Tumor Immunology: A Primer

Transcription

1 Transcript Details This is a transcript of a continuing medical education (CME) activity accessible on the ReachMD network. Additional media formats for the activity and full activity details (including sponsor and supporter, disclosures, and instructions for claiming credit) are available by visiting: Released: 02/10/2016 Valid until: 02/10/2017 Time needed to complete: 15 Minutes ReachMD info@reachmd.com (866) Tumor Immunology: A Primer Welcome to Project Oncology on ReachMD. This segment, entitled Tumor Immunology, is provided by Prova Education. Prior to beginning the activity, please be sure to review the faculty and commercial support disclosure statements as well as the Learning Objectives. Or if you re listening to this as a podcast, go to this activity on ReachMD.com forward slash Project Oncology. Dr. Kaufman: Hello, I m Dr. Howard Kaufman, and I m talking to you from the Rutgers Cancer Institute of New Jersey, in New Brunswick, New Jersey, where I am Chief Surgical Officer and Associate Director for Clinical Science, as well as a professor in the Department of Surgery. Today we will be discussing some of the concepts of tumor immunology and immunotherapy including 2018 ReachMD Page 1 of 7

2 the cancer immunity cycle, the tumor micro-environment, how to target the immune system for treating cancer, some of the major approaches to cancer immunotherapy, as well as some of the limitations of these approaches. So, to begin with, there has been recent publication suggesting that the way that the body immune system can recognize cancer can be nicely summarized by what s been termed the cancer immunity cycle. And in this cycle, the way that the immune system is alerted is that cancer cells, in part because of their genetic heterogeneity, will produce a number of mutated proteins and abnormal peptides that can then get released and picked up by peripheral antigen presenting cells such as dendritic cells. These dendritic cells can circulate to nearby secondary lymphoid tissue such as lymph nodes where they come in contact with B and T cells and can activate these cells in order to recognize tumor antigens. Under the influence of chemokines, these T and B cells can then traffic back to the tumor micro-environment where they can recognize the tumor antigen and then mediate direct lytic destruction of the tumor cells. Now, while we understand that many components of this process do operate in hosts with cancer, it s become increasingly clear over the past decade that the tumor microenvironment contains a number of suppressive mechanisms that tend to block this activity. This can be soluble factors that may be produced by the tumor or tumor stroma, such as cytokines like interleukin- 10, TGF beta, and VEGF or vascular endothelial growth factor, and it can also be a number of cell factors that have suppressor activity including myeloid-derived suppressor cells and regulatory T cells. Nonetheless, it s become clear in the clinic that those patients whose tumors are associated with a large number of infiltrating lymphocytes, predominantly T cells, will in fact have a better prognosis and this has been shown in a variety of cancers including ovarian cancer, colorectal cancer, lung cancer, and melanoma. Based on these findings, it s been clear that if one can actually increase the number of activated effector T cells in the micro-environment and limit the suppressive activities, one can actually take advantage of the cancer immunity system by targeting various aspects of this to improve the immune response and limit the amount of immune suppression. And this has actually led to a number of approaches to cancer immunotherapy that are now in the clinic. I d like to divide these approaches into three general categories. The first are using cytokines and, in fact, several cytokines have already achieved FDA approval for the treatment of cancer, including interferon-alfa which is approved for treating melanoma and renal cell carcinoma as well as hairy cell leukemia, and interleukin-2 which is FDA-approved for the treatment of melanoma and renal cell carcinoma. The second big advance in the field has been the use of what is termed T cell checkpoint inhibitors. And these are generally monoclonal antibodies that are used to block the co-inhibitory or off-signals that are present on the surface of T cells, and several of these are already approved in the clinic including ipilimumab which targets the cytotoxic T lymphocyte antigen 4 or CTLA-4. There are 2018 ReachMD Page 2 of 7

