James P. Allison e Robert D. Schreiber
Premio Balzan 2017 per gli approcci immunologici nella terapia del cancro
Sintesi delle ricerche: Berna, 16.11.2017 – Forum (video + testo – inglese)
As a basic scientist, I have been blessed by the opportunity to see my research findings translate into a powerful new strategy for cancer therapy. In 2006 I met a patient by the name of Sharon, a twenty-fouryear old who had recently graduated from college and gotten married. More than a year before I met her, she was told by her doctors that she had only a few months to live. Sharon had stage four metastatic melanoma, and tumors had spread to her brain, lungs, and liver. She had received multiple prior therapies but her cancer continued to grow and weaken her body.
As a last-ditch effort, she participated in a clinical trial of a then experimental drug called anti-CTLA-4 therapy. Within three months of starting treatment, her tumors shrank in size and then disappeared. When I met her a year later she hugged me and cried. She had just been told by her doctor that she showed no evidence of recurrent cancer. I was moved and cried with her. Sharon and I have become good friends. When her first child was born a few years later, she sent me pictures. Then pictures of her second child. She is now eleven years out from her battle with cancer and enjoying life with a vibrant family. I can’t help but cry whenever I tell this story. My meeting with Sharon was my first experience of how years of research as a basic scientist could have an impact on patients. Her experience, and those of many other patients who benefitted from this work, has provided inspiration to work to continue improving this therapy.
Cancer as a whole is caused by an assortment of different gene mutations leading to many very different diseases, all with their own distinct sets of genetic mutations. The fact that the worst cancers exhibit high genomic instability makes them prone to the accumulation of further mutations. What this means for the patient is that when we treat with new therapeutics that target a specific cancer cell mutation, the most aggressive cancers, even if initially responsive, often mutate again and become resistant to targeted therapy.
The beauty of immunotherapy is that the body already possesses a highly adaptive immune system that is capable of attacking and eliminating any foreign threat. By helping the body’s own immune system to fight off cancer, we can provide treatments that are generalizable to many cancers independent of the specific mutations that underlie them and that remain effective even as the cancer cells continue to mutate. The immune response is specific to the threat at hand and durable, often lasting an entire lifetime after the initial treatment.
One of the major unsolved issues in immunology in the early Nineteen Eighties was the nature of the T-cell antigen receptor and the mechanism by which it activates T-cells. In 1982, I identified and worked out the structure of a protein on the surface of T-lymphoma cells that appeared to be the T-cell antigen receptor protein. This provided fundamental knowledge facilitating the cloning of the two genes encoding the two proteins that comprise the T-cell receptor (1, 2).
But it wasn’t that simple. The T-cell receptor can be compared to the ignition switch of a car. It is needed to turn the car on and start the process of T-cell activation but it was not enough to get it going. A second, costimulatory signal that could only be provided by specialized antigen-presenting cells such as dendritic cells was required. Without it, T-cells failed to proliferate and failed to respond to antigen, a state defined as anergy. In 1992 in my lab, Fiona Harding showed that CD28, another protein on the surface of T-cells, was sufficient and necessary to provide these signals for full activation of naïve T-cells and to prevent induction of anergy in T-cell clones (3, 4).
Still, there was another important piece of the puzzle that had yet to be solved. Another receptor on the surface of T-cells, named CTLA-4, which bore significant homology to the T-cell receptor and to CD28, had been found. There was no scientific consensus on the potential function of CTLA-4 as most thought it was another positive costimulator. In 1992 and 1993, studies from my lab and Jeff Bluestone’s conclusively demonstrated that CTLA-4 is a negative costimulator that directly opposes CD28. Not long after, in 1995, we showed that blockade of CTLA-4 led to rejection of a number of different tumor types in animal models. Starting in 1998, I teamed with Alan Korman at Medarex to develop a fully human anti-CTLA-4 antibody ipilimumab (or «ipi» for short) (5, 6).
Medarex then conducted the first clinical trial for ipi against metastatic melanoma. In 2011, the FDA approved ipi as the first immune checkpoint inhibitor therapy for cancer. Since that time the FDA has approved no less than six different immune checkpoint inhibitor therapies for numerous cancers (see Table).
