CAR-T & Immunotherapy for Prostate Cancer: Latest Developments

•Immune checkpoint therapies : Some immune checkpoint inhibitors (e.g., ipilimumab) have shown significant response in a small group of metastatic castrate-resistant prostate cancer patients, while others (e.g., PD-1 inhibitors) have not achieved expected treatment outcomes. Identifying additional biomarkers and individualized treatment regimens are crucial for enhancing the efficacy of immune checkpoint therapy in prostate cancer.

•Bispecific T-cell engager (BiTE) therapies: Have shown promise in treating refractory blood cancers and are being explored in metastatic castrate-resistant prostate cancer. Preclinical studies show promising antitumor activity and safety for BiTEs which target Prostate-Specific Membrane Antigen (PSMA), but clinical evidence is limited. We don’t understand what the pathways are. Future directions include combining BiTE therapy with immune checkpoint inhibitors and exploring alternative tumor antigens (such as prostate stem cell antigen, and Delta-like Ligand 3). In solid tumors it is extremely difficult to find good antigens, which is a challenge for BiTEs and CAR-T therapies.

•Adoptive cell therapy, specifically CAR-T therapy : Being explored for the treatment of solid malignancies, including prostate cancer. Phase 1 clinical trial results show some tumor responsiveness, but also toxicity, and no significant survival benefit for metastatic castrate-resistant prostate cancer. Challenges to enhance CAR-T therapy efficacy in solid tumors include physical interference by cells in the tumor microenvironment (stroma), and reduced self-replication ability of CAR-T cells. Future research may support the feasibility of combining CAR-T therapy with other treatments, such as chemotherapies (e.g., docetaxel). How can a patient access CAR-T therapy? It's very early days for CAR T-cell therapy in solid tumors, and access is very limited to a handful of academic medical centers where there are open phase 1 trials. It’s early days for selecting patients who may benefit from these therapies. And patients may be concerned that the process includes pulling out T-cells right before trying to activate them, the step of killing your T-cells to then re-implant the CAR T, and needing to be in the hospital for several days to monitor side effects. What can be done to improve the tumor microenvironment for immunotherapy? There are a lot of molecular candidates in the tumor microenvironment which could be targeted, but research right now has not answered which candidates are the dominant ones which should be prioritized, which is one of the things current research is trying to figure out. There are drugs that can be repurposed today (like sorafenib, which can change macrophages from bad to good), but people don't know how to utilize these. It's not going to be perfect, which is a challenge. What’s next in tests to understand cancer and predict an individual’s response to a therapy, such as an immunotherapy? We have better technology that's been developed in the past five years, such as spatial sequencing and single cell approaches, that provide a higher level of resolution that may reveal insight that's more useful than what we have had. These technologies are being used in research labs to get a better understanding of cancer behavior through the tumor microenvironment, for example by counting cells (lymphocytes, TILs, CTL and Tregs) in the tumor microenvironment. At Penn they are using spatial biology and other technologies to try to understand questions like, “What's different in bone mets?” and “What's different in black patients?” But spatial tests are not available to individual patients to guide their treatment. A primary barrier is clinical actionability – patients have to understand what test results mean in a couple of weeks or a month; whereas researchers comb through the details for months. The largest area of combinatorial investigative research for CAR T-cells in solid tumors is modifying the many suppressive factors. There are probably two dozen approaches that are in sophisticated preclinical models, or approaching or are actively enrolling in phase 1 trials across solid tumors. We don't know what the important pathways are, or if there is even one such pathway. The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by the Cancer Patient Lab/Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action. You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health. Meeting Notes The information and opinions expressed on this website or platform, or during discussions and presenta presentations (both verbal and written) are not intended as health care recommendations or medical advice by by the Cancer Patient Lab/Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action. You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health. Discussion Outline 1.Introduction to today’s discussion. 