Immunotherapy for Metastatic Prostate Cancer: Latest Updates

•Is adaptable: as the cancer transforms, a good immune system will recognize that transformation and still recognize that cancer and be able to kill it.

•Has specificity: it recognizes foreign and self.

•Has memory: you should be able to get a memory response that's durable, if not curative. That's unique relative to the other drugs for prostate cancer, where you get on average about six months to a year. How do immunotherapies fight cancer? The immune system is made of a number of kinds of cells in the tumor microenvironment. Not all of the cells in the immune system are good, i.e., kill the tumor cells. When you get immunotherapy, your goal is to shift your immune tumor microenvironment so that you’re getting more of the good immune cells, and less of the bad immune cells. Do immunotherapies work equally well for all types of cancer? CAR T cells have been more effective in blood cancers, like lymphoma, and less effective in solid tumor cancers, like prostate cancer. Some cancers, such as melanoma or lung cancer, respond better to immunotherapies (e.g., immune checkpoint therapies), while others, like prostate cancer don’t. For some cancers there are more good immune cells present (e.g., cytotoxic T-cells) or more bad immune cells present (e.g., immunosuppressive myeloid cells). If you have metastatic castration-resistant prostate cancer, your chance of having bone metastases are somewhere between 70% to 80%. Immunotherapies have struggled to work on bone metastases. What are the current approaches to increase T-cells in the tumor microenvironment?

•Vaccines, e.g., Sipuleucel-T (Provenge)

•Immune checkpoint inhibitors, e.g., anti-CTLA-4 (Ipilimumab)

•CAR (chimeric antigen receptor) T-cells, e.g., targeted at PSMA (prostate-specific membrane antigen)

•T-cell bispecifics, e.g., PSMAxCD3 These therapies should be considered in combinations with other therapies. What are the promising future approaches to immunotherapies?

•T-cell bispecifics: The backbone of immunotherapy treatments in prostate cancer will likely be T-cell bispecifics. One arm recognizes the T-cell, es for Metastatic Castrate Resistant Prostate Cancer” These therapies should be considered in combinations with other therapies. What are the promising future approaches to immunotherapies?

•T-cell bispecifics: The backbone of immunotherapy treatments in prostate cancer will likely be T-cell bispecifics. One arm recognizes the T-cell, and the other arm recognizes the cancer. It can bring the T-cell directly into the cancer. In addition to PSMA (prostate- specific membrane antigen), other targets to latch onto which are being looked at in prostate cancer and have gotten the most attention are STEAP (six-transmembrane epithelial antigen of the prostate, a prostate-specific cell-surface antigen highly expressed in prostate tumors), TROP2 (Trophoblast cell-surface antigen 2, correlated with poor clinical outcomes and highly expressed in metastatic, treatment-resistant prostate cancer), and B7-H3 (also known as CD276, a member of the B7 family of immune checkpoint proteins, a cell surface immunomodulatory glycoprotein overexpressed in prostate cancers).

•Myeloid cells: There is research into drugs that can transform bad immunosuppressive (myeloid) cells into good ones, and manipulate the ratio, so you have more good than bad.

•Biomarkers predictive of responses: We need to do a better job of identifying the subsets of patients who will likely respond to treatments. There is too much “one size fits all” today. Fortunately there are emerging tests (e.g., from BostonGene) utilizing whole exome sequencing (WES) and bulk RNA-sequencing (RNA-seq), which show your tumor mutational burden, “microsatellite instability”, and mutational and immune landscapes. You can be immune-rich non-fibrotic, immune-rich fibrotic, or have an immunological desert. The efficacy of immunotherapy may be limited if you have highly fibrotic cancer, and if you have immune-rich, non-fibrotic cancer, you are more likely to respond (across all tumor types). Microsatellite instability also provides guidance. If you are “MSI high”, microsatellite instability high, that means that there are regions of your repeated DNA that have changed in length – show instability – and your mismatch repair is not working properly. If your test shows you are immune-rich fibrotic, you are not likely to respond to anti-PD-1 (e.g., pembrolizumab [Keytruda]), and you should consider a combination trial. Taking Keytruda alone, if it fails, may eliminate you from other trials, because a lot of these trials for novel immunotherapies exclude you if you have had prior immunotherapies, with the exception of Provenge. Furthermore, BostonGene have analyses looking deeper than “bulk RNA-seq” to “single-cell RNA-seq”. Understanding the spatial relationships of where the various immune cells are within the tumor microenvironment is important. What if the T-cells are in the margin of the tumor and not in the center of the tumor? Testing companies which have the infrastructure and money are decreasing the bioinformatics analysis time from six months to four weeks, and the costs are going down.

