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Low-Dose Radiation Ex Vivo Reprogrammed/Activated CAR T Cells Targeting B7-H3 on Prostate Cancer


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Metastatic prostate cancer (mPCa), which can be subdivided into hormone-sensitive (mHSPC) and castration-resistant PCa (mCRPC), is the lethal form of PCa , with a 5-year survival rate of 30%. Current therapies can prolong survival for mPCa patients; however, resistance invariably develops 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 immune checkpoint which is almost uniformly expressed on differentiated (bulk) PCa cells and PCa stem cells (PCSPs), which can cause therapeutic 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. Low-dose radiation (IR) by upregulating NF-B -stemness gene pathway empowers CAR T cells (IR CAR T) capable of producing a robust and long lasting anti-tumor activity. 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 tumor regression and long-term survival in the absence of toxicity.



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