Boost and attack approach for metastatic prostate cancer therapy!

From the Lee Lab, Human Biology and Clinical Research Divisions, Cancer Consortium

Metastatic castration-resistant prostate cancer (mCRPC) is resistant to first-line prostate cancer therapies that target the androgen receptor (AR) and is a terminal disease with a 3-year median overall survival rate. A common challenge for developing effective therapies for pre- and post-metastatic cancers is identifying an antigen or protein that is abundant on all or most cancer cells but absent or present at low levels on normal cells. The Lee lab at Fred Hutchinson Cancer Center has approached this challenge for metastatic prostate cancer by first screening for abundant cell-surface proteins on these tumor cells, and second, generating a targeted therapy approach that boosts immune cell activation for enhanced targeting effects of their antigen targeted therapy. Their findings of abundant STEAP1 as well as the generation and pre-clinical validation of a boost and attack approach for treating metastatic prostate cancer were published recently in Nature Communications and their developed therapy has received financial support by the National Cancer Institute Experimental Therapeutic program (NExT) for early clinical phase I trials starting in 2024.

Previous work by the Lee lab identified a cell surface antigen, or a protein that is present on the surface of cells and visible to nearby immune cells, that was highly abundant on metastatic prostate cancer cells. This protein was the six transmembrane epithelial antigen of the prostate 1 (STEAP1), a previously studied protein in the context of prostate cancer as well as other cancers. The function of this protein is to regulate cell growth and death signaling by forming complexes with other STEAP family members and activating signaling pathways within cells. The role of receptors, or proteins on the cell surface that respond to growth and cell death stimuli, are commonly altered in function or abundance to cause cancer. To determine if STEAP1 could be a good protein for targeted therapy, the researchers evaluated STEAP1 abundance on tumor biopsy samples from patients with mCRPC. “The Cancer consortium collaboration between Fred Hutch and UW helped in procuring mCRPC tissue specimens from the UW TAN cohort to analyze expression patterns of STEAP1 and PSMA in prostate cancer,” stated Dr. Vipul Bhatia, a postdoctoral researcher fellow in the Lee lab. A standard marker of metastatic pancreatic cancer cells is the prostate-specific membrane antigen (PSMA). PSMA abundance on the cell surface of metastatic prostate cancer cells was recently noted to be heterogeneous; some cancer cells have it while others do not. The Lee lab compared staining for PSMA to STEAP1 on metastatic prostate cancer patient samples and found that 60.5% (69 out of 114 samples) stained positive for PSMA and 87.7% (100 out of 114 samples) were positive for STEAP1. Importantly, only 1 sample out of 114 was positive for PSMA but negative for STEAP1, suggesting that STEAP1 is a better indicator of mCRPC cells than PSMA.

The patient biopsies used in this study came from 44 individuals (1-3 biopsies per person) in coordination with the University of Washington mCRPC Tissue Acquisition Necropsy (TAN) Prostate Cancer Biorepository Network. These samples were obtained from consenting patients who “are transported by ambulance after they pass (usually at home) to the University of Washington Medical Center for a rapid autopsy in which metastatic sites of disease are sampled [within an 18-hour time window],” stated Dr. John Lee. This is a remarkable gift and has allowed for numerous studies to advance cancer-based research. In this study, the researchers were able to investigate the heterogeneity of STEAP1 expression within an individual. At the patient level, broad expression of STEAP1 (95% of patients) was observed while PSMA was more limited (68% of patients). Thus, STEAP1 could be a more effective biomarker of disease than PSMA for mCRPC. This discovery has significant impacts for prostate cancer detection. However, upon further investigation of STEAP1 abundance, the researchers did observe heterogeneity in STEAP1 expression within patients, suggesting that not all cells would be sensitive to a STEAP1-targeted therapy. While some may see this as a roadblock, the Lee lab continued to pursue therapy development targeting STEAP1 with additional considerations that boosting immune cell-mediated anti-tumor activity may be needed for an effect therapeutic approach.