2.Introduction to immunotherapy in prostate cancer. (2:36) 3.Immunity checkpoint therapy and anti-tumor vaccines. (8:23) 4.What are the roadblocks to the field? (13:54) 5.Introduction to CAR T-cell biology. (18:54) 6.Tumor microenvironment and metastatic prostate cancer. (25:09) 7.Tumor agnosticism and biomarkers. (30:52) 8.Tissue agnosticism and validation. (34:42) 9.What can be done to improve the tumor microenvironment? (39:18) 10.How can patients get access to spatial phenotyping? (45:31) 11.Spatial transcriptomics and the microenvironment. (51:15) 12.Tumor antigens in liquid and solid tumors. (56:15) SUMMARY KEYWORDS T-cells, prostate cancer, tumor, tumor microenvironment, patients, vaccines, cancer, immune checkpoint, understand, therapy, cells, approaches, antigen, solid tumors, car, microenvironment, work, pathways, immunotherapy, target SPEAKERS Andrew Rech (51%), Allen Morris (19%), Brad Power (16%), Robert Gurmankin (3%), Gitte Pedersen (3%), Ricardo Salgado (3%), Brian McCloskey (2%), Amit Gattani (1%) Brad Power We're honored to have Andrew Rech with us today. Our connection to Andrew was through Pete Kane. I forget where Pete originally met you, Andrew, but we were very intrigued. We're always interested in immunotherapies. I have lymphoma. There has been some success with CAR-T in lymphoma, leukemia, and blood cancers; not so much in solid cancers. But we love the idea of immunotherapies and cancer vaccines and CAR-T. We've had several sessions on cancer vaccines, with Lisa Butterfield and Willie Hoos, talking about what cancer vaccines offer as a treatment option. You're deep in the research and science side of it – the cutting edge of what's out there. So we're very intrigued to hear about it. I love the notion that if you leverage the immune system, you're having a system fight the cancer system, as opposed to finding a mutation and having a targeted therapy, which is like a specific part of the system fighting the system. It may work, but it will often work for only a short period of time; whereas an immune system can get you a really durable response. Some people have gotten cures with CAR-T. So that's the context. We're really interested in and hoping to help advance your research, and hoping that you have great success in coming up with immunotherapies for prostate cancer. Andrew Rech 2:46 Thanks for the introduction. It's really wonderful to be able to talk to all of you. I was just thinking on my way into work that through my MD PhD at Penn and residency I've talked to a lot of patients, and I've talked a lot about my research. However, I don't think I've ever talked about my research with patients ever in my career. That's probably unfortunate, and I'm happy that the pattern is changing. It's really an honor to get to talk to you. By way of background, I'm a postdoctoral fellow in Carl June's lab at Penn. I'm a computational biologist. I'm not an oncologist. I'm a pathologist by clinical training, and I study the tumor microenvironment using new approaches in the context of CAR T-cell therapies. The clinical context for my research and perspective I'll be sharing in prostate cancer is trying to understand from some of our early phase 1 trials at Penn, what is going on with the cells in prostate tumors, and what do we need to change to see better responses to immunotherapy? I'm interested in approaching that from the perspective of trying to leverage the latest technology we can with the early clinical trials to try to make sense of what's happening with these cells. The theme, as many of you know, is that despite our advancements in understanding many aspects of the immune system with respect to cancer, in many ways, we're at a complete infancy in terms of understanding in prostate tumors and other solid tumors what is actually really key and important in the tumor microenvironment. I was going to give a little bit of an introduction to immunotherapy and prostate cancer and then talk about CAR T-cell therapy, which is a form of adoptive cell therapy. I’ll talk a little bit about our work at Penn and our approaches and a little bit about my own work and perspective, and then hopefully, leave most of the time for questions in my area of expertise, which is tumor microenvironment studies in prognostics and diagnostics in this area, which is what I'm really passionate about, interested in, and what I'd love to talk about and answer questions about. I wanted to start just with a little bit of an overview in 2023 with immunotherapies in prostate cancer before I talk specifically about CAR T-cells. What is the state of immune checkpoint therapy? As many of you know, immune checkpoint therapy is