Low-Dose Radiation Ex Vivo Reprogrammed/Activated CAR T Cells Targeting B7-H3 on Prostate Cancer
Abstract
Metastatic prostate cancer (mPCa), which can be subdivided into hormone-sensitive (mHSPC) and castration-resistant PCa (mCRPC), is thelethal form of PCa , with a 5-year survival rate of 30%. Current therapies can prolong survival for mPCa patients; however, resistance invariablydevelops and eventually causes death. To address this unmet clinical need, we have recently developed a novel chimeric antigen receptor(CAR) T cell immunotherapy (CAR T therapy) by reprogramming/activation of CAR T cells that recognize B7- H3(CD276), an immunecheckpoint which is almost uniformly expressed on differentiated (bulk) PCa cells and PCa stem cells (PCSPs), which can cause therapeuticresistance. B7-H3 expression increases in higher Gleason score prostate cancer and with progression to metastatic and castration-resistantdisease, and is correlated with cancer-specific mortality. Conversely, B7-H3 expression on normal tissue is minimal. Low-dose radiation (IR) byupregulating NF-B -stemness gene pathway empowers CAR T cells (IR CAR T) capable of producing a robust and long lasting anti-tumoractivity. The IR B7-H3 CAR T compared to non-IR CAR T shows much increased potency in 1) in vitro killing of differentiated PCa and PCSCs inhuman PCa cell lines, and 2) in vivo inhibiting PCa or breast cancer xenograft growth, as measured by complete or substantial tumorregression and long-term survival in the absence of toxicity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1191016
Entities
People
- Xinhui Wang
Organizations
- Massachusetts General Hospital