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GENERAL SCIENTIFIC SESSION 4 GENERAL SCIENTIFIC SESSION 4 Advances in Immunotherapy: Abhijit Guha Award Presentation John H. Sampson, MD, PhD, MBA Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina Correspondence: John H. Sampson, MD, PhD, MBA, Department of Neurosurgery, Duke University Medical Center, DUMC 3050, Durham, NC 27710. E-mail: [email protected] Copyright © 2016 by the Congress of Neurological Surgeons. CLINICAL NEUROSURGERY A lthough my area of expertise, the area that I have studied most, is immunotherapy, I wanted to start by taking a step back and looking a little bit at cancer in general. Despite what we know about cancer, until quite recently perhaps, we have had a very difficult time treating this disease, and it still claims the highest number of lives in the United States. When it comes right down to it, cancer is actually a very simple process. It really just involves a mutation of a gene, a very small change in something that is actually quite simple. Yet, we still have such a difficult time trying to understand how to treat this disease. When I started in the field of neuro-oncology, most people were working on chemotherapy and small-molecule inhibitors. The thought at the time was fairly simple: There was a particular pathway that would be activated by a mutation, and the activation of this pathway could be stopped by a small-molecule inhibitor or by inhibiting the particular genes and proteins downstream that this mutation was causing to be overactive or underactive, leading to autonomous cell growth. What we certainly learned very quickly is that tumors are not quite that simple and that tumors activate and inactivate genes and dysregulate cell growth in many ways. As we stopped one pathway, another would pop up, and then another and another. We really cannot stop cancer this way except in rare circumstances. Cancer is very darwinian; it does not have a plan going forward. It simply randomly mutates, and when it finds something that is advantageous, something that thwarts our best efforts at therapy, it simply uses that pathway. This unpredictability, of course, makes it very, very difficult for us to have any sort of organized approach to cancer therapy. In thinking about this, I decided to take a different approach, and 20 years ago, I went into the field of immunotherapy. I was told that it was a career-ending decision, which I did not take lightly. Yet, looking back now, I must say that I could not have timed this change better because the field of immunotherapy has become the most important area in cancer therapy. Today, and for the past couple of years now in fact, more than half of the drugs for cancer approved by the Food and Drug Administration have been immunotherapies. So, my timing was perfect, but it was not always clear which road I should travel. Many people for many years rejected the idea of immunotherapy, even though it was not a new idea. We did not understand much about the immune system, and we would typically be shunned at many scientific meetings because immunotherapy was thought to be hocus pocus or pseudoscience. Since that time, and over the past couple of decades, we have learned a tremendous amount about the immune system. We have learned that tumors actually can produce antigens that will be delivered to dendritic cells (DCs) and that we can use these antigens (proteins that are shed by tumors) to immunize patients. When we immunize patients, we can have these cells transmit the information to the lymph node, where they interact with T cells. We also learned that the tumor has innumerable ways of thwarting that response and reducing our ability to produce an effective immune response against the tumor. More recently, we have understood that this interaction between DCs, which coordinate the immune responses in our body, and T cells, which are the executors of that response, is very complex. Understanding this biology has now led to a number of therapies that I think will show a great deal of promise in our field and have already shown a great deal of promise in other cancers. I was very fortunate early in my career to have mentorship by people such as Darell Bigner and Bert Vogelstein, who, along with Albert Wong, discovered the type III epidermal growth factor receptor mutation (EGFRvIII) 2 decades ago. When I started in the field of immunotherapy, many of the proteins that were being targeted were overexpressed normal proteins, that is, proteins that were stimulating cell growth and were overexpressed by the tumor cell, causing their continued growth. These are proteins that are normal, and our immune systems have exquisite systems with multiple levels of backup to make sure we do not respond to normal proteins in our body, which protects us from autoimmunity. I also realized that if we were VOLUME 63 | NUMBER 1 | AUGUST 2016 | 85 Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited SAMPSON effective at targeting these normal proteins, we might expect that we would have a tremendous amount of toxicity, because targeting those proteins would lead to autoimmunity. As we have progressed in the field of immunotherapy, every time we have tried to target normal proteins, and we have done that successfully, it has led to autoimmunity, sometimes life-threatening autoimmunity. So, starting to focus my interest then on tumor-specific mutations seemed like a logical approach, but what was a disappointing surprise as we started to learn more about the genetics of these tumors was that most of the mutations in tumors are simply random, very incidental to the oncogenic process, and, perhaps most important, patient specific. Tumorigenesis appears to be a very darwinian approach, and every patient is different, so it became very difficult to understand how we might develop drugs that would target patients in a broad way. The EGFRvIII served as a very good example because it was fairly frequent in tumors such as glioblastoma, where it occurs in about a third of patients. It was also consistent from patient to patient, and it really was important to the oncogenic process. In the EGFRvIII, there is a deleted segment, a part that is removed from the extracellular domain. It splits