Immunotherapy of pancreatic ductal adenocarcinoma with human gammadelta T lymphocytes

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Circulating as well as tumor-infiltrating human γδ T cells kill various tumor cells in a MHC-non-restricted fashion. The dominant subset of human Vγ9Vδ2 γδ T cells recognizes isopentenyl pyrophosphate (IPP), an intermediate of the mevalonate pathway, which is increased in tumor cells. The augmented production of IPP in transformed cells can be further increased by therapeutically administered nitrogen-containing-bisphosphonates (n-BPs). We have shown the efficacy of human Vγ9Vδ2 γδ T cells against pancreatic ductal adenocarcinoma (PDAC) in vitro as well as in vivo after adoptive transfer of γδ T cells and n-BPs/IL-2 into SCID mice. Several pilot studies published by others reported a selective activation of γδ T cells and a partial reduction of tumor growth in renal or prostate cancer patients after treatment with n-BPs and low dose IL-2. To promote γδ T cell-based immunotherapy, the following issues will be addressed: (i) optimization of in vitro expansion and cytotoxic effector activity of tumor-reactive γδ T cells; (ii) characterization of cytotoxicity against PDAC cell lines including direct effects of n-BPs, regulation of interacting molecules and tumor escape mechanisms in the interplay of γδ T cells and PDAC cells; (iii) use of an adoptive transfer model in SCID-Beige mice for further preclinical characterization of PDAC-reactive γδ T cells and anti-tumor effects of n-BPs; (iv) γδ T cell focused immune-monitoring in proof-of-principle studies in patients with advanced PDAC treated with n-BPs plus low dose IL-2; and (v) establishment of GMP protocols for ultimate adoptive transfer of γδ T cells into patients.