Immunotherapy for Solid Tumors: CAR T-Cell & BiTEs Update
Featuring: Saul Priceman, PhD, Brad Power, Kayla Yup
In short
Immunologist Saul Priceman, PhD, explains how two cutting-edge immune treatments — CAR-T cells and bispecific T cell engagers (BiTEs) — are being tested against solid tumors like prostate, breast, ovarian, and pancreatic cancer. He walks through why solid tumors are harder to treat than blood cancers, what early clinical trial results look like, and what patients can access today versus what is still in development. This is most useful for patients with advanced solid tumors who want to understand immune-based treatment options beyond standard chemotherapy.
- •Ask your oncologist whether any BiTE or CAR-T clinical trials are open at your center — BiTEs like AMG 509 (targeting STEAP1 in prostate cancer) are in trials now, and about 30% of participants saw PSA drop 90% or more.
- •The only FDA-approved cancer vaccine for a solid tumor right now is Sipuleucel-T (Provenge), and it is for prostate cancer — ask if you qualify.
- •Check clinicaltrials.gov for the most current status of CAR-T trials, since enrollment opens and closes frequently.
- •If your tumor has been described as 'cold' (not responding to immunotherapy), ask your doctor about combination approaches being studied to make cold tumors more responsive — this is an active area of research.
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Update on Immunotherapies (CARs and BiTEs) for Solid Tumors” (Saul Priceman, PhD) [ #117] Brad Power and Kayla Yup October 23, 2024 “Every institution under the sun, but certainly in the United States, should be doing cellular immunotherapy, whether it's CAR-T cell therapy or other immunotherapy approaches, because I do believe that rewiring the immune system probably has a hand in every single human disease, and certainly in cancer.
Meeting Summary
Advanced cancer patients see immunotherapy (a treatment leveraging the immune system) as offering one of the best paths to a durable response. Cellular immunotherapies have demonstrated success in achieving durable remissions for advanced cancer patients in blood cancers; however, they have had limited success in solid tumors, such as prostate, pancreatic, or breast cancer.
There is one cancer vaccine approved, and it is in prostate cancer (Provenge). Supplementing a patient’s immune response by engineering their killer white blood cells to recognize, bind to, and eliminate the tumor is a new and transformational area of cancer immunotherapy.
•T cell bispecifics: antibodies (proteins that help the body's immune system identify and destroy harmful substances like bacteria and viruses) that physically link T cells (white blood cells in the immune system which kill foreign cells) with cancer cells
•TILs (tumor-infiltrating lymphocytes) : white blood cells that are extracted from a patient's tumor and used to treat cancer
•TCR (T-cell receptors) T cells : protein complexes on the surface of T cells that recognize antigens and trigger immune responses
•CAR (chimeric antigen receptor) T cells : T cells (white blood cells) that have been genetically modified to express a synthetic receptor that enables them to better identify and kill tumor cells Saul Priceman, PhD, is the Founding Director of KSOM/NCCC Center for Cancer Cellular Immunotherapy Research at the University of Southern California. He is uniquely qualified to describe the landscape of new immunotherapy treatment options available to cancer patients with solid tumors. He is a scientist with a strong understanding of cancer biology and tumor immunology for the preclinical/clinical development of novel cancer immunotherapies, with over 15 years of in-depth knowledge of molecular and cellular biology related to cancer and inflammation/autoimmune research, with a strong focus on metastatic disease in prostate, breast, and ovarian cancer. His current laboratory research focuses on clinically relevant metastatic cancer models to develop combination therapy strategies to improve the durability “Update on Immunotherapies (CARs and BiTEs) for Solid Tumors” (Saul Priceman, PhD) [ #117] and potency of CAR-T cells, and ultimately the overall immunotherapy response in solid tumors. He received a B.S. in microbiology from UCSB and a PhD in Molecular and Medical Pharmacology from UCLA. How does your immune system fight cancer? The immune system has evolved to protect us from pathogens such as bacteria, viruses, and fungus. When an infection arises, the immune response is triggered, all of the infection is eliminated, and then the immune response goes back down. But a memory of the infection persists, and you get a healthy memory cell, so that if you see that pathogen again, it can react quickly. What are the challenges in leveraging the immune system to fight solid tumors?
