In this section
@misc{Li:2023:10.1158/0008-5472.c.6511806.v1,
author = {Li, C and Course, MM and McNeish, IA and Drescher, CW and Valdmanis, PN and Lieber, A},
doi = {10.1158/0008-5472.c.6511806.v1},
title = {Data from Prophylactic <i>In Vivo</i> Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models},
type = {Other},
url = {http://dx.doi.org/10.1158/0008-5472.c.6511806.v1},
year = {2023}
}
TY - GEN
AB - <jats:p><div>Abstract<p>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 <i>in vivo</i>. The technology involves HSPC mobilization and intravenous injection of an integrating HDAd5/35++ vector. <i>In vivo</i> 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 <i>in vivo</i> 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<sup>−/−</sup> brca2<sup>−/−</sup>), both in a
AU - Li,C
AU - Course,MM
AU - McNeish,IA
AU - Drescher,CW
AU - Valdmanis,PN
AU - Lieber,A
DO - 10.1158/0008-5472.c.6511806.v1
PY - 2023///
TI - Data from Prophylactic <i>In Vivo</i> Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models
UR - http://dx.doi.org/10.1158/0008-5472.c.6511806.v1
UR - https://doi.org/10.1158/0008-5472.c.6511806.v1
ER -