Prophylactic In Vivo Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models.

Population-wide testing for cancer-associated mutations has established that more than one-fifth of ovarian and breast carcinomas are associated with inherited risk. Salpingo-oophorectomy and/or mastectomy are currently the only effective options offered to women with high-risk germline mutations. Our goal here is to develop a long-lasting approach that provides immunoprophylaxis for mutation carriers. Our approach leverages the fact that at early stages, tumors recruit hematopoietic stem/progenitor cells (HSPC) from the bone marrow and differentiate them into tumor-supporting cells. We developed a technically simple technology to genetically modify HSPCs in vivo. The technology involves HSPC mobilization and intravenous injection of an integrating HDAd5/35++ vector. In vivo HSPC transduction with a GFP-expressing vector and subsequent implantation of syngeneic tumor cells showed >80% GFP marking in tumor-infiltrating leukocytes. To control expression of transgenes, we developed a miRNA regulation system that is activated only when HSPCs are recruited to and differentiated by the tumor. We tested our approach using the immune checkpoint inhibitor anti-PD-L1-γ1 as an effector gene. In in vivo HSPC-transduced mice with implanted mouse mammary carcinoma (MMC) tumors, after initial tumor growth, tumors regressed and did not recur. Conventional treatment with an anti-PD-L1 mAb had no significant antitumor effect, indicating that early, self-activating expression of anti-PD-L1-γ1 can overcome the immunosuppressive environment in MMC tumors. The efficacy and safety of this approach was further validated in an ovarian cancer model with typical germline mutations (ID8 p53-/- brca2-/-), both in a prophylactic and therapeutic setting. This HSPC gene therapy approach has potential for clinical translation. SIGNIFICANCE: Considering the limited prophylactic options that are currently offered to women with high-risk germ-line mutations, the in vivo HSPC gene therapy approach is a promising strategy that addresses a major medical problem. ©2019 American Association for Cancer Research.