•Immune system exhaustion : The immune system can get tired of fighting cancer if it sees the tumor too much. If the tumor doesn't completely go away early in the process, the immune cells become exhausted, and are just not as functional. They may need to be reactivated.
•Tumor heterogeneity and evolution : We go after a target which is uniquely on the cancer cell (e.g., PSMA or PSCA in prostate cancer), but the target has to be expressed on 100% of the cancer cells to get a complete response, but they aren’t. There's heterogeneity, or a mosaic of cell types that make up the cancer cells. So we get less than a 100% response. Some of the cancer cells without the target survive.
•Hiding: The immune system never saw the tumor in the first place, because tumors can be clever, able to block recognition by the immune system. How do immunotherapies work to treat cancer? Immunotherapies (a treatment leveraging your immune system) offer one of the best paths to a durable response -- they are fighting a biological system (your cancer) with another system (your immune system), rather than the hit-and-miss, less durable approach of targeting a biomarker with a single drug or poisoning your cancer with chemotherapy. The idea is to try to find what's different about the tumor that is allowing it to avoid the immune system. Sometimes the tumor turns things back on that are generally turned off in people, sometimes it turns up the volume on things that are generally turned down. So if you can find these reactivated genes, you can perhaps get the immune system to recognize them and attack them. But the immune system doesn't usually recognize them without a vaccine because a successful tumor shields itself from t the immune system by being a terrible antigen-presenting cell. Immunotherapies offer a treatment option to nearly every cancer patient because they are neither targeted to a specific “tissue of origin”, like lung cancer or colon cancer, nor are they targeted to a biomarker, a protein that your cancer cells overexpress, like BRCA or EGFR. What is happening at the cutting edge of immunotherapy approaches in solid tumors? “Bispecific T cell engagers” and “CAR-T cells” are two types of immunotherapies currently being tested against solid tumors. “Update on Immunotherapies (CARs and BiTEs) for Solid Tumors” (Saul Priceman, PhD) [ #117]
•Bispecific T cell engagers (BiTEs) : antibodies (proteins that help the body's immune system identify and destroy harmful substances like bacteria and viruses) that physically link T cells (white blood cells in the immune system which kill foreign cells) with cancer cells. The idea is that this linkage will trigger the activation of T cells and induce targeted killing of the tumor cells. There are currently over three BiTEs being pursued for treatment of prostate cancer. For example, AMG 160, a BiTE that targets Prostate- Specific Membrane Antigen (PSMA, a receptor that is uniquely on prostate cancer cells), was found to elicit a robust response rate with limitations related to toxicities and anti- drug antibodies in a Phase I clinical trial. AMG 509, a BiTE targeting STEAP1 (six- transmembrane epithelial antigen of prostate 1, is a protein that is overexpressed in many types of cancer, such as prostate cancer, and is a promising target for cancer therapy because it is specific to cancer cells and on the membrane), showed better efficacy and less toxicity in phase 1 (safety) studies, and will likely proceed to phase 3 (efficacy studies). Next generation PSMA bispecifics are also being tested.
•CAR-T cells: T cells (white blood cells) that have been genetically modified to express a synthetic receptor that enables them to better identify and kill tumor cells. There are various CAR T cell therapies being developed to target PSMA and PSCA (Prostate Stem Cell Antigen, another receptor uniquely on the surface of cancer cells) in prostate cancer. Dr. Priceman published a list of some clinical trials currently testing these therapies. His lab at City of Hope is working on CAR T cell therapies for four cancers in particular: prostate, breast-to-brain metastasis (which is breast cancer that has spread to the brain), ovarian cancer, and pancreatic cancer. What can you access today?
•Sipuleucel-T (also known as Provenge) is FDA approved for prostate cancer.
•Bispecific T cell engagers for prostate cancer, which are in clinical trials. (For example, AMG509: targets STEAP1 in a clinical trial.) About 30% of patients had their PSA (a blood measure of prostate cancer strength) drop 90% or more. Most patients had a PSA reduction of 50%, which is striking. In coming years, the toxicities will be better managed, and this trial indicates that “cold” solid tumors (those that usually don’t respond to immunotherapy) can respond.
•CAR-T cell therapies for prostate cancer, which are being tested in clinical trials. (Note: some trials on Dr. Priceman’s list may no longer be actively recruiting or may have been terminated, need to check https://clinicaltrials.gov for the latest.)