The immune system has two equally important tasks; it must recognize and eliminate foreign threats, and it must recognize itself and not mount a damaging or potentially fatal attack. As such, the immune system and T-cells specifically are highly regulated by a network of positive and negative signals.
The initial signal by which the T-cell receptor binds its specific ligand partially activates the T-cell but does not lead to proliferation. Without an additional «coactivating» signal through the CD28 receptor, T-cells enter into a state termed anergy, where they fail to proliferate and do not respond to the threat. This signal comes from dedicated antigen-presenting cells, which take up peptides and other molecules from dead tumor cells and display them on their surface. T-cells that encounter APCs presenting the appropriate peptide antigen along with B7 on the cell surface become «cross-primed», after which they proliferate and differentiate into one of many T-cell fates, many of which directly or indirectly attack the tumor cell. Some of these populations can also persist, providing lasting immunity against a specific threat. This process is complicated by the fact that as soon as a T-cell is activated, it begins to produce the negative coactivator CTLA-4 and traffic it to the cell surface. Since CTLA-4 has a 3-fold greater affinity for B7 molecules on the APC surface than CD28, the ability of the immune system to mount an effective anti-tumor response becomes a race against time between positive and negative regulatory signals.
At this point, I had one of those «aha» moments that are so rare in science or even in life. We and others had shown in mouse models that solid tumors did not have costimulatory activity. Further, we showed that if we forced expression of the B7 molecules, tumors which normally grew and were lethal in mice were quickly rejected, and the mice became resistant to rechallenge with that tumor. Normallym it seemed that tumors could only provoke an immune response when they died under inflammatory conditions, and their debris, including antigens, were ingested by phagocytic antigen-presenting cells in the context of costimulatory B7 molecules, a process called cross-priming. This would result in productive generation of T-cells, which would expand and potentially eliminate the tumor. However, this would also initiate the CTLA-4 mediated inhibitory program which would eventually stop the response. The key was that the tumor, as a result of lack of costimulatory ligands, would have a head start. If the CTLA-4 program terminated the response before all the tumor cells were eliminated, the tumor would win. What if we could block the negative signal CTLA-4 and let the T-cell response continue long enough to cause complete tumor rejection?
We decided to test this hypothesis by applying an antibody that blocked CTLA-4 on the T-cell surface into tumor-bearing mice and observing the effect on tumor growth. I was so amazed by the initial data, which showed complete tumor rejection, that we repeated the experiment this time blinded to which mice were treated and which were controls. We saw that, after an initial lag, anti-CTLA induced consistent, durable anti-tumor responses in all animals tested across a wide range of tumor types. While I by no means stopped pursuing the fundamental mechanisms of T-cell regulation, I now wanted to bring checkpoint inhibition to the clinic (7).
Up against years of skepticism, the path to translating CTLA-4 checkpoint inhibition into the clinic was not as straightforward as I would have hoped, even in light of our exciting findings. After three years of trying, I was able to convince my friend, Alan Korman, then with Medarex, to work with us. Medarex had a new mouse model for producing fully humanized antibodies, which they used to develop a human version of anti-CTLA-4. They then proceeded to conduct the first clinical trials for metastatic melanoma, a previously treatment-resistant cancer with extremely poor prognosis.
Eventually, BMS purchased Medarex and took over the clinical development of ipilimumab, the human anti-CTLA-4. In 2010, a randomized, placebo-controlled trial of ipilimumab in late-stage metastatic melanoma was reported. The result showed about a four-month increase in median survival. This alone would have been sufficient for approval by the United States Food and Drug Administration, because no drug had ever shown any increase in survival in a randomized trial. However, more important was the fact that the tail of the survival curve flattened out at about 20% between two and three years. A subsequent trial of almost 5,000 patients for whom at least ten years of follow-up was available showed that 22% of participants were alive ten years after a single round of treatment with ipilimumab (8, 9).
