Tumor-promoting Versus Tumor-antagonizing Roles of γδ T Cells in Cancer Immunotherapy

Abstract

Emerging evidence suggests that nitrogen-containing bisphosphonates have direct and indirect anticancer effects including immunomodulatory effects. Using in vivo targeting of bisphosphonate-reactive γδ T cells by adding low-dose interleukin-2 to zoledronic acid, we evaluated the safety, pharmacodynamics, and antitumor activity of this immunotherapy approach in 21 adults with advanced malignancies (renal cell carcinoma [RCC], malignant melanoma, and acute myeloid leukemia). A total of 58 treatment cycles were administered and the median number of treatment cycles was 2.7 (range, 1 to 6). The regimen was well tolerated, with no grade 3 to 4 drug-related adverse events, except for fever. No objective responses were observed in both cohorts of solid tumors (RCC and malignant melanoma), whereas 2 patients with acute myeloid leukemia (25%) achieved objective tumor responses (partial remission). Pharmacodynamic analyses showed significant in vivo activation (interferon-γ production) and expansion of γδ T cells in all evaluable patients. High pretreatment serum vascular endothelial growth factor (VEGF) levels and an unexpected increase in VEGF induced by zoledronic acid plus low-dose interleukin-2 were correlated with the lack of a clinical response. In conclusion, this study indicates that immunotherapy-induced VEGF can limit clinical innate tumor immune responses, especially for angiogenesis-dependent solid tumors. Our data challenge the current cellular immunotherapy paradigms in the treatment of cancer.

BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia

“…Although N-BP could be a promising therapy in hematologic malignancies, 13,28 our data confirm that some primary AML blasts with poor monocytic differentiation are poorly sensitized by N-BP to Vg9Vd2 T cells lysis. 16 These monocytic Low AML were shown to have poorly active mevalonate pathway.…”

“…10 The anti-leukemic effect of TCR agonists was supported by a trial showing partial remission in two AML patients receiving N-BP with IL-2. 13 As Vg9Vd2 T cells are altered in patients, 12,14 the adoptive transfer of these cells emerges as a promising alternative. 15 However, 50% of N-BP-treated blasts still failed to enhance allogeneic gd T cells cytotoxicity in vitro, suggesting that novel-triggering agents are still warranted.…”

γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes

“…26, [33][34][35][36] Vd1 cells reside within epithelial tissues, especially at sites of cytomegalovirus (CMV) replication, and exert potent cytotoxic effects against acute lymphoblastic leukemia (ALL) or AML cells, 37 chronic lymphocytic leukemia cells, [38][39][40] and primary multiple myeloma cells. 41 Overall, gd T lymphocytes are important effector cells, especially in situations where the function of adaptive immunity is impaired, such as those characterizing early immune recovery after haplo-HSCT depleted of ab T cells and CD19…”

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

“…Most interestingly, Kunzmann and colleagues noticed an unexpected increase in serum VEGF in response to zoledronate/IL-2 and found that this spike correlated with a lack of clinical response. 53 Therefore, the authors concluded that cd cell-derived VEGF induced by the treatment can limit clinical outcomes by harnessing innate tumor immunity. Transcriptome profiling of TCRVc9Vd2 1 cd T lymphocytes revealed that these cells upregulate expression of VEGF upon activation, 54 raising a special consideration for angiogenesisdependent solid tumors.…”