Novel CAR design dually targets HER2+ breast cancer and MDSCs to improve efficacy in solid tumors
DOI:
https://doi.org/10.58445/rars.466Keywords:
CAR T cell therapy, Breast cancer, MDSCs, Immunotherapy, Cancer, HER2Abstract
CAR T cell therapy is a promising immunotherapy that has been approved by the FDA for use in blood cancers, but has yet to be efficacious in solid tumors due to limitations including antigen escape, on-target off-tumor effects, tumor infiltration challenges, toxicities, and the immunosuppressive tumor microenvironment. Current strategies to overcome these obstacles are ongoing and include dual target CARs, combination therapy with checkpoint blockade, local CAR administration, and targeting immunosuppressive microenvironment cells. However, additional studies are still needed to continue to improve the efficacy of CAR T. In this proposal, we first review the function of T cells in the immune system, and discuss how CAR T cell therapy enhances immune response to cancer. We also review current strategies being tested to overcome limitations in CAR T cell therapy on solid tumors. We then propose a novel CAR design that targets HER2 on breast cancer and secretes a NBD peptide that is receptive to endocytosis into MDSCs through CD73. The NBD peptide blocks the Nf-Kb signaling pathway which reduces the immunosuppressive qualities of MDSCs in the tumor microenvironment. This design requires preclinical studies to validate its efficacy and safety before being used in clinical trials. If successful, this proposal could present a novel therapeutic option for patients with HER2 positive breast cancer that would then need to be followed up with clinical studies.
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