Abstract 4130: Genetically modified hematopoietic stem cells for improvement of immunotherapies against solid malignancies

Abstract

Abstract Hematopoietic stem cells (HSCs) are routinely used in the clinic to treat several diseases and their side effects, including cancers. Our group has previously shown that the combination of HSCs with two different immunotherapies improves survival in brain tumors, but it is still not curative. In this study, we wanted to explore whether modifying HSCs can drive them into a dendritic cell phenotype or suppress them from becoming immunosuppressive myeloid cells at the tumor microenvironment to increase survival when combined with immunotherapy in a glioma model. HSCs have been historically challenging to grow in vitro for long-term culture due to the short periods of time they remain undifferentiated, which creates an extra challenge for the genetic modification of HSCs. Here, we test different in vitro conditions for expansion and modification of murine and human HSCs by employing the following methods for modulation of HSCs: shRNA lentiviral delivery, overexpression constructs, RNA electroporation, CRISPR, and AAV. This study describes the efficacy of each method as well as the observed limitations of each technique on HSCs. Furthermore, preliminary data shows IL6R downregulation as a candidate for driving HSCs into the dendritic cell lineage. Ultimately, these genetically modified cells will be used as an adjuvant therapy to improve the efficacy of various immunotherapeutic strategies against solid malignancies. Citation Format: Laura Falceto Font, Dan Jin, Connor P. Francis, Bayli DiVita Dean, John W. Figg, Brianna McDonald, Catherine Flores. Genetically modified hematopoietic stem cells for improvement of immunotherapies against solid malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4130.