The use of immunotherapy approaches, or therapies that wield the immune system like a sharpened sword to kill specific cells or defend against pathogens, take several forms (immune checkpoint inhibitors, DNA cancer vaccines, antibody-drug conjugates (ADC), T cell engaging bispecific antibodies (T-BsAb), and chimeric antigen receptor (CAR) T cells) and have had success in clinical trials. The Lee lab “developed second generation STEAP1 directed CAR T cell therapy, which shows pre-clinical efficacy across multiple prostate models,” stated Dr. Bhatia. One of the pre-clinical models used was a humanized mouse model which by no easy feat was engineered to express the human STEAP1 gene from the same locus as mouse STEAP1. In this model, “we establish that STEAP1 CAR T cells are safe and show anti-tumor response in immunocompetent mice,” shared Dr. Bhatia. This demonstration of therapeutic efficacy in reducing tumor volume was modest and unfortunately short-lived but notable by extending survival from 12 to 21 days. While thinking about why this response to therapy was so short-lived, the researchers investigated whether a key antigen presenting molecule (beta-2-microglobulin) was affected by STEAP1 CAR T cell therapy. Indeed, this component of the antigen presenting molecule (MHC class I molecule) was downregulated following treatment, making these cancer cells “cold” or poorly recognized by T cells and resistant to T cell-mediated killing.

STEAP1 CAR T cells and CBD-IL-12 were combined to treat mCRPR in pre-clinical models of disease and shown to modestly decrease tumor size and slightly increase survival of mouse models while enhancing anti-tumor immune cell responses.
STEAP1 CAR T cells and CBD-IL-12 were combined to treat mCRPR in pre-clinical models of disease and shown to modestly decrease tumor size and slightly increase survival of mouse models while enhancing anti-tumor immune cell responses. Image was provided by Dr. Bhatia

“To combat cold prostate tumor microenvironment and loss of antigen presentation machinery post STEAP1 CAR T cell therapy – we collaborated with our colleague at Kings College London, Dr. Jun Ishihara, and utilized collagen binding domain IL-12 (CBD-IL-12) in combination with STEAP1 CAR T cells leading to an increase in overall survival by diversifying immune response and engaging of host immunity,” stated Dr. Bhatia. CBD-IL-12 has been used in other cancer models to convert “cold” tumors to “hot” ones by enhancing IFN-γ signaling, an activator of inflammation and cell-mediated immunity. Importantly, CBD-IL12 limited the rebound in tumor growth following STEAP1 CAR T cell administration with a modest, increased survival in the human STEAP1 expressing humanized mouse model. With few effective options, including a PSMA targeting therapy, for mCRPC patients, these incremental advancements in therapy efficacy for STEAP1 CAR T cells provide a viable alternative, and early clinical phase I trials will begin in 2024. Future work in the Lee lab will direct efforts to engineer dual target CAR T cells that counter the likely resistance mechanism of antigen downregulation and to couple “STEAP1 CAR T cells with cytokines to remodel the immunosuppressive prostate tumor microenvironment,” concluded Dr. Bhatia.

The spotlighted research was funded by the Department of Defense Prostate Cancer Research Program Award, Fred Hutch/ UW cancer Consortium Safeway Pilot Award, Seattle Cancer Case Alliance/Swim Across America Award, The Pacific Northwest Prostate Cancer SPORE, the Institute for Prostate Cancer Research, The Doris Duke Charitable Foundation, NCI, JSPS Overseas Research Fellowship, Prostate Cancer Foundation Investigator Award, and Movember Foundation-Prostate Cancer Foundation Challenge Award.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member John Lee contributed to this work.

Bhatia V, Kamat NV, Pariva TE, Wu LT, Tsao A, Sasaki K, Sun H, Javier G, Nutt S, Coleman I, Hitchcock L, Zhang A, Rudoy D, Gulati R, Patel RA, Roudier MP, True LD, Srivastava S, Morrissey CM, Haffner MC, Nelson PS, Priceman SJ, Ishihara J, Lee JK. 2023. Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy. Nat Commun. 14(1):2041.