But why is the clinical benefit limited to a fraction of the patients? There are several possibilities. One is that since ipilimumab works during T-cell priming, if that is not happening while the antibody is still present in active level in the patients, it will not be effective. Another is that there might be other immunological checkpoints. In 2001, a group consisting of Arlene Sharpe, Gordon Freeman, and Tasuku Honjo showed that PD-1, a molecule originally discovered by Honjo, was another negative regulator of T-cell responses (10).
Since that time more immune checkpoints which provide targets for cancer therapies have been uncovered. Nivolimumab (or nivo for short), an anti-PD-L1 antibody, blocks the interaction between PD-1 and PD-L1 and is now an FDA-approved immune checkpoint inhibitor therapy. A clinical trial combining nivo with ipi for the treatment of metastatic melanoma showed that an impressive 60% of patients were cured of the disease. Ipi/nivo combination therapy is now a standard of care for metastatic melanoma (11-13).
While a wealth of evidence shows that combinations of immune checkpoint inhibitors together or with other anti-cancer therapies drastically increase the response rate, selecting the best combinations for a particular patient and cancer remains difficult. There are currently over 1300 clinical trials exploring the safety and efficacy of various immunotherapies and combinations, selected in a non-systematic manner, which makes it extremely difficult to accumulate enough patients for a given combination. Accurate and rational design of immunotherapy combinations would reduce the number of active cancer immunotherapy trials, and greatly accelerate the approval of more effective combinatorial treatments. Up to this point, prediction of immune checkpoint inhibitor combinations has been hindered by gaps in the knowledge of the specific T-cell populations and the downstream molecular pathways involved.
Castrate resistant prostate cancer (CRPC) has long been known as an immune desert, as very few T-cells infiltrate the tumor. Our recent work shows that anti-CTLA4 therapy promotes T-cell infiltration into the tumor, but fails to provide any anti-tumor response. A closer examination of the prostate tumor microenvironment revealed the presence of molecules related to other T-cell inhibitory pathways, namely PD-L1 and VISTA. Based on that observation, we decided to test combined anti-CTLA-4 and anti-PD-1 therapy, and found that while each was ineffective separately against castration resistant prostate cancer, their combination could provide an effective therapy because anti-CTLA-4 drives T-cells into the tumor while anti-PD-1 allows them to attack previously resistant cancer cells. These findings led to the initiation of a clinical trial of combined anti-CTLA-4 and PD-L1 inhibitor therapy for this devastating disease. Initial results from a patient in this trial show an unheard-of complete disappearance of PSA in response to only two doses of the combined therapy. Because very few patients – most older and frail by the time of treatment – are unable to complete a full course of four doses, we are attempting to amend the protocol to only include the first two doses of the combination therapy needed to eliminate the cancer (14).
Our current work seeks to use drug combinations to enhance immune checkpoint therapy in order to cure more patients and more cancers. In order to accomplish this, we are undertaking a multipronged approach that seeks to design combinations of current and new checkpoint inhibitors with: 1) other checkpoint inhibitors,
2) conventional therapies,
3) therapeutic vaccines, and
4) targeted therapies. Our ultimate goal is to provide new combination therapies that, rather than shifting survival curves incrementally to the right, ‘raise the tail’ of these curves, signifying long-term disease cures.
I would like to point out that all of the cancer therapies presented here arose as a consequence of basic science studies that sought to unravel the fundamental biology of the T-cell response. Without continuing basic science findings, we will run out of knowledge to translate into the clinic.
Finally, all scientific pursuits are based on the idea that objective truth exists and that through observation and testing we can establish facts about the world around us and act on those facts to improve our own lives and the lives of others. There is another movement these days that seeks to question scientific truths and present «alternative facts». These alternative facts have traditionally been known as lies or falsehoods, and turning to them can only serve to reverse the gains that scientific progress has made over previous decades and centuries.
The pace of change toward immunological approaches to the treatment of cancers is accelerating, creating a shortage in the availability of scientists trained in the field who are required to build on these remarkable advances and clear the new hurdles that have arisen toward further expansion of immunotherapy to previously resistant disease. With the research funds provided by the Balzan Prize, my project will establish a postdoctoral fellowship to recruit outstanding young investigators to receive training in basic cancer immunotherapy research. This will serve as part of a continuing effort to train the next generation of researchers to advance cancer immunotherapy deeper on the basic science and translational level. Three career investigators who wish to learn about cancer immunotherapy translational research as basic scientists who conduct immunotherapy research studies on patient samples will be supported for one year each with this award mechanism.
I would like to acknowledge all the students, fellows, and colleagues from UC Berkeley, Memorial Sloan Kettering, and the MD Anderson Cancer Center who contributed to this work over the past almost thirty years. And, of course, my partner in science and life, Padmanee Sharma.
Thank you, Peter. I also want to voice my thanks to the Balzan Foundation for this incredible honor, and to also second Jim’s point that it’s really rare to see an organization take such great care to recognize basic research and how that can be translated into clinical research. So I’m very grateful for being a part of today’s ceremony.
I’m going to tell you a little story about a controversy that has lasted about a hundred years, and that we were in part involved in settling. And this was whether the immune system could in fact see developing cancers and influence their outcome. The story really begins close to the turn of the twentieth century, in the 1900s when the great immunologist Paul Ehrlich proposed that cancer would occur in incredible frequency if it weren’t for host defenses, meaning immunity, to prevent the outgrowth of continuously arising cancer cells. A great idea, but the problem was that very little was known about the immune system at the time, and so nothing really happened with this idea for more than fifty years.
In the early Nineteen Fifties to early Nineteen Sixties, two other great immunologists, Macfarlane Burnet from Australia and Lewis Thomas from the United States, were the first to conceive of a concept that they called «cancer immunosurveillance», something to describe natural immune resistance against cancer. They predicted that certain immune cells, like T-cells, would be the major effector cells in this process. However, at the time there was actually very little available data underlying this concept. Nevertheless, it made so much sense that people in immunology and tumor biology and medicine all jumped on the cancer immunosurveillance bandwagon, perhaps in retrospect, a little bit too uncritically. Well, like all good concepts, however, it was put to the test within ten years by an individual named Osias Stutman, who really performed beautiful experiments to test the two basic tenets of cancer immunosurveillance. Those were that if you mice that were immunodeficient, those mice should develop more spontaneous cancers, and carcinogen-induced cancers, compared to their wild-type immunocompetent counterparts. And so by doing this, he in fact could not find any evidence at all that supported cancer immunosurveillance, and in fact his experiments were considered to be so critical and so convincing, that even though the groups that had jumped on the cancer immunosurveillance bandwagon jumped off again, probably just as uncritically. What this left then was the field to say was that the immune system couldn’t possibly see developing tumors. That’s a statement right out of one of my reviews from one of our early papers submitted to a journal, and from that point on, for the next twenty years, the field of immunology went on to ignore any role of the immune system in cancer development.
But things change, and one of the things that changed was the realization that the Stutman experiments (done very well, I should say) were in fact flawed, because the presumably immunodeficient mouse that was used actually had an immune system, at least a partial immune system. And so over the next twenty years or so, during that time, we and others developed the ability of going in and genetically engineering mice, or using specific antibodies against components in mice, that would completely inactivate their immune systems. We decided that it was worthwhile going back and reevaluating the statement that the immune system could never see a developing cancer. Thus, in experiments that we performed initially with Lloyd Old in New York, you can see here that what we were able to show was that when you take immunodeficient mice and immunocompetent mice and you challenge them with a cancer-causing chemical, the immunodeficient mice developed more cancers more rapidly than the wild-type mice. Immunosurveillance does in fact occur, but what we went on to show was that it was only part of the story. Any cancer that’s formed in an immunocompetent individual, that arises in that individual, that defeats the immunosurveillance process – all of this has now been qualitatively changed. It now becomes, in fact, a stronger cancer. My friend Antonio Lanzavecchia uses the adjective «fit», and we also applied it. These cancers then become more «fit» to survive in an immunocompetent host.
