Optimizing Tumor-Reactive γδT Cells for Antibody-Based Cancer Immunotherapy

Abstract

Monoclonal antibodies (mAbs) constitute the most rapidly growing class of human therapeutics and the second largest class of drugs after vaccines. The treatment of B-cell malignancies and HER2/Neu(+) breast cancer has benefited considerably from the use of therapeutic mAbs, either alone or in combination with standard chemotherapy. Frequent relapses, however, demonstrate that the bioactivity of these mAbs is still suboptimal. The concept of improving the anti-tumor activity of mAbs is well established and potentiating the cytotoxicity induced by anticancer mAbs can be achieved by strategies that target the downstream cytolytic effector cells. The recruitment of Fcγ receptor-dependent functions appears well suited in this regard, because several lines of evidence suggest that enhancing antibody-dependent cellular cytotoxicity (ADCC) induced by therapeutic mAbs may directly improve their clinical efficacy. The cytolytic effector cells involved in ADCC are FcγR-expressing natural killer (NK) cells, but also γδ T cells can be amplified and finetuned for stronger ADCC activity. γδ T cells are raising a considerable interest in the immunotherapy community given their intrinsic antitumor activity that can be boosted by stimulation with synthetic phosphoantigens (PAgs), or with drugs that cause their accumulation into target cells, like aminobisphosphonates (N-BPs), and low doses interleukin (IL)-2. The field is interesting, and several papers have already explored this approach in solid and haematological malignancies. Thus, we propose that enhancing the efficacy of mAbs by combination with γδ T cell activation may have considerable therapeutic potential for a variety of malignancies, most especially for patients whose FcγR alleles impair ADCC.

Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells

“…An enhanced efficacy against Her2 þ breast cancer cells has been described after adoptive transfer of expanded gd T cells together with a humanized anti-Her2/neu mAb (trastuzumab) into human Her2 þ mammary carcinomabearing SCID mice (32). A recent review summarized the evidence that the combination of gd T-cell-based immunotherapy with mAb in general exerts a considerable therapeutic potential for a variety of malignancies (33). In all these studies, gd T cells bind to mAb-labeled tumor cells via FcRgIII (CD16) and thereby exert antibody-dependent cell-mediated cytotoxicity.…”

“…gd T cells have been shown to lyse human colon cancer stem cells, which might provide an additional advantage for gd T-cell-based immunotherapy (50). Meraviglia and colleagues demonstrated a considerable therapeutic potential for gd T cells in treatment of Her2-expressing breast cancer as well as B-cell malignancies by co-application of therapeutic mAb alone or in combination with chemotherapy (33). Because bispecific antibodies have demonstrated a higher cytolytic potential than mAbs (29), even better responses might be achieved by using bispecific antibodies engaging CD3 or the gd TCR instead of mAb in combination with a gd T-cell-based immunotherapy, possibly further supporting chemotherapy.…”

Comparative Characterization of Stroma Cells and Ductal Epithelium in Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma

“…high amounts of TGF-β1 [4] tended to be more abundant in PDAC than in CP tissues. Thus, an efficient strategy to enhance γδ-T cell activity and to probably overcome immunosuppression of the stromal composition might be the usage of enhancer of γδ-T cell cytotoxicity [36]. In addition, strategies to eliminate or suppress regulatory T cells and myofibroblasts might be beneficial.…”

Repeated Systemic Administrations of Both Aminobisphosphonates and Human Vγ9Vδ2 T Cells Efficiently Control Tumor Development In Vivo

“…Several strategies have been proposed to enhance antitumor efficacy of such active immunotherapies targeting gd T cells. Both the enhanced expression of CD16 on Vg9Vd2 PBL, compared with ab PBL, and the ability of activated Vg9Vd2 T cells to mediate Ab-dependent cellular cytotoxicity toward solid and hemopoietic tumors, either in vitro or in vivo in xenografted mice, provide a strong rationale for combination approaches involving gd agonist molecules and antitumor mAb (25)(26)(27)(28). In this regard, treatment with anti-CD20 mAb (Rituximab), PAg, and IL-2 for patients with follicular lymphoma and tumor relapse or resistance after a first line of rituximab treatment resulted in an increased rate of complete responses, when compared with historical groups treated with a second line of rituximab alone or rituximab and IL-2 (13).…”