the gene in a way that maintains the read frame but inserts a novel glycine and brings 2 distant parts of the protein together. This protein sequence then becomes something that is not present anywhere else in the body but is present only in the tumor. That is exactly what we would hope the immune system would be able to respond to, so we simply took that protein sequence and attached it to a nonspecific adjuvant called KLH. This drug now is known as Rindopepimut because it has been licensed to Celldex Therapeutics. The first thing that we noticed, in fact it was Amy Heimberger who noticed it, was that patients who received this vaccine, even though some of them would experience recurrence, no longer expressed EGFRvIII mutation in their tumors. Wild-type expression was maintained, however. This suggested to us that maybe we were doing something. As many of you know, single-arm phase II trials can often provide misleading results. However, if we can build evidence that we are doing something biologically, we can have more confidence that we are actually having a significant effect. The other thing we started to notice was that patients with bulky tumor masses started to have radiographic responses, which certainly was unexpected. We almost naively expected responses to occur very quickly. With immunotherapy, as has been borne out now over the long term, the responses are often quite delayed, sometimes taking 3, 6, or even 9 months, and sometimes, patients with these types of responses actually have an increase in the enhancement of their mass before it starts to shrink. This information and findings from a number of phase II trials at both Duke and MD Anderson and then across the United States showed that we were perhaps extending survival in these patients, and that led to what we call the ACT IV Trial, a large, blinded, randomized trial conducted at . 240 sites in 26 countries worldwide that recently completed accrual. In the meantime, because we had started to see some responses in patients with bulky disease, we asked whether patients with 86 | VOLUME 63 | NUMBER 1 | AUGUST 2016 recurrent tumors and bulky disease might also respond to immunotherapy. This went against the conventional wisdom that tumors were so immunosuppressive that we really could not treat bulky tumors. The ReACT Trial was developed to study this theory and was led by Dave Reardon and me. This study took patients who had not received bevacizumab and randomized them in 1-to-1 in a blinded fashion to receive bevacizumab and a control vaccine, which consisted of everything but EGFRvIII peptide, vs the study vaccine, which included the EGFRvIII peptide. We showed in those patients that we were able to see responses much more frequently, almost twice as often, in patients who received the control vaccine and that those responses were much more durable. In addition, we were able to show that patients not only could come off steroids more frequently but also could stay off steroids for a longer period of time with these vaccines. Finally, in both the intent-to-treat population (ie, any patient who was considered for vaccine) and per-protocol patient population (ie, those who received the appropriate protocol-based vaccine), we saw a statistically significant improvement in survival. This is very rarely, if ever, seen in patients with recurrent glioblastoma. One of the difficulties with the EGFRvIII vaccine, however, is that it attacks glioblastoma in only a third of patients and a particular genetic subset. More than a decade ago, Charles Cobbs identified antigens or proteins from Cytomegalovirus that appear to be present in glioblastoma tumors. To date, this remains a controversial finding, although multiple laboratories across the country have now confirmed the finding. In fact, if you ask Cytomegalovirus biologists what cells they use to grow their viruses in vitro, it turns out they use glioblastoma cells. So, there appears to be a specific tropism for this particular virus in these tumors. The IE 1 and pp65 proteins of the Cytomegalovirus are present fairly homogeneously in these tumors, but they are not present in the normal brain. This allowed us to subvert Cytomegalovirus proteins for a tumor-specific vaccination. Moreover, we knew very well how to produce immune responses against viral antigens. We did an initial study targeting this virus, and I must say that the results were not spectacular. As we would have expected, patients died at about 18 months, and they progressed usually within 6 to 12 months. This failure caused us to think about what we were not doing right. We looked at the literature and got the suggestion that if we did something at the vaccine site to precondition it, then we might be able to generate better immune responses. Taking a clue from some preclinical data from other laboratories, we decided to do something similar in our patients and randomize them to a skin preparation before vaccination with unpulsed DCs or a shot of tetanus. These were patients who were previously immune to tetanus. Our hypothesis was that this would create sort of an immunologically stimulated milieu in which our vaccine would be well received. We randomized these patients to each arm, and then we gave them Cytomegalovirus pp65 RNA–loaded DCs. Patients then underwent standard-of-care treatment. On their fourth vaccine, we radiolabeled the DCs that we gave at the vaccine site and looked at whether they migrated to the lymphoid effectively. Each patient received either the unpulsed DCs or the tetanus unilaterally and then received www.neurosurgery-online.com Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited ADVANCES IN IMMUNOTHERAPY: ABHIJIT GUHA AWARD PRESENTATION immunizations on both sides of the groin with Cytomegalovirus pp65-pulsed DCs, but they had preconditioning on only the 1 side. We saw the hot spots where we injected the vaccine and then saw where the vaccine migrated to the lymph nodes. In the patients who received preconditioning with unpulsed DCs, we saw a slight increase in the migration of the vaccinating DCs to the lymph node over what was present in the literature, but not much. However, in the patients preconditioned with tetanus, we saw a considerably improved migration of the DCs to the lymphoid, and of course, if the DCs do not make it to the lymph node, then they are not going to produce an effective immune response. We also started to notice that tumors in these patients, the ones in whom we saw better DC migration, were actually not progressing. It turned out that there was a very strong correlation between progression-free survival and overall survival and DC migration. This study was randomized. It was prospective. It was blinded. We were able to show that the progression-free survival in the patients who received tetanus was . 