“Update on Immunotherapies for Metastatic Castrate Resistant Prostate Cancer”

“Update on Immunotherapies for Metastatic Castrate Resistant Prostate Cancer” (Sumit Subudhi) [#66] Brad Power August 3, 2023 “When we give immunotherapies, our goal is to shift the immune tumor microenvironment in a patient's cancer, so that we're getting less of the bad ones, and more of the good ones.

” – Sumit Subudhi “The backbone of immunotherapy treatments in prostate cancer is likely going to require T-cell bispecifics.” – Sumit Subudhi “One of the major issues in prostate cancer that we haven't overcome yet, and why immunotherapies have largely failed, is because we treat it as a ‘one size fits all’.

” – Sumit Subudhi Meeting Summary Patients with advanced prostate cancer and their caregivers face a daunting challenge. Though early stage or localized prostate cancer is highly treatable, the 5-year survival rate for metastatic prostate cancer is less than 30%.

While there are many systemic treatment options (hormonal therapy, chemotherapy, vaccine, and radioligand therapy), for these patients, each treatment eventually fails. Advanced cancer patients see immunotherapy (a treatment leveraging the immune system) as offering one of the best paths to a durable response.

Immunotherapies have demonstrated success in achieving durable remissions for advanced cancer patients; however, they have had limited success in solid tumors, such as prostate cancer. There is one cancer treatment vaccine (sipuleucel-T or Provenge) approved, and it is in prostate cancer. Although it does not provide durable responses, it improves a survival benefit without much toxicity.

Immune checkpoint therapies, T-cell bispecifics, and CAR T-cells are immunotherapy strategies that have the potential of providing durable and even curative responses in patients with metastatic prostate cancer. Dr. Sumit Subudhi is uniquely qualified to describe the landscape of new treatment options available to advanced prostate cancer patients, especially immunotherapies.

He is an associate professor in the Department of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center. His research focuses on investigating the immunological mechanisms responsible for tumor rejection and clinical benefit.

He is the principal investigator of multiple immunotherapy clinical trials for patients with prostate cancer, and he conducts translational laboratory studies related to those trials. His research enables the development of novel immunotherapy strategies for the treatment of advanced prostate cancer.

He received the Prostate Cancer Foundation’s Young Investigator Award in 2014 and the V Foundation–Lloyd Family Clinical Oncology Scholar Award in 2017. Dr. Subudhi holds a BA in biology from The University of Pennsylvania and an MD and PhD from The University of Chicago. Why immunotherapy?

“Update on Immunotherapies for Metastatic Castrate Resistant Prostate Cancer” (Sumit Subudhi) [#66] We all know that the immune system can be used to

–Lloyd Family Clinical Oncology Scholar Award in 2017. Dr. Subudhi holds a BA in biology from The University of Pennsylvania and an MD and PhD from The University of Chicago. Why immunotherapy?

“Update on Immunotherapies for Metastatic Castrate Resistant Prostate Cancer” (Sumit Subudhi) [#66] We all know that the immune system can be used to fight infections, whether viral or bacterial, or even for example COVID, where many of us have been vaccinated to help fight it. With immunotherapy we're trying to manipulate the immune system to kill cancer cells.

The immune system is different from other treatment options, such as a therapy targeted at a genomic mutation, because it is a biological system that is fighting the cancer, which can lead to more durable responses, and even cures.

The immune system … ●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.

“Update on Immunotherapies for Metastatic Castrate Resistant Prostate Cancer” (Sumit Subudhi) [#66] 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

“Update on Immunotherapies for Metastatic Castrate Resistant Prostate Cancer” (Sumit Subudhi) [#66] We all know that the immune system can be used to fight infections, whether viral or bacterial, or even for example COVID, where many of us have been vaccinated to help fight it. With immunotherapy we're trying to manipulate the immune system to kill cancer cells.

The immune system is different from other treatment options, such as a therapy targeted at a genomic mutation, because it is a biological system that is fighting the cancer, which can lead to more durable responses, and even cures.

The immune system … ●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.

“Update on Immunotherapies for Metastatic Castrate Resistant Prostate Cancer” (Sumit Subudhi) [#66] 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,

t Subudhi) [#66] 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?

ing 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.

“Update on Immunotherapies for Metastatic Castrate Resistant Prostate Cancer” (Sumit Subudhi) [#66] 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.