Gamma Delta T Cell Therapy for Cancer: It Is Good to be Local

Abstract

Human gamma delta T cells have extraordinary properties including the capacity for tumor cell killing. The major gamma delta T cell subset in human beings is designated Vγ9Vδ2 and is activated by intermediates of isoprenoid biosynthesis or aminobisphosphonate inhibitors of farnesyldiphosphate synthase. Activated cells are potent for killing a broad range of tumor cells and demonstrated the capacity for tumor reduction in murine xenotransplant tumor models. Translating these findings to the clinic produced promising initial results but greater potency is needed. Here, we review the literature on gamma delta T cells in cancer therapy with emphasis on the Vγ9Vδ2 T cell subset. Our goal was to examine obstacles preventing effective Vγ9Vδ2 T cell therapy and strategies for overcoming them. We focus on the potential for local activation of Vγ9Vδ2 T cells within the tumor environment to increase potency and achieve objective responses during cancer therapy. The gamma delta T cells and especially the Vγ9Vδ2 T cell subset, have the potential to overcome many problems in cancer therapy especially for tumors with no known treatment, lacking tumor-specific antigens for targeting by antibodies and CAR-T, or unresponsive to immune checkpoint inhibitors. Translation of amazing work from many laboratories studying gamma delta T cells is needed to fulfill the promise of effective and safe cancer immunotherapy.

Similar local recurrence but better function with curettage versus resection for bone giant cell tumor and pathological fracture at presentation

“…Recent study showed gamma delta T cells produce interleukin‐17A that promotes bone formation and facilitates bone fracture healing . As gamma delta T cells have extraordinary properties including the capacity for tumor cell killing, the activated gamma delta T cells during fractured bone healing may have killed both mononuclear cells and multinucleated osteoclast‐type giant cells.…”

“…43 Recent study showed gamma delta T cells produce interleukin-17A that promotes bone formation and facilitates bone fracture healing. 44 As gamma delta T cells have extraordinary properties including the capacity for tumor cell killing, 45 et al reported that the rate for major complications was higher after resection when compared with curettage with adjuvants (16% versus 4%, respectively). 29 In contrast, in the present study, the complications rate was comparable between curettage and resection (15.2% versus 15.4%).…”

γδ T cells in cancer: a small population of lymphocytes with big implications

“…124,125 An additional perquisite of using cd T cells for immunotherapy lies in their ability to crosspresent processed tumor antigen to ab T cells, and this process is retained in CAR-cd T cells, further enhancing their antitumor effects. 124,125 An additional perquisite of using cd T cells for immunotherapy lies in their ability to crosspresent processed tumor antigen to ab T cells, and this process is retained in CAR-cd T cells, further enhancing their antitumor effects.…”

“…Recently, cd T cells have been incorporated into CAR therapy, producing sufficient cells from Vd1 + and Vd2 + subsets for clinical studies. 124,125 An additional perquisite of using cd T cells for immunotherapy lies in their ability to crosspresent processed tumor antigen to ab T cells, and this process is retained in CAR-cd T cells, further enhancing their antitumor effects. 124…”

Prostate Cancer

“…Proliferation of PC tumor cells was suppressed in severely immunodeficient mice, and an initial study using the gd T-cell agonist zoledronate in combination with IL-2 presented with promising results in patients with metastatic PC. 37 Immune responses against the tumors are dependent on the subset of T cell recruited to the site of the tumor, which is dependent on the chemokine and cytokine gradient defining the specific type of inflamed cells. The Tregs, through their immunosuppressive effects, favor tumorpromoting characteristics; and the same has been demonstrated in PC patients, in whom elevated levels of Tregs conferred poor survival rates and a greater possibility of death.…”