Post-Doctoral Fellow or Research Associate
Most solid tumor contain large numbers of M2-polarized macrophages that suppress anti-tumor T cell immunity. M2 macrophages can be converted to the pro-inflammatory M1 phenotype by deletion of the gene encoding the inhibitory p50 NF-kB subunit, leading to activation of NF-kB target genes. We and others find that multiple solid tumors (melanoma, sarcoma, glioblastoma, colon cancer, prostate cancer, pancreatic carcinoma, and neuroblastoma) grow slower in mice lacking NF-kB p50, with increased numbers of activated T cells within tumors (Barberi et al 2018, PMID 30030559).
To translate these findings to benefit patients, we have utilized adoptive transfer of p50-deficient immature myeloid cells (p50-IMC), expanded from the bone marrow of p50(-/-) mice. We find that p50-IMC slow the growth of prostate cancer, pancreatic carcinoma, and neuroblastoma (Suresh et al 2020, PMID 31940589; Cheng et al 2021; PMID 33480449). We utilize immature myeloid cells because mature cells often adhere to solid organs such as the liver. These immature cells develop into mature M1 macrophage and activated dendritic cells in the tumor micro-environment and draining lymph nodes, where they activate T cells to slow tumor growth.
The new post-doctoral fellow will conduct studies, using mouse tumor models, designed to improve p50-IMC efficacy. One approach will be expression of chimeric antigen receptors (CARs) in p50-IMC. Combination of p50-IMC or p50-IMC/CAR cells with T cell checkpoint inhibitors or other immunotherapies will also be explored. To model clinical translation, we have developed means to efficiently knockout the genes encoding p50 using CRISPR/Cas9. The new fellow will also conduct experiments using these p50KO-IMC. In addition to use of syngeneic mouse models, the fellow will conduct related experiments using human cancer cells in immune-deficient mice.
We are working closely with a nearby biotechnology firm to develop human p50-IMC for clinical evaluation. The new fellow will have the opportunity to interact with scientists at this firm and to become familiar with the steps needed to commercialize a new cell therapy product.
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