Dissecting the cellular components of ex vivo γδ T cell expansions to optimize selection of potent cell therapy donors for neuroblastoma immunotherapy trials

gamma delta T lymphocytes represent an emerging class of cellular immunotherapy with preclinical promise to treat cancer, notably neuroblastoma. The innate-like immune cell subset demonstrates inherent cytoxicity toward tumor cells independent of MHC recognition, enabling allogeneic administration of healthy donor-derived gamma delta T cell therapies. A current limitation is the substantial interindividual gamma delta T cell expansion variation among leukocyte collections. Overcoming this limitation will enable realization of the full potential of allogeneic gamma delta T-based cellular therapy. Here, we characterize gamma delta T cell expansions from healthy adult donors and observe that highly potent natural killer (NK) lymphocytes expand with gamma delta T cells under zoledronate and IL-2 stimulation. The presence of NK cells correlates with both the expansion potential of gamma delta T cells and the overall potency of the gamma delta T cell therapy. However, the potency of the cell therapy in combination with an antibody-based immunotherapeutic, dinutuximab, appears to be independent of gamma delta T/NK cell content both in vitro and in vivo, which minimizes the implication of interindividual expansion differences toward efficacy. Collectively, these studies highlight the utility of maintaining the NK cell population within expanded gamma delta T cell therapies and suggest a synergistic action of combined innate cell immunotherapy toward neuroblastoma.

Automated summary

γδ T lymphocytes are a promising cellular immunotherapy for neuroblastoma. The expansion of these cells can be enhanced by stimulating with zoledronate and IL-2, leading to the expansion of highly potent natural killer (NK) lymphocytes. The presence of NK cells correlates with the expansion potential of γδ T cells and the overall potency of the therapy. However, the combination of the therapy with an antibody-based immunotherapeutic seems to be independent of γδ T/NK cell content. Overall, maintaining the NK cell population in expanded γδ T cell therapies plays an important role in synergistic action towards neuroblastoma.