One of the most useful aspects of the Web is its vast capacity, giving us a great place to post valuable content that would not fit into our print publication. The following excerpts from the contributed input of six KOLs supplement the article, “Immuno-Oncology Takes Over,” in the June issue of Life Science Leader. The KOLs:
LLEW KELTNER, M.D., Ph.D.
President and CEO, Epistat
SUSAN F. SLOVIN, M.D., Ph.D.
Attending Physician, Member Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center; Professor of Medicine, Weill-Cornell Medical College
ALAN VENOOK, M.D.
Professor, Department of Medicine (Hematology/Oncology), UCSF
JEDD WOLCHOK, M.D., Ph.D.
Chief, Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center
LAWRENCE FONG, M.D.
Professor, Department of Medicine (Hematology/Oncology), UCSF
TIM F. GRETEN, M.D.
Head, Gastrointestinal Malignancy Section; Senior Investigator, Thoracic and Gastrointestinal; Oncology Branch, Center for Cancer Research, National Cancer Institute
THE CLINIC AS LAB
Sometimes the distinction between basic and clinical research fades in relevance. The AACR (American Association for Cancer Research) annual meeting this year held many presentations of studies using mouse and other preclinical models, but seldom without a reminder of their inherent fickleness as predictors of human response to cancer and cancer therapy. IO had advanced by clinical application of mechanistic theory, but the clinical results have since outpaced the theoretical understanding.
“One of our mantras is that the clinic is now the lab,” says Dr. Lawrence Fong. “Doing experiments in mouse models or other models may not reflect what goes on in people, and now, with new techniques in biology, if we hit a particular target and so we can actually study that in a person. We now have really sophisticated tools that allow us to tease apart an immune response. We can look at patient samples, even though they may be limiting, but now actually really get a better understanding of what’s happening biologically as we give these patients these various drugs.”
Many people in the IO field would still count CTLA-4 inhibitors as the centerpiece of cancer immunotherapy, with or without combined anti-PD-1. Anti-CTLA-4 champions Drs. James Allison and Padmanee Sharma of MD Anderson, as well as Dr. Jedd Wolchok and others on our KOL panel, are still doing plenty of clinical work on ipilimumab and related compounds, including a large variety of combination trials. Mainly, though, their work centers on understanding why every immunotherapeutic approach has limited success, and that gets back to understanding more and more about the immune system and its responses to cancer. Meanwhile, most researchers and practitioners — often the same brave people — seem to favor the CTLA-4/PD-1 blocking combination.
“Anti-CTLA-4 may not be as broadly applicable as an anti-PD-1, but CTLA-4 is still a very important target for an immune response,” says Fong. “Anti-PD-1/anti-PD-L1 therapy works as a single agent in a lot of different cancers, but in some cancers it doesn’t work, and anti-CTLA-4 could be one of those agents that help to enhance that response. Kidney cancer is a disease where there’s now some published data showing combination therapy improves clinical responses; others include lung cancer.”
At AACR, Alan Korman, head of IO discovery at BMS, showed how his company is testing a set of second-generation versions of the ipi molecule and trying to answer some basic questions about the original compound. Does ipilimumab deplete T-reg cells? How does it cause SAEs? In the meantime, the more general question of whether Yervoy complements Opdivo haunted AACR. The recent Phase 3 CheckMate-067 trial of ipi and PD-1 blocker nivolumab in treatment-naïve advanced melanoma showed somewhat lower risk of death and more durable responses with the combo, but the study had a good problem to have: too few people died in both arms to reach a median-survival (OS) endpoint. Wolchok was the principal investigator in the study and presented an update at this year’s ASCO (American Society of Clinical Oncology) meeting showing significant improvement in progression-free survival (PFS) in the combination group. Overall, the study was encouraging to the anti-CTLA-4 camp but may not sway the skeptics.
“Anti-CTLA-4 was the first agent out there commercially, and it works,” Dr. Llew Keltner acknowledges. “A small percentage of patients have had complete responses to anti-CTLA-4, and for those patients, who clearly would have died otherwise, it’s a miracle. Is there any benefit for combining CTLA-4 and PD-1/PD-L1 inhibitors? I have not yet seen data that proves it wouldn’t have been better to just put these people on anti-PD-1 at the earliest possible date instead.”
READING THE SIGNS
A great deal of discussion in the IO community is now devoted to prediction and confirmation of treatment response based on PD-1/PD-L1 expression in tumors, immune-cell activation, or other factors in the tumor micro-environment. The obvious need for diagnostic tools reflects the inadequacy of old methods and the seemingly counterintuitive ways tumors and immune cells interact. Tumors themselves, in their witches-brew composition — picture The Thing from the 1970s version — confound all attempts to probe deeper into the cancer-immunity interface.
