours Phase I-II published August 2011 in Nature Reviews Drug Discovery, where they Imiquimod TLR7 agonist Basal cell Approved for basal cell argue that therapeutic vaccines are (Meda/Graceway carcinoma, VIN carcinoma; in Phase III /iNova) and CIN for VIN and CIN more widely applicable than preven - tive ones, as most human cancers have BCG Intravesical Urothelial cancer Approved several causal agents. Such vaccines administration of BCG as adjuvant can be developed in a variety of ways,

17 “Benefit from both chemotherapy and radiotherapy may be related to immunological factors” therapy and the new targeted thera - dendritic cells, making tumour cells much longer to respond to treatments, pies. But as usual with cancer, things more susceptible to immune attack,” and tumours may grow for a while. are not so clear-cut. Take chemother - he says. “It feels counterintuitive Benefits may not emerge for months apy – as Ottensmeier says, “We are because one of the side-effects of or possibly years, which can leave learning that both old and new chemotherapy is immune suppression oncologists and patients facing diffi - chemotherapies that are not immuno - with decreased immunity to bacteria, cult decisions about whether to con - logical in nature do produce immuno - but in recent years we have evidence tinue with treatments. Lesterhuis also logical effects. Some think that that immune response to tumour anti - notes that there can be unexpected chemotherapy is going to immuno- gens is not decreased and may alarm side-effects, such as the high rate of suppress the patient, but that’s not the immune system towards cancer.” acute renal failure that occurred in a true for all drugs. For example, there He points to another study, a phase trial of a combination therapy for kid - is a recent paper in the JCO that II trial that has attracted interest, ney cancer. Generally, side-effects found the number of immune cells in where Yervoy was combined with can be severe in immunotherapy, as breast cancer predicted more benefit chemotherapy in non-small-cell lung found in trials of Yervoy, and can from chemotherapy. It means that cancer. “It showed longer progression- require fast medical action. when we have been focusing only on free survival depending on the sched - Inevitably, there are cost and regu - the cytotoxics in terms of poisoning uling of the two drugs, and phase III is latory issues concerning the new cancer cells, it may be much more now starting. The other exciting thing agents. When Provenge hit the head - complex than that.” The benefit from is that it is in lung cancer, which was lines, it was on account of its price tag both chemotherapy and radiotherapy, thought to be a non-immunogenic dis - as much as anything else. Yervoy is not he adds, may be related to immuno - ease.” The anti-PD-1 agent has also far behind, at about €85,000 for one logical factors and not primarily to shown some good responses in lung course of infusions in the Netherlands, the toxic effects. cancer, he adds. for example. A recently established This is pointing to new directions cancer drugs fund in the UK is cover - for investigation with conventional Towards the end game? ing costs there, but at a ‘tear-inducing’ treatments and with targeted therapies But the successes so far should not dis - price, says Ottensmeier. to find out whether they can work in guise the many obstacles for making As with other therapies, there is a conjunction with immunological treat - more progress in immunotherapy. need to identify patients who will ment. “Some are particularly good and While investigation and tools are devel - benefit. His own group presented a some really bad – we need a case-by- oping fast, major gaps in knowledge poster at ASCO on early work on a case analysis to understand the prin - remain regarding, for example, optimal biomarker for gauging who might ben - ciples,” he says. dosage, scheduling and how to meas - efit from Yervoy for melanoma. Using Investigating the effects of plat - ure response. The rulebook for cyto - a proprietary panel of tumour-associ - inum-based chemotherapies in com - toxic drugs is no good here; as ated antigens, they found that among bination with immunotherapy is Lesterhuis and colleagues point out patients treated with the therapy, Lesterhuis’s own field and he’s recently in their review paper, maximal tolerated those with pre-existing antibodies returned from a spell as a visiting dose and tumour response rate have against two or more antigens were scientist at the tumour immunology proved not to be valid as markers for significantly more likely to survive. group at the University of Western immunotherapies, and there is much They concluded that the melanomas Australia. “I’ve found that there are less – if any – correlation between drug in these patients “are immunologi - beneficial effects in induction of exposure and efficacy and/or toxicity. cally more visible”, and so more likely immunity, such as by activating In particular, patients may take to respond to activation of immunity.

