Low-Dose Radiation Ex Vivo Reprogrammed/Activated CAR T Cells Targeting B7-H3 on Prostate Cancer
Abstract
Prostate cancer (PCa) is the most common non-cutaneous cancer and second leading cause of cancer-related deaths among American men. Metastatic PCa (mPCa), which can be subdivided into hormone-sensitive PCa (mHSPC) and castration-resistant PCa (mCRPC), is the lethal form of PCa and is associated with a 5-year survival rate of 30%. All current available therapies, including hormonal therapies targeting androgen receptor signaling, taxane chemotherapies, alpha-emitting radionuclides, and dendritic cell therapy, can each prolong survival to modest extents for patients with mPCa, but unfortunately, resistance invariably develops and eventually causes death. To address this urgent unmet clinical need, we propose to implement a new immunotherapy approach that relies on taking lymphocytes from a patient blood and genetically engineering them to become potent antitumor effector cells (referred to as CAR T cells or CAR T), which are then administered back to the same patient to eliminate cancer cells. This approach has shown unprecedented efficacy in blood cancers, but has not had as much success for solid tumors. We have developed CAR T cells targeting a specific molecule called B7-H3, which is selectively, almost uniformly, and highly expressed on PCa cells and PCa stem cells (PCSCs) that cause treatment resistance. B7-H3 expression increases in higher Gleason score prostate cancer and with progression to metastatic and castration-resistant disease and is correlated with cancer-specific mortality. Conversely, B7-H3 expression on normal tissue is minimal. Thus, our homemade B7-H3 CAR T showed no evidence of toxicity in immunodeficient mice bearing human solid tumors. In general, however, CAR T therapy has not shown sustained anti-tumor activity for solid tumors. To solve this problem, we propose to test in preclinical mPCa models of human mHSPC and mCRPC in mice the novel strategy of using low-dose radiation to reprogram and activate mPCa patients’ blood cell-derived B7-H3 CAR T cells to empower them with robust, potent, and long-lasting anti-tumor activity. Specifically, we will optimize the dose of ionizing radiation (IR) and CAR T cell expansion time to reprogram B7-H3 CAR T cells (IR B7-H3 CAR T) toward acquiring the properties of CAR T stem memory cells, the key component for sustained tumor regression or rejection in blood cancer patients, before infusing them into mice bearing human mHSPC or mCRPC. We will also evaluate whether IR CAR T can induce a strong host anti-tumor immune response in a humanized mouse model, as B7-H3 is an immune checkpoint molecule; evidence indicates that inhibition of B7-H3 boosts host anti-tumor immunity. As a result, administration of IR CAR T to mice bearing multiple mPCa lesions should result in tumor eradication or rejection. Next, we will evaluate the safety of IR B7-H3 CAR T in the new humanized NSG-SGM3 mouse model, which can recapitulate all major CAR T associated toxicities. Last, we will assess the frequency and intensity of the B7-H3 molecule recognized by the B7-H3-specific antibody 376.96, which was used to make the IR B7-H3 CART cells, on PCa cells and PCSCs present in tumor samples from mPCa patients. This study will also allow us to establish a method to identify potential mPCa patient candidates who did not respond to current therapy for future clinical trials using IR reprogrammed B7-H3 CART cell therapy. In summary, this project will directly address the challenge of reducing mortality from mPCa. We expect that, following optimization in clinically relevant mouse models, the outlined novel strategy could be rapidly translated in the clinic. As a result, it could be used for the treatment of the vast majority of mPCa patients whose tumors express the molecular target (B7-H3) and could induce durable or even curable responses in patients suffering from this dismal disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110433
Entities
People
- Xinhui Wang
Organizations
- Massachusetts General Hospital
- United States Army