•Combinations of immune checkpoint blocking antibodies (in clinical trials). (See for example the slide titled: Select ongoing checkpoint inhibitor trials in mCRPC.) What will be available soon?
•Other BiTEs
•A faster CAR-T manufacturing process: “vein-to-vein” (blood extraction through engineering and reinfusion) will go from about six weeks to a week or two. “Update on Immunotherapies (CARs and BiTEs) for Solid Tumors” (Saul Priceman, PhD) [ #117]
•“Allogeneic” vs. “autologous” CAR-T: make CAR-T cells from a healthy person and treat dozens of people (vein-to-vein time of zero) vs. using the patient’s T cells What is being researched for the future?
•Distinguishing characteristics between cancers that are immunologically “hot” (will respond to immunotherapy) and those that are “cold” (manage to hide from the immune system)
•Combining therapies to turn “cold” cancers “hot” in solid tumors (will respond to immunotherapy), such as pancreatic cancer
•Tests to predict whether a patient will respond to an immunotherapy How can I learn more about immunotherapies for solid tumors?
•See our discussion with Dr. Sumit Subudhi on “Update on Immunotherapies for Metastatic Castrate Resistant Prostate Cancer”
•Lisa Butterfield on cancer vaccines here
•Willy Hoos on personalized neoantigen vaccines here
•Gary Onik on personalized in vivo immunotherapy for “cold” cancers here
•BostonGene on predicting immunotherapy response with a diagnostic test here
•Matthew Dons on growing your white blood cells here
•Contact Dr. Priceman to further explore the use of AI and machine learning in predicting patient response to CAR-T-cell therapy and on making "cold" tumors more responsive to immunotherapies at priceman@usc.edu 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, 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. “Update on Immunotherapies (CARs and BiTEs) for Solid Tumors” (Saul Priceman, PhD) [ #117] Meeting Notes KEYWORDS CAR-T cells, cancer immunotherapy, solid tumors, prostate cancer, cellular immunotherapy, USC, City of Hope, immune checkpoint blocking, bi-specific T cell engagers, PSMA, PSCA, clinical trials, AI in cancer, patient response prediction, adoptive cell therapy SPEAKERS Saul Priceman (76%), Brian McCloskey (13%), Robb Owen (7%), Rick Davis (2%), Roger Royse (2%) CHAT CONTRIBUTORS Rick Davis, Robb Owen, Alane Watkins, David Plunkett, Alexander Lalov, Steven Merlin, Chris Apfel, Roger Royse, Brian McCloskey SUMMARY Brian McCloskey introduced Dr. Saul Priceman, highlighting his expertise in CAR-T cell therapy. Dr. Priceman detailed the evolution of CAR-T cells, their effectiveness in hematologic malignancies, and challenges in solid tumors. He discussed the importance of identifying immunologically cold tumors and the potential of bi-specific T cell engagers. Dr. Priceman shared success stories, including a glioblastoma patient with dramatic responses and a prostate cancer patient with significant PSA reductions. He emphasized the need for better predictive models to identify responding patients and the potential of AI in enhancing immunotherapy efficacy. The session concluded with a Q&A addressing various aspects of CAR-T cell therapy and its applications. OUTLINE Introductions
•Dr. Saul Priceman has expertise in CAR-T.
•He has recently moved to USC.
•He worked previously at City of Hope.
•He has a vision for expanding cellular immunotherapy at USC. Overview of Cancer and Immune System
•The immune system can be rewired to treat various diseases, especially cancer.
•Cancer is complex. It is a mosaic of different cell types.
•Cytotoxic T cells have a role in identifying and killing cancer cells.
•Tumors can be immunologically cold or warm, e.g., in prostate cancer and melanoma. CAR-T Cells and Bi-Specific T Cell Engagers “Update on Immunotherapies (CARs and BiTEs) for Solid Tumors” (Saul Priceman, PhD) [ #117]
•Current immunotherapies, such as CAR-T cells and bi-specific T cell engagers, have limitations and big potential.
•CAR-T cells have a role in targeting cancer markers.
•The clinical data and FDA approvals for CAR-T cells in hematologic malignancies show the potential.
•CAR-T cells, bi-specific T cell engagers, and antibody-drug conjugates are different in terms of efficacy and durability. Challenges and Future Directions
•There have been challenges and successes in applying CAR-T cells to solid tumors, with glioblastoma and gastric cancer as examples.