a type of therapy that blocks inhibitory pathways on T-cells. And the common inhibitory pathways that have been targeted clinically and are FDA approved targets in other tumor types are CTLA-4, and components of the PD-1 pathway. The thinking behind these therapies is that you can block these inhibitory pathways on T-cells and thereby augment their anti-tumor response. In prostate cancer, anti CTLA-4 has shown responses, albeit in a small group of patients with very specific immune characteristics. And overall, with some exceptions, PD-1 inhibitors have really not achieved the outcomes that we hoped for a larger population of patients with prostate cancer. One direction for the field with respect to immune checkpoint therapy now is combination strategies. And furthermore, at a 30,000 foot view in prostate cancer, that’s what's needed and where we are. In terms of my interest in the area, it is trying to understand what it is about the minority, small percent of patients who respond to these therapies that's different about the tumor. And how can we identify those patients upfront if it's possible, and then learn from that. To summarize the lesson for CAR T-cell therapy from the immune checkpoint literature in the past decade, we really need to understand what makes patients different than tumors different with respect to immune function, and not just at the genomic level, but at the level of the tumor environment and how immune cells of the person interact with with tumor cells. Brad Power 8:02 Would you just do the basics quickly on checkpoints versus vaccines? Those are both treatments leveraging the immune system, but this is the checkpoint angle? Andrew Rech 8:14 Those are both strategies which are being investigated as cancer therapies. The idea is that for immune checkpoint therapy, these drugs work on T-cells, which already exist, and some of which may have anti-tumor function. By blocking these inhibitory pathways, the thinking is that those T-cells, which may not be functioning optimally for any one of a number of reasons or may not be effective against tumor cells, at baseline, could be made more effective by blocking these inhibitory signals. The thinking is that you have a gas pedal and you have a brake. It's very finely tuned because the immune system has this homeostasis all the time between protecting us from external threats and preventing autoimmunity at a broad level. So if you change that balance, potentially you can uncover an anti-tumor response again against tumor cells by T-cells. CTLA-4 and PD-1 were among the first immune checkpoint pathways discovered on T-cells and those were among the first translated. After a long period of time this became among the first FDA-approved immunotherapeutics in tumor types which had a very high clinical need. Vaccines take a different approach. Broadly, the idea with a vaccine is that you know something about antigens that the tumor expresses, and they could either be specific to tumor cells, because they're derived from mutations that are derived from things that are expressed by tumor cells, which are different from normal cells. Or they could just be selective in some way. That, for instance, are something called the cancer testis antigens (a category of tumor antigens with normal expression restricted to male germ cells in the testis but not in adult somatic tissues), which are these proteins, which are just not expressed everywhere in the body. In some cases, they can act like tumor antigens. In any case, if you know those things, you can design a vaccine in a manner that is broadly similar to how you would design a vaccine against a pathogen. And by administering that vaccine, the rationale is that you would uncover a T-cell response which is directed against that and act as a target on tumor cells. People have taken a lot of approaches, such as one called neoantigen vaccines. The idea behind this class of therapies is that each of us has a tumor that has different mutations because of random chance and variability. If you can sequence that tumor and understand what the mutations are that are different at a genomic level from normal cells in a given patient, you could design peptides around those differences and target tumor cells in that way. The end pathway is the same, and that both are attempting to augment the cell type that we think has so much promise for targeting tumor cells. But these are actually quite different ways. And of course, people have combined them as well. Brad Power 11:32 One common thing that everybody could relate to would be how this relates to COVID vaccines. That was mRNA. It's like a cancer vaccine, but it was going after COVID as the pathogen? Andrew Rech 11:49 I'm not familiar with any work that has looked directly at the impact of COVID vaccines or