Delta One T cells for adoptive immunotherapy of CLL

Purpose: The V1+ subset of T lymphocytes is a promising candidate for cancer immunotherapy but the lack of suitable expansion/ differentiation methods has precluded therapeutic application. We set out to develop and test (preclinically) a V1+ T cell-based protocol that is GMP-compatible and devoid of feeder cells for prompt clinical translation. Experimental design: We tested multiple combinations of clinical-grade agonist antibodies and cytokines for their capacity to expand and differentiate (over 2-3 weeks) V1+ T cells from the peripheral blood of healthy donors and chronic lymphocytic leukemia (CLL) patients. We characterized the phenotype and functional potential of the final cellular product, termed Delta One T (DOT) cells, in vitro and in vivo (xenograft models of CLL). Results: We describe a very robust two-step protocol for the selective expansion (up to 2,000-fold in large clinical-grade cell culture bags) and differentiation of cytotoxic V1+ (DOT) cells. These expressed the Natural Cytotoxicity Receptors (NCRs), NKp30 and NKp44, which synergized with the T-cell receptor to mediate leukemia cell targeting in vitro. When transferred in vivo, DOT cells infiltrated tumors and peripheral organs, and persisted until the end of the analysis without showing signs of loss-of-function; indeed, DOT cells proliferated and produced abundant IFN- and TNF-α, but importantly no IL-17, in vivo. Critically, DOT cells were capable of inhibiting tumor growth and preventing dissemination in xenograft models of CLL. Conclusions: We provide a clinical-grade method and the preclinical proof-of-principle for application of a new cellular product, DOT cells, in adoptive immunotherapy of CLL.

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