•The challenges of applying CAR-T cells to solid tumors include the tumor microenvironment and antigen heterogeneity.
•Dr. Priceman’s lab works on PSCA-directed CAR-T cells for prostate cancer, including animal studies and clinical trials.
•Multi-targeted approaches have big potential.
•There are ongoing trials and collaborations at USC and other institutions to advance cellular immunotherapy. “Update on Immunotherapies (CARs and BiTEs) for Solid Tumors” (Saul Priceman, PhD) [ #117]
Full transcript
Brian McCloskey 0:00 I'm a co-founder of the Cancer Patient Lab. We're very honored today to have Saul Priceman join us. Before I get into an introduction to him, I wanted to remind folks of a few things regarding this session. First off, this is not medical advice, so please make sure to consult your physician before you take any action on any information that you would learn today.
We are a nonprofit, and so all of our expenses are paid for through the great support of our community. If you'd like to join or if you'd like to donate, please go to our website and hit the donate button and you can make a donation there. I am super excited to have Dr. Saul Priceman join us today.
I've known Saul now for probably four years or so when we met in DC at a convention, and Saul has been very helpful in my journey as a prostate cancer patient. I'm happy that he's here. For many years, he was driving the CAR-T development at the City of Hope, and just in September, Saul became the founding director of the Keck School of Medicine and Norris Cancer Center, cancer cellular immunotherapy research at USC.
He is an expert in CAR-T and has driven many, many programs. Today he's going to talk about what CAR-T is, particularly as it relates to solid tumors, which is going to be most appropriate for our community, and what the latest and greatest is with CAR-T. I'm excited to have him join us, and looking forward to an interactive conversation. Saul Priceman 3:09 A little background to me.
I'm 45 years old, and I've lived in Los Angeles for 42 of those years. I went to UC Santa Barbara for undergrad. I worked at a company called Amgen, which you may have heard of in Thousand Oaks for a couple of years, and decided to go get my PhD at UCLA.
After that, I went straight to City of Hope, and have spent the last 14 years there as a postdoctoral fellow and moving all the way through junior faculty to an Associate Professor position, and then, as Brian said, in September, I moved to USC to lead their cancer cell therapy center.
It's a great opportunity, because, you know, City of Hope has been well established in this area, with 40 plus years of bone marrow transplants, which is the most—someone's going to get mad at me—but the archaic version of cellular immunotherapy, and over the last 20 or so years, have been doing what we now term as synthetic engineering and adoptive cellular therapy, and I'll describe that. My move to USC is really to build that out here.
The idea is that every institution under the sun, but certainly in the United States, should be doing cellular immunotherapy, whether it's CAR-T cell therapy or other immunotherapy approaches, because I do believe that rewiring the immune system probably has a hand in every single human disease, and certainly in cancer.
If we can redirect the immune system to identify that cancer, that is the most likely to provide durable therapeutic responses, as opposed “Update on Immunotherapies (CARs and BiTEs) for Solid Tumors” (Saul Priceman, PhD) [ #117] to what we're all used to, which is types of chemotherapies or other druggable entities that you have to take over and over again.
And there's no evolution of that therapy—once you have resistance to that therapy you're in need of something else, rather than what the immune system could provide, which is something that evolves with the cancer and could be there for much longer or indefinitely.
We could go into an immunology 101, and we could describe how you know when you're vaccinated at a very young age or infected with something at a very young age, your immune system recognizes it, and can recognize it for the rest of your life. If we can do that with cancer, that would be the best approach. Brian McCloskey 6:23 We've got a pretty scientific crowd even with our patients, so don't hold back. Saul Priceman 6:31 I love that.
I have 30-odd slides, so I'm going to run through some of them, and I may skip some of them, but they'll be there. And I can send the slide deck over to the Cancer Patient Lab, and you can all read through it, and I'm obviously always around if there are questions. We can provide my email address. “Update on Immunotherapies (CARs and BiTEs) for Solid Tumors” (Saul Priceman, PhD) [ #117] I thought I'd start here: What makes up cancer?
When I was growing up and learned about cancer, I thought it was all cancer cells sitting in a mass, but the reality is, it's a mosaic of all different types of cells.
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