Are Chimeric Antigen Receptor (CAR)-T Cells Ready for Prime Time in Prostate Cancer?

COVID-19 has affected everything we do in medicine and science. This certainly includes cancer research, and many clinical trials have placed temporary holds on patient accrual to reserve hospital/intensive care unit beds, preserve personal protective equipment, and limit person-to-person contact. However, we must be optimistic and start to plan for a future when the COVID-19 pandemic calms down. The first wave of clinical trials to reopen must importantly take into account the risk/benefit ratio for the patient.

The more dire the study population's prognosis, the higher priority we ought to place on reopening relevant trials for patient accrual, especially if the therapeutic agent(s) have promise for high efficacy. Not surprisingly, this first wave of trials will include many hematological malignancy trials, and that should include those with autologous cellular immunotherapies, such as CAR-T cells.

Yet as a genitourinary oncologist, I have a mild sense of envy on this topic of CAR-T cell therapy, as I hope for a day where our patients can be treated with these exciting therapies. Therefore, I’ve focused this month’s article on considerations for developing CAR-T cell therapeutics for prostate cancer patients.

CAR-T cells utilize designer fusion proteins to recognize and specifically destroy cells bearing a target surface epitope. These engineered cells have the ability to identify antigens in a major histocompatibility complex (MHC)-independent manner, unlike unmodified T cells that require T cell receptor (TCR)-mediated antigen recognition. The CAR itself is a chimeric recombinant molecule that encompasses an extracellular antigen identification zone for Signal 1, a spacer, a transmembrane zone, and intracellular signaling moieties that facilitate Signal 2 costimulation and resultant signal transduction. First-generation CARs depended heavily upon a single-chain fragment variable to recognize tumor-associated antigens specifically, however, they lacked the costimulatory intracellular molecule (e.g. CD28, CD137) on second and two costimulatory molecules on third-generation CARs.1 These costimulatory molecules successfully promote the production of cytokines such as IL-2 that activate, proliferate, and prolong survival of T cells.2 Fourth generation CARs, termed TRUCKS, add a proinflammatory factor such as IL-12 to provide higher tumor cell kill and potentially avoid the need for preparatory or conditioning chemotherapy.3 

Generally, leukapheresis is utilized to collect peripheral blood mononuclear cells to create autologous therapy.4 T cells are then isolated and activated via CD3/CD28 cross-linking. The CAR is introduced by transfection or transduction with retroviral/lentiviral methodologies. The CAR-T cell products are then expanded and frozen for delivery. Prior to CAR-T cell infusion, cytotoxic chemotherapy may include cyclophosphamide and/or fludarabine. These are utilized to deplete immunosuppressive cells, such as regulatory T cells, and cytokines in the tumor microenvironment.

Early studies with CAR-T cell therapy showed impressive efficacy in chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and refractory B cell lymphoma.5-10 However, these tend to be monoclonal diseases, often driven by a limited set of oncogenes. Hematological malignancies tend to be more homogenous with a uniform expression of target antigens which may explain the high response rates and durability after CAR-T cell therapy. On the contrary, solid tumors tend to have more heterogeneity of disease and polyclonality. There are also physical epithelial barriers and a more hostile tumor microenvironment with greater immune-exclusion to cope with.

All of these concerns with treating solid tumors with CAR-T cells apply directly to prostate cancer. With the exception of microsatellite unstable prostate cancers, the mutational load tends to be low.11 This typically portends a less immune attractive environment in the tumor itself. When considering target antigens, prostate-specific antigen (PSA) is excreted from the tumor, posing a challenge for CAR-T cell delivery to its intended tumor target. Prostate acid phosphatase (PAP) can be expressed in other tissues and when prostate tissue is damaged, large amounts of PAP are released into the blood, posing similar challenges.12 Prostate stem cell antigen (PSCA) is fixed on the cell membrane of prostate cells, is specific to prostate tissue, offers expression levels of 90-100% with the highest expression in bone metastases, and is not released into the blood.13 Prostate-specific membrane antigen also has very high prostate tissue specificity and has already proven to be a useful target for both diagnostic imaging and theranostics.14 Both PSMA and PSCA are seemingly logical target antigens, and CAR-T cell constructs are already engaged in the clinical investigation for patients with prostate cancer.

There is very limited early CAR-T cell treatment experience in prostate cancer. The first trial utilized a first-generation CAR targeted to PSMA. With the poor persistence of these CAR-T cells, two of five patients had PSA ≥ 50% decline.15 The other trial with publicly presented data used a second-generation CD-28-based CAR targeted to PSMA. This trial had two of four patients with stable disease and some cytokine release syndrome when higher numbers of CAR-T cells were administered in a second dosing cohort.16 These early experiences emphasize the need to design rational next-generation CARs.

Next-generation CARs may attempt to counter the immunosuppressive microenvironment of a solid tumor. For example, transforming growth factor-beta (TGF-B) is secreted by tumor and stromal cells, has immunosuppressive properties, and plays a role in the progression of prostate cancer.17 As a result, some CARs are attempting to counteract these effects by including a dominant-negative TGF-B receptor, and one is already in a trial focused on patients with prostate cancer (NCT03089203).