3 two FDA-approved agents that target the programmed cell death-1 receptor or PD-1. These are pembrolizumab and nivolumab which are now approved for the treatment of melanoma, renal cell carcinoma, and non-small cell lung cancer, and there is a lot of interest in using monoclonal antibodies that are targeting the program cell death ligand 1 or PD-L1. Other interesting strategies in development include the oncolytic viruses and, in fact, the first FDA-approval of an oncolytic herpes virus was achieved in October of 2015 for the treatment of melanoma. And I also want to discuss today adoptive T Cell therapy and vaccine therapy, as these have been very high priorities in the field. So, first let s talk about the cytokines. Interleukin-2 is a pleiotropic cytokine that has many effects on the immune system. In general, IL-2 acts as a proliferative signal for T cells and B cells and while this is potentially good for activating and expanding effector T cells that can fight tumors, one of the problems with interleukin-2 is that it may also expand the regulatory cells that can suppress immune responses. At present, it is unclear to us why interleukin-2 is effective in some patients but, nonetheless, we have shown that IL-2 can preferentially expand effector cells over regulatory T cells in some patients and this can lead to durable responses. Over the last 20 years it has become clear that interleukin-2 can induce durable objective responses in approximately 15 to 20% of patients with both melanoma and renal cell cancer, and in many cases partial responses can be durable for many years. Long-term followup of IL-2 patients have shown that those patients who achieve a complete response are highly likely to remain in response 15 to 20 years later. In fact, close to 90% of patients in complete response will remain there for 20 years. The biggest advance in the field of immunotherapy has been the targeting of co-stimulatory and coinhibitory molecules that influence the ability of T cells to maintain anti-tumor activity, and just to quickly review how these cells work, the activation of T cells depend on two signals. The first is the T-cell receptor recognizing a peptide bound to MHC class I molecules on an antigen-presenting cell. If that is the only interaction that occurs, the T cell will often undergo apoptosis or become anergized in a way to protect the body from having T cells activated against self-proteins. However, when CD28, a costimulatory molecule is activated by its ligands CD80 or 86 on antigen-presenting cells, the T cell will actually undergo a proliferative activity, it will differentiate into its effector functions, and will start producing cytokines such as interleukin-2 that help to further expand these T cells into activated effector cells. These T cells can then go and actually recognize tumor antigens and eliminate tumor cells. Shortly after the activation of these T cells; however, a molecule called CTLA-4 is mobilized to the surface and it will bind to CD80 and 86 with higher affinity than CD28 and this will deliver an inhibitory signal and cause the T cell to undergo cell cycle arrest. This is a process in which the T cell can undergo homeostatic regulation and not become too overly active. The problem in cancer is that you want the T cells to be maintained for a longer period of time, and this process may actually start 2018 ReachMD Page 3 of 7

4 eliminating tumor fighting T cells. An antibody that blocks the interaction of CTLA-4 with the CD80 and 86 has been developed, and this allows T cells to remain active for a longer period of time. This antibody, called ipilimumab, was studied in a clinical trial in which patients with advanced melanoma were treated with the ipilimumab alone or in combination with a gp100 peptide vaccine, and compared to patients who had the peptide vaccine alone. The result of this trial showed an improvement in overall survival for patients who had ipilimumab, whether alone or with the vaccine, compared to patients who had the vaccine alone. Interestingly in this study, progression-free survival was not seen and this was due to the kinetics of response which can be quite slow with ipilimumab, an important point in taking care of patients who are being treated with ipilimumab. Long-term data has now become available with up to 5 years of followup suggesting that close to 21% of patients who achieve a good response with ipilimumab may still be alive, without disease progression, up to 5 years later. This suggests that, like other immunotherapies, this treatment is associated with durable long-term responses. In addition to CTLA-4, another immune checkpoint has been called the program cell death 1, or PD-1. PD-1 has long been recognized by immunologists as a marker of T cell exhaustion and when PD-1 binds to its ligand, called PD-L1, the T cell will be eliminated from the body. And, perhaps, it was a surprise that cancer cells often will express PD-L1 and this is possibly a mechanism by which tumor cells can eliminate potential T cells and reduce them as a threat to their ongoing existence for the cancer cell. And so, a number of monoclonal antibodies have been developed that bind to PD-1 or PD- L1 and prevent this interaction and again will allow T cells to remain active for a longer period of time. And in this figure, we re simply showing that PD-L1 is being expressed widely by melanoma cells, and there are now up to 15 other types of cancer which have been shown to express PD-L1 at high levels and clinical trials are underway in many of these types of cancer. Some of the earliest work was done with a PD-1 directed antibody called pembrolizumab in patients with melanoma, and the initial reports suggested really quite dramatic effects with the vast majority of patients exhibiting tumor regression and many of the regressions were associated with very long-term durable responses. Another anti- PD-1 monoclonal antibody called nivolumab has also been developed and has been approved, and recently there have been studies in which these antibodies have been combined. And, in fact, an early Phase I study which combined nivolumab and ipilimumab together, suggested close to a 70% response rate with many of these responses being quite durable and quite profound. This has now been replicated in the Phase III setting which led to FDA approval of this combination for the treatment of patients with advanced melanoma. An important part of these studies was the suggestion that patients whose tumors expressed high levels of PD-L1 may be more likely to respond to these therapies. Although this has not been completely validated, a number of clinical trials have reported this outcome and many oncologists do recommend looking at PD-L1 expression as a potential biomarker for identifying patients more likely to respond to these therapies. Interestingly, in the combination study of 2018 ReachMD Page 4 of 7