Fong notes: “There are a lot of examples with immunotherapies where you get an improvement with overall survival, but if you look at response rates or progression free survival — in other words, the time to which a tumor grows or progresses — you don’t see a significant difference there. This is absolutely one of the challenges with immunotherapy: it may improve survival even though there are signs of the tumor getting worse. We’re just starting to scratch the surface of why that is, but it really requires us thinking differently about what the endpoints of those trials should be. The response rate may not be the right measure for some cancers and for some immunotherapies.”
Patient selection —based on predicting response, benefit, toxicity — is one of the issues for clinical trials, says Fong. “We recently published an observation of patients who develop immune-related side effects to anti-CTLA-4 treatment, and they have specific changes in their circulating T cells. That could be a predictor of whether this person might develop toxicity, in which case you might manage them differently.”
“At the present time, more exploration is needed to understand who might benefit from specific checkpoint inhibitors as well as identifying those patients who would be at higher risk of severe adverse events,” Dr. Susan Slovin says. “There remains a lot of work to be done exploring the tumor/stromal microenvironment and how drugs affect the interplay between tumor and effector cells. In particular, understanding the roles of ICOS [inducible T-cell costimulator, or CD278], VISTA [V-domain Ig suppressor of T cell activation], and MDSC [myeloid-derived suppressor cells] remain important in assessing how the microenvironment responds to therapy. There are continued concerns that not all commercial antibodies or scoring systems for PD-L1 are the same. Concerns remain regarding the lack of relationship of PD-L1 expression with response in different malignancies; in other words, not all tumors respond the same to the class of checkpoint inhibitors. Overall, combination approaches appear to be better than single agents. Agents that modulate the immune system, either directly or indirectly, are now being evaluated. I would not be surprised that molecules that have not been used within the last 25 years suddenly make a resurgence given that there may be unique properties that may contribute to immunologic enhancement.”
Visualizing the interior and immediate surroundings of a tumor has been a high hurdle, mainly because conventional biopsy and micro-imaging techniques remain unequal to the task. Biopsies sample a thin cylinder of tissue extracted from the tumor via a needle. Similarly, microscopes examine super-thin slices cross-sectioning the tumor and environs. But both subjects vary tremendously in three dimensions. A tumor is not just varied in composition, it is outrageously heterogeneous in containing a great number of different cell types — cancer, non-cancer, living, non-living.
“Almost every cancer cell in a tumor may be different from its fellow, have different DNA, because that’s what cancer cells do — they mutate,” Keltner explains. “There are also many non-tumor cells in tumors, and those cell types, in general, have been recruited by the tumor because the tumor is evolving so fast and by chance, some of those cells will mutate in a way that they influence non-tumor cells within the tumor to help the growth of the tumor cell, to keep the tumor cell alive. Through natural selection, that tumor cell proliferates and then you’ve got the whole tumor recruiting all kinds of cells. Tumors evolve really fast because they are genetically degraded. They have mutations that increase mutation rates.”
So, is a tumor high in PD-1/PD-L1? If the right contrast medium could light up the whole tumor at once, and if a way existed to interpret the image, it might be possible to give a real answer to the question. Dr. Tim Greten describes a related idea now developing in sync with progress in medical imaging: “The new technology for digital, 3D imaging of the spatial configuration of cells, antigens, and other constituents of a tumor allow us to make complex analysis of tumor heterogeneity and the tumor microenvironment, which is more complicated than people thought. Another fascinating area is the microenvironment studies, which is the tumor itself in all its complexity — its genetic complexity, metabolic complexity, and immune complexity — and it may be affected by factors we don’t even think of right now.”
But one factor almost everyone is thinking about now is T cells known as tumor infiltrating leukocytes (TILs). Many companies have joined the race to develop a TIL booster, or co-stimulator, as the first agent to turn “cold” tumors, unresponsive to checkpoint blockade, into “hot,” responsive ones. But are TILs really the ones to boost? Some are — but only the kind called memory CD8 cells. Others, namely the immuno-suppressive Tregs, are to be avoided.
