“Immunotherapy in Prostate Cancer - CAR-T and the Tumor Microenvironment”

“Immunotherapy in Prostate Cancer - CAR-T and the Tumor Microenvironment” (Andrew Rech) [#63] Brad Power, Allen Morris June 28, 2023 “What is going on with the cells in prostate tumors, and what do we need to change to see better responses to immunotherapy?

” – Andrew Rech “We're using spatial biology approaches, in particular combined with other things, to try to understand some of the big axes like, ‘What's different in bone mets?’ ‘What's different in black patients?

’” – Andrew Rech Meeting Summary What can new technologies help us see about what is going on with the cells in prostate tumors, and what we need to change to see better responses to immunotherapy? Advanced cancer patients see immunotherapy (a treatment leveraging the immune system) as offering one of the best paths to a durable response.

Cancer vaccines (one immunotherapy approach) have a lot of potential because they offer a possible treatment option to nearly every cancer patient. And immunotherapy offers the promise of durable responses -- it is fighting a biological system (the cancer) with another system (the immune system), rather than the hit and miss, less durable paradigm of targeting a biomarker with a single drug.

Immunotherapy has demonstrated success in blood cancers, like leukemia and lymphoma. However, immunotherapy has had limited success in achieving durable remissions for advanced cancer patients with solid tumors. There’s one cancer vaccine approved, and it is in prostate cancer (Provenge).

It's not great for survival, but it is a shift away from chemotherapy, a little more time, and for the most part, non-toxic time. Once in a while cancer vaccines have had safe and immunogenic results. Patients need more potent T-cell-redirecting strategies.

T-cell therapies are made by collecting T-cells (a type of immune system white blood cell, also called a lymphocyte) from the patient and re-engineering them in the laboratory to produce proteins on their surface called chimeric antigen receptors, or "CARs". The CARs recognize and bind to specific proteins, or antigens, on the surface of cancer cells.

Andrew Rech, MD, PhD, Post-Doctoral Research Fellow, University of Pennsylvania, Department of Pathology and Laboratory Medicine, Laboratory of Carl H. June is uniquely qualified to talk about the current state of next-generation immunotherapies in prostate cancer and the ongoing efforts to understand and enhance engineered T-cell therapies.

He is a computational biologist, not an oncologist, a pathologist by clinical training. He studies the tumor microenvironment using new approaches in the context of CAR T-cell therapies. In this discussion Dr.

“Immunotherapy in Prostate Cancer - CAR-T and the Tumor Microenvironment” (Andrew Rech) [#63] and the latest "bedside-back-to-be

reviewed current phase I trials (tests of the safety, side effects, best dose, and timing of new treatments, the best way to give them, and how they affects the body)

“Immunotherapy in Prostate Cancer - CAR-T and the Tumor Microenvironment” (Andrew Rech) [#63] and the latest "bedside-back-to-bench" approaches (the process by which the results of research done in the laboratory are directly used to develop new ways to treat patients). What is the state of key immunotherapies, especially for treating prostate cancer?

●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?

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.

“Immunotherapy in Prostate Cancer - CAR-T and the Tumor Microenvironment” (Andrew Rech) [#63] 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.

“Immunotherapy in Prostate Cancer - CAR-T and the Tumor Microenvironment” (Andrew Rech) [#63] Meeting Notes The information and opinions expressed on this website or platform, or during discussions and presenta

e program, treatment, product or other course of action that might affect your health.

“Immunotherapy in Prostate Cancer - CAR-T and the Tumor Microenvironment” (Andrew Rech) [#63] 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 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.

“Immunotherapy in Prostate Cancer - CAR-T and the Tumor Microenvironment” (Andrew Rech) [#63] system can get y