Combining CAR T Cells with Blockade of Tumor-Induced Immunosuppression to Target Metastatic Prostate Cancer
Abstract
Metastatic castration-resistant prostate cancer presents a formidable challenge for developing effective anticancer therapies. While the cancer may initially respond to therapy, once metastasized from the prostate, the tumors find ways to resist both the patient’s normal immune defenses and the chemotherapy/radiation treatments. Immunotherapy is a powerful new approach that directs and stimulates the patient’s own immune system to combat cancer and is potentially more effective and less toxic than conventional chemotherapy and radiation therapies. In recent years, immunotherapy has shown long-lasting remissions in blood cancers, as well as in some solid cancers. We propose an adoptive immunotherapy for metastatic prostate cancer by which a patient’s immune T cells are (1) removed from the blood, (2) genetically reprogrammed with chimeric antigen receptors (CARs) that can directly bind to prostate stem-cell antigen (PSCA) expressed on the surface of prostate cancer cells, and (3) reintroduced into the patient’s bloodstream where they multiply, seek out, and destroy the PSCA-expressing tumor cells. CAR T cell immunotherapy is showing particularly impressive outcomes for leukemia and other blood cancers and is now under active investigation in solid cancers. In August 2019, we initiated a phase 1 clinical trial evaluating the safety, feasibility, and bioactivity of PSCA-specific CAR T cells in patients with metastatic castration-resistant prostate cancer. Still, two major challenges exist in developing CAR T cell therapies for solid tumors: 1. The majority of CAR targets that are highly expressed in cancer cells are also expressed at varying levels in normal tissues, therefore posing possible toxicity concerns. PSCA is over-expressed in prostate cancer cells, but also expressed at low levels in several normal tissues including esophagus, colon, stomach, and kidney. 2. Solid cancers have developed strategies to evade the patient’s immune defenses by sending out chemical signals that can suppress an anti-tumor immune response. Immune-suppression can also decrease the effectiveness of immunotherapies like PSCA-CAR T cells and will need to be addressed in rational combination strategies and direct improvements to the CAR T cell therapy. We have addressed the first toxicity issue with support from a DOD Idea Development Award (W81XWH-17-1-0208, PI: Priceman) by establishing a mouse prostate cancer model with PSCA expression at similar levels and in similar normal tissues as in humans. Using this model, we demonstrated safety and efficacy of PSCA-CAR T cells, complementing our early safety signals in the phase 1 trial. To address the immune suppression that is likely limiting overall therapeutic responses of PSCA-CAR T cells, we propose to unleash the patient’s immune system with drugs that block signal transducer and activator of transcription 3 (STAT3) signaling. STAT3 is a master regulator of the antitumor immune response. At City of Hope, we have recently demonstrated that combining STAT3 blockade with PSCA-CAR T cells greatly magnifies killing and overall therapeutic response. This new proposal will interrogate molecular and cellular mechanisms underlying this response, specifically how STAT3 blockade relieves the suppression of CAR T cells and promotes anti-tumor responses. We also aim to interrogate the two main inhibitory signals that are regulated by STAT3, namely PD-L1 and TGFß. To enhance PSCA-CAR therapy, we will engineer PSCA-CAR T cells that simultaneously bind PSCA and block these two factors in the tumor for improved eradication of prostate cancer. We will first test these therapies individually and then in combination in mice with metastatic prostate cancer. An important technical aspect of our proposal is that, to assess the importance of the immune suppression and its relief by STAT3 blockade, we will use a mouse model that more closely resembles the immune-suppressive tumor micr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110354
Entities
People
- Saul J Priceman
Organizations
- Beckman Research Institute of City of Hope
- United States Army