For some scientific clarity, Keltner refers to Charles G. Drake, M.D., Ph.D., co-director of hematology/oncology and cancer immunotherapy programs at Columbia University. Drake has done some of the seminal research in cancer immunity mechanisms, both basic and clinical, and he questions the typical TIL hypothesis. TILs are only part of the picture, according to Drake; the important parameter in whether a tumor is cold or hot is the ratio of Tregs to memory CD8s. If that ratio is too high, no matter how many TILs you have instilled, the tumor will stay cold. “Hot really means a specific up-regulation of activated CD8s in the tumor, not just T cell infiltration of the tumor,” says Keltner. “But to know which is occurring, you must select for memory CD8s out of all the T cells that have infiltrated into the tumor.” Again, Keltner gives high marks to Merck for pushing beyond traditional biopsies and imaging whole tumors and micro-environments to observe the presence, distribution, and interaction of immune cells, antigens, and other constituents.
Such imaging will eventually become an integral part of IO clinical trials, Keltner believes — as does Dr. Sharma and many others. A way of imaging PD-L1 in tumors is already feasible, though the technical challenge of imaging CD8 and other immune cells has so far proven insoluble.
Beyond the helter-skelter race to develop a safe and effective co-stimulator, one time-tested method known to boost T cell activation against tumors is to ablate the cancerous tissue. Ideally, the ablation would be one that relies mainly on apoptosis, turning the tumor into an “apoptotic mass” of dead, neoantigen-covered cells that practically shout at the immune system to usher memory T cells to the site. Once there, the T cells imprint on the apoptotic mass and will key other immune cells to seek out and destroy remaining tumor tissue and related metastatic tumors throughout the body. All forms of ablation are likely to be tested, however, even those that produce mainly necrosis, a messy and even toxic cell-death process that is arguably less immunogenic than apoptosis.
“My group and others are actively exploring the relative merit of different forms of local ablation, whether it be radiation therapy, cryoablation, radio frequency ablation, or other forms of tumor destruction,” says Wolchok. “I think we still have much to learn about the relative immunogenicity of all those approaches.”
Greten has led extensive studies of ablative methods and their effects. “We are working on how various forms of ablation could generate T cells and generally be immunogenic. We started this three years ago, and now we are at the point that we have shown you can combine treatments, say, anti-PD-1 with radiation, to achieve higher response rates,” he says.
“If you kill tumors apoptotically, the dead cells release all of the immune-activating neoantigens, not only activating T cells against any remaining tumor cells, but also cutting off any evolutionary escape route for the cancer,” Keltner asserts. “If you can cause enough CD8 T cell response and then treat with anti-PD-1, you have a really good chance of eliminating or at least controlling disease for a very long period of time in the great majority of patients. I believe we will see this clearly with a bunch of new apoptotic kinds of therapies.”
Ablation also takes care of one now well-recognized obstacle to any cancer treatment — the micro-environment surrounding tumors with fibrous tissue and other barriers to penetration by therapeutic agents. Ablation is the opposite of targeting, other than by physical area; it does not distinguish between tissues. Point it at the tumor or at its surroundings, all of the ablated area of cells will die.
“With a lot of drugs that have been highly tailored to be specific only to cancer cells, you may kill the tumor but leave the microenvironment, so the cells that survive can say, ‘Thank you for leaving the matrix for me. Now I will regrow and I’ll be even tougher at resisting therapy.’ You’ve got to whack the whole thing, the cellular microenvironment, the non-cellular microenvironment, the tumor cells, supportive cells within the tumor,” Keltner says.
CELL OUT, CELL IN
On the other end of the band from ablation and developing in parallel to off-the-shelf immuno-therapeutics is CAR-T (chimeric antigen receptor therapy), which involves removing T cells from a patient, training them to recognize the patient’s cancer, and reintroducing the engineered cells back into the body. Most of our KOL contributors remain optimistic that the logistical and business challenges of CAR-T will yield to solution and don’t necessarily see the procedure as a competitive alternative to off-the-shelf approaches.
“Perhaps there is a role for manipulating immune checkpoints at the same time as you’re redirecting T cells toward targets of interest on the tumor,” says Wolchok, whose group is also working with CAR-T. “We are seeing these different approaches come together — the science is driving the field forward in a very strong way, and thankfully there are considerable technical advances as well. Dr. Carl June’s group at the University of Pennsylvania is applying new knowledge of inhibitory and agonist pathways to enhance the activity of the CAR-T cells. Such developments have allowed our group to do sophisticated manipulation of CAR-T cells under the leadership of Dr. Michelle Settling.”
Wolchok believes the CAR-T model will thrive in the same type of research-treatment settings that have fostered blood stem-cell transplants. “Again, advances in the technology of cell expansion are coming along well, allowing for more widespread application.”
