Therapeutic responses following adoptive transfer of T cells correlate to levels of long-term T cell persistence. Lymphodepletion and exogenous γc cytokine administration can improve T cell persistence following adoptive transfer, but their effects are not uniform and toxicities are significant. To overcome these limitations, we designed a chimeric γc cytokine receptor (CγCR) composed of Interleukin-7 (IL-7) tethered to IL-7Rα/CD127 that confers exogenous cytokine independent, cell intrinsic, STAT5 cytokine signals.
View Article and Find Full Text PDFTumors exploit immunoregulatory checkpoints that serve to attenuate T cell responses as a means of circumventing immunologic rejection. Programmed death ligand 1 (PD-L1) is a negative regulator of T cell function and is frequently expressed by solid tumors. By engaging programmed death 1 (PD-1) on activated T cells, PD-L1(+) tumors directly render tumor-specific T cells, including adoptively transferred T cells, functionally exhausted.
View Article and Find Full Text PDFThe anthracycline chemotherapeutic agent doxorubicin is converted by the enzyme carbonyl reductase 1 (CBR1) into its cardiotoxic metabolite doxorubicinol. Cbr1+/- mice have been shown to be protected from doxorubicin-induced cardiotoxicity, and the inhibition of CBR1 activity may be a useful means of ameliorating the side effects of doxorubicin in patients undergoing chemotherapy. Because reduced conversion to doxorubicinol increases circulating levels of the more effective parent drug doxorubicin, it was hypothesized that therapeutic efficacy against tumors might also be enhanced.
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