After contemplating all this, I’ll admit that re-opening CAR-T cell trials for patients with hematological malignancies should take priority over those with prostate cancer during our worldwide recovery from COVID-19, as the risk/benefit ratio and patient experience is more promising at this time for patients who harbor hematological malignancies. However, it is not unreasonable to consider opening and reopening prostate cancer-specific CAR-T cell trials in the next wave, as the patients eligible for these trials generally have limited to no other treatment options. Additionally, a young, otherwise healthy patient, with aggressive prostate cancer disease biology might warrant serious consideration for a CAR-T cell trial. Forward-thinking measures allow us to recognize that this COVID-19 pandemic won’t last forever. Hence, there should be optimism and enthusiasm for CAR-T cell trials in prostate cancer, and it is worth perusing the list of trials below for patient referral and future trial accrual.

Ongoing CAR-T clinical trials including prostate cancer patients

Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine, Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center

References: 

1. Ramos, Carlos A., and Gianpietro Dotti. "Chimeric antigen receptor (CAR)-engineered lymphocytes for cancer therapy." Expert opinion on biological therapy 11, no. 7 (2011): 855-873.
2. Carpenito, Carmine, Michael C. Milone, Raffit Hassan, Jacqueline C. Simonet, Mehdi Lakhal, Megan M. Suhoski, Angel Varela-Rohena et al. "Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains." Proceedings of the National Academy of Sciences 106, no. 9 (2009): 3360-3365.
3. Chmielewski, Markus, Caroline Kopecky, Andreas A. Hombach, and Hinrich Abken. "IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively Muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression." Cancer research 71, no. 17 (2011): 5697-5706.
4. Gorchakov AA, Kulemzin SV, Kochneva GV, Taranin AV. Eur Urol 2019; 77:299-308.
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7. Maude, Shannon L., Theodore W. Laetsch, Jochen Buechner, Susana Rives, Michael Boyer, Henrique Bittencourt, Peter Bader et al. "Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia." New England Journal of Medicine 378, no. 5 (2018): 439-448.
8. Park, Jae H., Isabelle Rivière, Mithat Gonen, Xiuyan Wang, Brigitte Sénéchal, Kevin J. Curran, Craig Sauter et al. "Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia." New England Journal of Medicine 378, no. 5 (2018): 449-459.
9. Neelapu, Sattva S., Frederick L. Locke, Nancy L. Bartlett, Lazaros J. Lekakis, David B. Miklos, Caron A. Jacobson, Ira Braunschweig et al. "Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma." New England Journal of Medicine 377, no. 26 (2017): 2531-2544.
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11. Lawrence, Michael S., Petar Stojanov, Paz Polak, Gregory V. Kryukov, Kristian Cibulskis, Andrey Sivachenko, Scott L. Carter et al. "Mutational heterogeneity in cancer and the search for new cancer-associated genes." Nature 499, no. 7457 (2013): 214-218.
12. Rajasekaran, Sigrid A., Jason J. Christiansen, Ingrid Schmid, Eri Oshima, Kathleen Sakamoto, Jasminder Weinstein, Nagesh P. Rao, and Ayyappan K. Rajasekaran. "Prostate-specific membrane antigen associates with anaphase-promoting complex and induces chromosomal instability." Molecular cancer therapeutics 7, no. 7 (2008): 2142-2151.
13. Gu, Z., George Thomas, J. Yamashiro, I. P. Shintaku, F. Dorey, A. Raitano, O. N. Witte, J. W. Said, M. Loda, and R. E. Reiter. "Prostate stem cell antigen (PSCA) expression increases with high gleason score, advanced stage and bone metastasis in prostate cancer." Oncogene 19, no. 10 (2000): 1288-1296.
14. Dorff, Tanya B., Stefano Fanti, Andrea Farolfi, Robert E. Reiter, Taylor Y. Sadun, and Oliver Sartor. "The Evolving Role of Prostate-Specific Membrane Antigen–Based Diagnostics and Therapeutics in Prostate Cancer." American Society of Clinical Oncology Educational Book 39 (2019): 321-330.
15. Junghans, Richard P., Qiangzhong Ma, Ritesh Rathore, Erica M. Gomes, Anthony J. Bais, Agnes SY Lo, Mehrdad Abedi et al. "Phase I trial of anti‐PSMA designer CAR‐T cells in prostate cancer: possible role for interacting interleukin 2‐T cell pharmacodynamics as a determinant of clinical response." The Prostate 76, no. 14 (2016): 1257-1270.
16. Slovin, Susan F., Xiuyan Wang, Melanie Hullings, Gabrielle Arauz, Shirley Bartido, Jason Stuart Lewis, Heiko Schöder et al. "Chimeric antigen receptor (CAR+) modified T cells targeting prostate-specific membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC)." (2013): 72-72.
17. Wikström, Pernilla, Pär Stattin, Ingela Franck‐Lissbrant, Jan‐Erik Damber, and Anders Bergh. "Transforming growth factor β1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer." The Prostate 37, no. 1 (1998): 19-29.