5 nivolumab and ipilimumab, the presence of PD-L1 expression did not seem to make any difference, and so it s been suggested that perhaps patients who lack PD-L1 expression may be better enrolled in combination treatment regimens rather than monotherapy agents. As I mentioned, PD-L1 is expressed in a large number of tumors and while the PD-1 and PD-L1 axis is under intense investigation and has already achieved FDA approval in a number of cancers, many others are in clinical development and we anxiously await the results of these pivotal studies. So, I want to finish up by talking about some of the more novel therapies that are out there now which target the immune system. So, one of the more interesting is the use of adoptive T cells, and the basic premise of this approach is that if the T cells have been suppressed in the patient with cancer, if you can take them out of the body, you may be able to either reinvigorate them, or genetically engineer them to have a stronger cancer-fighting activity, and then they can be reintroduced into the patient, either alone or in combination with some other immunotherapies. And, in fact, this approach has achieved some initial exciting results in clinical studies. One of the important genetic approaches has been to use what are called chimeric antigen receptors. These are basically antibody-like molecules that can be genetically engineered into T cells once taken out of the patient s body, and so that the receptor region of the antibody can actually recognize any particular tumor antigen, for example, CD19 in patients who have CD19-expressing B-cell leukemias or lymphomas. And then the tail-end of these receptors can include the various T cell receptor signaling molecules such as CD3 zeta or they can include a number of co-stimulatory molecules to help further activate these T cells. Sometimes these have been referred to as first, second, and third generation receptors, based on the number of additional co-stimulatory signaling pathways that are included in the product. Clinically, these have been associated with sometimes quite dramatic responses and here is a patient who has a very large tumor 7 days before receiving adoptive T cell transfer, and then you can see that within 3 weeks of therapy the entire tumor has become necrotic, and within 2 months of treatment the tumor is completely demarcated from the patient, and this patient went on to have a complete response to this therapy. Further research is needed to study this in a prospective manner to determine the full potential for adoptive cell therapies. Oncolytic virus immunotherapy is a different approach which utilizes either live or genetically-modified viruses to fight cancer and it does this through a dual mechanism of action. First, oncolytic viruses are preferentially able to replicate in cancer cells and generally do not replicate or cause disease in normal cells. By killing the cancer cell in the context of a viral infection, the cancer cell will release a number of both pathogen-associated and danger-associated molecular patterns that help to stimulate a strong 2018 ReachMD Page 5 of 7

6 innate immune response. The dying cancer cell can then be taken up by antigen-presenting cells and this can ultimately lead to an adaptive immune response which can really help to develop long-term memory and antitumor effects. One such approach has utilized a herpes simplex virus type 1 that has been genetically modified by deleting the neurovirulence factors so that the virus is no longer pathogenic and including a gene encoding the cytokine GMCSF. This virus has been called talimogene laherparepvec or T-VEC for short, and has the brand name of Imlygic. The talimogene laherparepvec is administered in the office. Patients come in and have the tumor size measured, so this has to be cutaneous or subcutaneous tumors that can be clinically assessed or imaged by ultrasound, and the virus is simply administered in a 4-quadrant injection to the tumor and the site is then covered with a dry gauze and a Tegaderm dressing. In a randomized Phase III clinical trial, with the durable responses, the primary endpoint T-VEC treatment was associated with a significant improvement in durable response of 16.3% compared to 2% in the control group. The T-VEC treatment was also associated with a significant improvement in objective response rate of 26.4% compared to 5.7% for the control. Interestingly, close to 11% of patients also had a complete response, meaning that both injected lesions and un-injected lesions completely responded, suggesting that these patients had an immune response. Based on this study, a clinical trial in which the T-VEC is being combined with the ipilimumab has been started and the early results of the Phase Ib study were recently reported and showed a 50% response rate with a 22% complete response rate, with many patients developing quite rapid responses. Importantly, the side effects associated with the oncolytic virus therapy have generally been very well tolerated and have included a low-grade fever and chills and some injection site reaction. So, in conclusion, it s very clear that the immune system can recognize both foreign pathogens as well as cancer cells, tumor surveillance appears to be a normal function of the immune system, and the cancer immunity cycle is a way in which we can demonstrate that cancer cells can ultimately be recognized by the immune system and eradicated through pharmacologic manipulation. Several approaches to immunotherapy are currently in the clinic. These include cytokines, T cell checkpoint inhibitors, and oncolytic viruses. Many other therapies including adoptive T cell therapy and combination approaches are under intense clinical investigation. While much of this work has started in diseases such as melanoma and renal cell carcinoma, the impact of tumor immunotherapy is thought to be likely to extend to many other types of cancer and the recent FDA approvals, in non-small cell lung cancer, in particular, really highlight the ultimate impact that this approach may have for patients with cancer. Thank you for your attention. Again, this is Dr. Howard Kaufman at the Cancer Institute of New Jersey ReachMD Page 6 of 7

7 ANNOUNCER CLOSE: You have been listening to Project Oncology on ReachMD. To earn your CME credit, please take the post-test and activity evaluation. Or if you re listening to this as a podcast, go to ReachMD.com forward slash Project Oncology ReachMD Page 7 of 7