So the next bit of work that we and others focused on was asking the question, «Well, what does this process really entail?» The first thing we did was to realize that cancer immunosurveillance, as I’ve mentioned, was only part of the story. This was much more an editing function of the immune system –just like a writer throws out ideas, or sometimes discards and ideas. Sometimes they hold on to ideas, and shape them, and then sometimes, they eventually come out with a finished document. We called this cancer immunoediting because this was what the immune system was doing to cancer. We realized that the immune system can see developing cancer cells and destroy them, and called that elimination. We realized that sometimes cells escape elimination, but are held in a state of immune-mediated dormancy, a state that we called «equilibrium». Ultimately those tumor cells that do arise and become clinically apparent escape immune control. Therefore enter into this final stage that we call «escape» and that very much involves the productions of the molecules like CTLA-4 that you heard Dr. Allison speak about.
For the next several years, we spent a lot of our time defining the cells and molecules that participate in the cancer immunoediting process, and sometime around 2012, we and our colleagues at the institution as well as colleagues from all over –including James Allison – were able to show that we could use state-of-the-art genomics approaches, bioinformatics approaches, and immunological approaches to define the targets of the immune system in these developing cancers. And it turns out, they were antigens formed by mutations that occur in all tumors, something that James Allison had predicted many years before we were actually able to show it experimentally. Thus, this was a very important state because we understood that what cancer immunoediting did was destroy tumor cells that had these very strong mutant antigens, called «neo-antigens», leaving behind tumor cells that had weaker antigens that could nevertheless be subsequently treated with immunotherapy. The key cell in this process was in fact the T-cell.
Two years later, we adapted this whole process to establish tumors, and entered into the field of cancer immunotherapy. This paper is a turning point for our laboratory, because we now focus on how we can use our understanding of immune reactions against cancer therapeutically. This means that we basically can identify these mutant neo-antigens in tumors very rapidly, in a manner of weeks. It used to take individuals six months to a year to identify them. We’re able to show that the T-cells that are activated by the very antibodies that James Allison just spoke about, anti-PD-1 and anti-CTLA-4, prefer to react against these mutant antigens, because they’re really foreign proteins. In fact, we could then show that we could make a vaccine comprised of these foreign proteins, or pieces of these foreign proteins, and be as successful in treating at least pre-clinical mouse models of cancer as effectively as the checkpoint antibodies themselves.
This really led to a change in thinking in terms of cancer vaccines. As you know, cancer vaccines are a very old approach. As immunologists, we should be vaccinating against foreign proteins. The problem in the earlier attempts to use cancer vaccines, however, was that we were trying to target self-proteins, proteins that we are normally immunologically tolerant to, and even if we could do such a thing, our immune system might induce auto-immunity against normal cells that had those normal proteins. But using these tumor neo-antigens gives us an entirely different approach to targeting cancer, because the only cells that express these mutant antigens are the tumors themselves. Thus, we are essentially now looking at very specific responses against a protein that is quite foreign to our normal genome.
This has led to several institutions, including our own at Washington University, to establish clinical trials to try and use tumor neo-antigen vaccines to specifically target cancers in each individual based on their own mutational profile of their cancer. There are nine different cancer types that are being targeted at Washington University. Some are very easy because they have a lot of mutations, such as melanoma and small cell lung cancer, but some are very difficult, including a cancer that Dr. Allison works on, prostate cancer. Pancreatic cancer and glioblastoma are also very difficult.
And so, as a PhD, I’m sort of left now on the side, waiting and wringing my hands and hoping for the best effect of these vaccines. But we won’t be sitting here quietly doing nothing. We’re going back from the bed back to the bench side, so we’ve gone from the bench to the bedside, and now we’re going back to the bench, to understand again this process of immune responses against cancer in much more detail, and we’re doing this by performing two different kinds of high-dimensional analyses that are giving us views into the process that have never been possible in the past. This is in fact what we’re seeing here, and this is the project that we are doing with the Balzan Foundation funds. So I just would like to end here by acknowledging and certainly thanking my many past students and post-docs whom I’ve had the honour of working with for all these years, my dedicated staff that have put in years of superb work, all my mentors, my colleagues, my friends at Washington University and elsewhere for their advice, constructive criticisms, and support, and of course my family for everything. I especially wish to thank the Balzan Foundation for this truly remarkable honor. Thank you very much.