•Immunotherapy combinations : For prostate cancer, the backbone most likely will be a T-cell bispecific. Then, depending on what the resistance mechanism is, you probably have to add an immune checkpoint therapy. In addition, because prostate cancer has a lot of myeloid cells in it, you probably also need a drug targeting immunosuppressive myeloid cells (e.g., agents targeting the adenosine pathway).

•Adaptive design trials for immunotherapy combinations : Adaptive design trials allow modifications to a trial after its initiation, without undermining its validity and integrity, to make it more flexible, efficient, and fast. For example, an adaptive design trial for immunotherapy combinations could start off with everyone getting PD-1. The responders would keep on PD-1, and the non-responders would start adding things, e.g., a vaccine. Then you could start identifying who actually needs more therapies in combination and who doesn't.

•Combining radiation therapies with immunotherapies : There is research into figuring out the ideal radiation dose, and which of the radiation therapies (proton, SBRT, or EBRT) are ideal for promoting the immune system. For example, some researchers believe that a lower dose of radiation will leave behind some of the cancer cells but also some of the good immune cells, which can then be combined with immunotherapies to get a better response.

•CTLA-4 inhibitors : Most immune checkpoint inhibitor attention goes to PD-1/PD-L1 inhibitors, like pembrolizumab (Keytruda). Using a similar mechanism, ipilimumab (Yervoy) binds to another protein expressed on T-cells, CTLA-4, blocking its inhibitory signal on T-cells, which allows the T-cells to destroy the cancer cells. In 2014, a study indicated that the antibody works by allowing the patients' T-cells to target a greater variety of tumor antigens, rather than by increasing the number T-cells attacking a single antigen. Now that ipilimumab and tremelimumab are off patent, a new generation of CTLA-4 inhibitors are being developed, because CTLA-4 inhibitors have the ability to drive T-cells into a cold tumor and also cause antigen spread. In addition, some of the patients who have responded to PD-1 have responded because of previous failures from anti-CTLA-4. There are indications that anti-CTLA-4 drugs modulate the tumor microenvironment so that in the future anti-PD-1 can be effective. 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 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 presentations (both verbal and written) are not intended as health care recommendations or medical advice by 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 Dr. Subudhi. (0:02) 2.Not all immune cells are good for prostate cancer. (6:13) 3.Biospecifics and how they work. (12:33) 4.Oncogene-driven transformation. (19:51) 5.What’s the next effective therapy for patients who are not responding? (24:35) 6.Hormonal ablation vs. High androgen therapy. (28:13) 7.Where do you find the most effective use of provenge? (35:04) 8.Optimal time to pursue BiTEs (Bispecific T-Cell Engagers). (40:01) 9.Prostate cancer and immunotherapy. (46:42) 10.Tumor microenvironment and immunotherapy. (53:07) 11.Is anti-CTLA-4 making a comeback? (59:00) 12.TLR agonists to boost immune response in prostate cancer. (1:06:44) SUMMARY KEYWORDS prostate cancer, patients, cancer, immunotherapies, T-cells, question, tumor, talking, vaccine, therapy, showed, respond, immune system, data, psm, specific, trial, ablation, targets, lung cancer SPEAKERS Sumit Subudhi (73%), Ricardo Salgado (5%), Rick Stanton (5%), Jonathan Starr (4%), Gitte Pedersen (3%), Brad Power (3%), Brian McCloskey (3%), Rick Davis (1%), Robert Gurmankin (1%), Russ Hollyer (1%) Meeting