18 Ottensmeier says that the current focus “And the excitement about anti- “It is a result of the memory of the is mainly on treating established dis - CTLA-4 is not only that it works in a immune system, both in B cells, ease, but attention will also turn more small number of patients, but also which make antibodies, and T cells. to prevention of recurrence, and pri - that there is a group of patients who do They hang around for decades – mary prevention and prevention of dis - not have recurrence after you’ve fin - probably for life. If they are enabled ease development – the HPV vaccine ished treatment, and it’s a paradigm to see the tumour, then they can for cervical cancer being an obvious shift that I think we will see with vac - do what our current drugs have not example of a primary prevention. cines and T cell transfer as well. been able to do.”

ENLISTING 196 BILLION T CELLS TO HELP FIGHT STAGE 4 MELANOMA

hen Hein Jambroers, a 47-year-old event coordinator from Jambroers says that TIL is a major procedure involving several Roemond, a city in the southeast of the Netherlands, found stages and people need to be physically fit. “First I had an oper - a small mole on his leg that was growing, he went to his ation to remove some tumour to get the antigen-specific T cells, doctor, who sent him to the local hospital, where it was found to be but I got an infection and had to wait another month while that was melanoma. He then went to the university hospital in Maastricht for treated. I then went back to have white cells removed from my operations on his spleen and lymph nodes – but one year later, the blood and had a week of chemotherapy.” That process – called cancer returned with tumours on his leg. This was summer, 2010. lymphodepletion – is needed to eliminate competing lymphocytes “I went back to Maastricht and they said they couldn’t help me and regulatory T cells. Meanwhile, the as the cancer was now in my blood. I went to Rotterdam too specific T cells were cultured for infusion and was told again there was no treatment. So I – there were about 196 billion in his started Googling.” case, which he received in October last Jambroers found the story of a Belgian year. “I was told that 196 billion is an woman who had been treated with ipili - extremely high number of cultured mumab in Brussels, and tracked her cells – the results of all the world - down on LinkedIn. After talking to wide TIL trials show anything over her, and her oncologist, he was 150 billion gives a good chance of advised to see John Haanen at complete remission.” the National Cancer Institute (NKI) But the treatment was not over – in Amsterdam, who was working on he also had four infusions of IL-2, the latest melanoma trials. and had to go into intensive care “I was first put on vemurafenib as his liver and kidney began to [Zelboraf], the new BRAF inhibitor, fail. A week later, he was well and that worked well at first – a enough to go home. A check spot on my liver vanished and He feels that, even now, many doctors are still revealed the tumours had shrunk others shrank to a pea. But then it unaware of where to refer people by 25 –30%, and he was soon back stopped working and tumours in at work. “After another two weeks my leg grew again, to egg size, within one month.” He was then there was a 50% shrinkage, and by Christmas there were no active offered Yervoy, which had worked in other patients in Amsterdam. tumours – just one lump with fluid. By April this year it looked like “I had four infusions but it didn’t do anything – it is thought it could I was cured – there was only scar tissue and nothing in my blood.” work after several months but there was no change in my blood Jambroers, pictured here with his wife Varadi and daughter Jenna, work at all. I was told they were not expecting an anti-PD-1 trial has become an advocate for melanoma patients, telling his story before 2012.” on websites and in Dutch newspapers. There is much more He had already asked about adoptive T cell lymphocytes (TIL) in about the latest treatments now available, but he feels that, even 2010, but had been told there were no plans to try it. Thankfully now, many doctors are still unaware of where to refer people. he then got a call inviting him to be one of the first three patients “I know how hard it is if you can’t find information and I’m happy in the Netherlands to undergo the treatment, under Haanen. to tell my story whenever I can.”

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