36.6 months and the overall survival was . 50 months. In fact, as these data have matured, half of our patients who received this vaccine have lived . 5 years with newly diagnosed, histologically confirmed glioblastoma. Unfortunately, the control patients in this study who received unpulsed DCs progressed and died, as you might expect given the typical clinical course of glioblastoma. We went to the laboratory to try to understand why this was working, because I actually thought this was a fluke. I challenged one of our graduate students, Kristen Batich, to try to understand this. The first thing we noticed quite by accident, because we did not expect this, was that when we put the DCs in both sides, even though only 1 side got the tetanus, we got an increase in the migration on both sides. This was one of those serendipitous findings that someone brought to one of our laboratory meetings, saying “Hey, I think there is a problem with the data here because we really should not be seeing migration on the contralateral side.” What we learned from that, or what we hypothesized from that, was that this must be a systemic effect. Something must be happening throughout the patient to help this migration occur and maybe help stimulate the immune responses. I think that most of the people in funding organizations would this call this a fishing expedition, but because we had serum saved from patients, we literally looked at every chemokine and cytokine known to see if there was anything that would predict the responses here. We did the same experiments in mice. Quite fortuitously, we found that the chemokine CCL3, also known as macrophage inflammatory protein-1a, was elevated not only in all the mice but also in all the humans, and nothing else was significantly elevated. We then looked at CCL3 knockout mice to see if we could reverse this effect if we knocked out this gene. We could. If CCL3 is knocked out, the enhanced DC migration completely goes away. Perhaps most important, we were later able to show that if we give CCL3 simply as a drug intravenously, we can produce the same effects that tetanus does given intradermally. Therefore, we now believe that we can use this chemokine as a drug to CLINICAL NEUROSURGERY profoundly affect immune responses throughout the host. On the basis of these data in both our patients and mouse models, along with the mechanisms studies, we were able to publish this finding in Nature recently. So, what are the current problems? Where will we fail to cure patients with this devastating disease? As I mentioned before, cancer is darwinian, and despite our attempts to vaccinate against a particular antigen, the cancer may simply discard this antigen to “adapt” to the immune response. So, unless we kill all the cells in the patient, cells will remain that have a different genetic complement, and those cells may again produce a tumor that we have to reanalyze and reapproach through immunotherapy or in combination with other therapies. One of the main problems with immunotherapy is that there can be what we call antigen escape variants, which make it difficult for us to treat patients with just vaccines alone. Recently, however, there has been an explosion in the field of a less specific immunotherapy approach: checkpoint inhibition. These are drugs, usually antibodies, that can either stimulate T cells or block interactions that typically turn T cells off. A plethora of these drugs are now coming on the market. In fact, these drugs have been approved for several cancers, even stage 4 melanoma, for which there has never been a drug that had significant efficacy. Fortunately, we have been lucky enough to study this in glioblastoma with Bristol Myers Squibb in a large, international, randomized phase 3 trial looking at the PD-1–specific antibody Nivolumab. Accrual to this trial has finished, and we should hear results soon. However, there is some concern that patients with glioblastoma may not have enough mutations for these drugs to work effectively. It is starting to be shown that the number of mutations in these cancers predisposes patients to respond to these drugs. But what about patients with medulloblastoma who have very, very few mutations? I do not think we are quite over the wall yet with all of these cancers. Finally, despite my initial comments that cancer was based on a particular mutation that we can target, the reality is that as we learn more about our genome, we find that there are a number of alterations in tumor cells that are not specific mutations in the genome. These are things like methylation or posttranslational modifications of proteins that could have very profound effects and may not be detected by the immune system. We still have a number of challenges ahead, and I look forward to every milestone in the journey as we continue the fight against glioblastoma. Disclosure John H. Sampson has held a consultant or advisory role for Celldex Therapeutics and BrainLab; reports stock ownership of Istari, honoraria from Bristol-Myers Squibb, and research funding from Celldex Therapeutics. He holds no employment or leadership positions nor has he given expert testimony that conflicts with this work. He receives funding under the Duke University Faculty Plan from license fees paid to Duke University by Celldex Therapeutics. Duke University also has the potential to receive patent-related royalties. John H. Sampson has an equity interest in Annias Therapeutics, which has optioned intellectual property from Duke related to the use of the pepCMV Vaccine in the treatment of glioblastoma multiforme. VOLUME 63 | NUMBER 1 | AUGUST 2016 | 87 Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited