Improving Adoptive Immunotherapy Using Less-Differentiated T Cells

Abstract SCI-49

Recent findings in mice and humans indicate that current treatments based on the adoptive immunotherapy of cancer might be vastly improved with the use of “younger” cells. Analysis of human clinical trials conducted at the NCI reveals that poor clinical responses after ACT are associated with short telomeres and low expression of CD27, a costimulatory molecule, whose loss may indicate poor proliferative capacity. In a mouse model of adoptive immunotherapy developed in our laboratory (pmel-1), we found that transfer of less differentiated tumor-specific T cells results in substantially greater tumor regression compared with the transfer of terminally differentiated cells. Using progressively less-differentiated, Wnt-stimulated T cells, we have been able to reduce the number of tumor-specific T cells needed to induce tumor regression by almost 1,000-fold. Thus, reprogramming terminally-differentiated cells to less-differentiated T cells might substantially increase the success of adoptive immunotherapy. The possibility of cellular de-differentiation was vividly illustrated by groundbreaking work from Yamanaka showing that expressing transcription factors such as Oct-3/4, Sox2, Klf-4 and c-Myc could re-program the mouse somatic cells and induce pluripotent stem cells. Subsequently, human iPS cells were generated using a similar genetic approach. We seek to generate iPS-derived, tumor-specific lymphocytes that are robustly proliferative, have long telomeres and are unencumbered by the epigenetic changes associated with terminal differentiation, exhaustion and senescence. If significant safety concerns can be addressed preclinically, we plan to infuse iPS-dervied, tumor-specific T cells to treat patients with metastatic cancer that is refractory to all available treatments.