Abstract

Particularly within the last half decade, the field of γδ-T cell cancer immunotherapy has enjoyed a major expansion reflected in the growing number of publications in this area. The increased efforts of numerous investigators –– with their accordingly varied strategies and approaches –– is occurring largely on account of key biological, technological and pharmaceutical advances, all of which have converged in such a manner as to now give clinicians and scientists a variety of highly rational, yet practical options as they design and execute human clinical trials intended to exploit the innate antitumor properties of endogenous (i.e., patient-derived) γδ-T cells for the immunotherapy of a wide variety of human malignancies. This review is not intended to serve as a comprehensive survey of the growing field as this has been expertly reviewed in the recent past. Rather, this review will attempt to highlight some of the newly recognized biological issues –– and by extension, practical concerns –– which have become central to the field. One such critical issue relates to the findings that in only some patients is it possible to efficiently activate and/or expand endogenous γδ-T cells either in vivo or ex vivo, irrespective of the method used to stimulate these cells. This is in contrast to what is observed in normal healthy donors where robust ex vivo expansion or activation of γδ-T cells is readily achievable. In light of such observations, the emerging general consensus is that there may exist a poorly-defined “cancer-associated γδ-T cell impairment” occurring in patients –– an impairment which might preclude the widespread use of strategies which rely upon activating or expanding potentially tumor-reactive endogenous γδ-T cells. With this in mind, we discuss new strategies being developed to address this emerging challenge. This includes the development of models allowing for the adoptive transfer of tumor-reactive allogeneic (donor-derived) γδ-T cells obtained from otherwise healthy individuals. This, as well as other challenges –– both biological and practical –– will be discussed in the context of developing the next generation of human clinical trials intended to exploit the innate antitumor properties of γδ-T cells.