To draw a hard line between academic and industry science in immuno-oncology is impossible. In the development of the first approved anti-CTLA-4 drug ipilumimab, for instance, Jim Allison and his team began working with BMS early and kept up the relationship all the way through Phase 3 trials. “Academic science remains pivotal for influencing clinical and research trial design. The collaboration with industry has fostered not only facilitation of trials financially but have actually resulted in bringing new drugs to market sooner,” says Slovin.
How will academic science continue to influence and guide commercialization of new IO treatments? “This is a great challenge,” says Venook. “So far at least, the pharmaceutical industry has not solicited as much input as we might wish, although it is probable that going forward, there will be more opportunity for collaboration.”
Is there enough transparency going on in the scientific research or is it starting to be more difficult as academics and companies take more proprietary approaches? Wolchok is optimistic: “I would say it’s definitely headed strongly in the direction of collaboration. I will point very personally to the emergence in the past year of the Parker Institute for Cancer Immunotherapy, for which Memorial Sloan Kettering is one of the founding members. One of the founding principles of this group, which contains some of the more important research teams in immuno-oncology, is the absolute necessity of collaboration. A recent paper in Nature was a joint effort of our group here, along with John Wherry, Tara Gangadhar, and Robert Vonderheide’s team from Penn, another member of the Parker Institute, to better understand attributes in patients who respond to PD-1 blockade. This is work that might have been impossible through one group’s efforts alone, but putting competition to the side and just doing the right thing for science and for patients, we were able to push forward a very impactful publication. The Parker Institute is a very novel funding model, but I also have the great fortune to co-lead one of the Stand Up to Cancer Dream Teams in lung cancer — again, collaboration, transparency, sharing unpublished data, and all of that are tacit understandings of how we’re going to make progress in the most efficient way.”
Keltner points to similar efforts elsewhere. “Shuguang Tan and his team at The Chinese Academy of Sciences in Beijing recently published an article about the way pembrolizumab and nivolumab actually bind. The Chinese company BeiGene also helped us understand some things about the binding. There is also a lot of unpublished work frantically going on now to figure out the differential binding of the various anti-PD-1 antibodies, and what does it mean in terms of toxicity, efficacy, and combinations.”
Companies seem to be continuing with basic research to understand immunotherapy mechanisms in parallel with their clinical development — right? “Well, yes and no,” says Greten. “The field is moving so rapidly that I see a lot of confusion in the work. A lot of companies say, ‘Why don’t we test our drug with this, that, and the other thing just to see if it will work?’ Or they test it only in a mouse model, then the question comes up, which is the best mouse model for the test? I do see a lot of preclinical work, but at the same time there is a danger in having such a huge number of clinical trials, with the huge number of patients enrolled in the trials, but without a solid rationale based on good preclinical data. We are dealing with a huge amount of information and complexity, and we really have to work to understand what is happening. That will be a huge challenge, but that is where the future is.”
OVER THE MOGULS
Immuno-oncology now rules oncology. But that doesn’t mean IO is an easy, downhill ski. As noted in out Update last year, cancer immunotherapy could be in danger of becoming a luxury only the richest patients and their families can afford. Venook boils it down to a few choice words: “The costs and charges must come down for these new agents to be impactful and affordable.” Most others among our KOL contributors have voiced similar concerns, yet all look with hope to a future of carrying out the scientific mission.
“Dealing with the costs associated with immunotherapies is one of our greatest hurdles,” Fong says. “But another big challenge will be dealing with the clinical responses from all of the different studies now going on. There’s a steady stream of data for all these different trials. The important part is continuing to make progress and getting information out into the public domain. That is where all these meetings in the field are so important because they help us keep track of the data as it comes out.”
“For a long time, IO was considered a somewhat speculative approach to cancer therapy, and what it really took was a very firm foundation of basic science supporting the interventions that we move forward into the clinic,” Wolchok concludes. “Now we have evidence that for some patients with some cancers, immuno-oncology is an everyday, standard approach. We all recognize that this is not a curative intervention for every patient by itself, and in some diseases, we still have to understand better what the tumor immune cell interactions are in order to develop more effective immune strategies. Of course, we are trying to be optimistic, but we don’t want IO to turn into a bubble, based on unrealistic expectations. We recognize firmly that immunotherapy approaches may need to be paired with sort of orthogonal anti-cancer strategies.”
We look at the Combination Cancer Immunotherapy series and subsequent updates as a continuing dialog among many of the important players in the field. Our KOLs and others have actually credited the series with promoting increased collaboration among all players. If you would like to take a part in this discussion, please feel free to email me at firstname.lastname@example.org with brief answers to the following questions. Hopefully, depending on the total response, we will publish selected answers at a future date.