Improving Immunotherapy Against B-Cell Malignancies Using γδ T-Cell–specific Stimulation and Therapeutic Monoclonal Antibodies

Abstract

Tumor antigen–targeting monoclonal antibodies (mAbs) are an important element of current cancer therapies. Some of these therapeutic mAbs enable antibody-dependent cell mediated cytotoxicity (ADCC) against tumor cells. However, cancer-related functional impairment of immune effector cells may limit the clinical efficacy of antibody treatments. We reckoned that combining mAbs with cell-based immunotherapies would provide a clinically relevant synergism and benefit for cancer patients. Here, we focus on γδ T cells, as earlier studies demonstrated that γδ T-cell–based therapies are safe and promising for several types of malignancies. Similar to natural killer cells, their antitumor effects can be enhanced using antibodies, and they could, therefore, become a versatile effector cell platform for use with a variety of licensed therapeutic mAbs against cancer. In this study, we explore the potential of a combination therapy of activated γδ T cells with rituximab and the more recently developed mAbs (obinutuzumab and daratumumab) in different B-cell malignancies in vitro. Obinutuzumab outperformed the other mAbs with regard to direct target cell lysis and ADCC by γδ T cells in several CD20+ cell lines and primary lymphoma specimens. We demonstrate that comparatively few CD16low γδ T cells are sufficient to mediate a strong ADCC. Using Fc-receptor-positive B-cell lymphomas as target cells, ADCC cannot be blocked by high concentrations of immunoglobulins or anti-CD16 antibodies, but both substances can promote cell mediated target cell lysis. This study expands on earlier reports on the therapeutic potential of distinctive tumor antigen–targeting mAbs and facilitates the understanding of the mechanism and potential of ADCC by γδ T-cell subsets.

Cancer immunotherapy with γδ T cells: many paths ahead of us

“…Therefore, the combination of clinically used therapeutic antibodies with adoptive Vδ2 T cell transfer might enhance the efficacy. 200 , 201 Further, γδ T cell activity is also regulated by checkpoint receptors. Vδ2T cells transiently upregulate PD-1 expression upon activation.…”

Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

“…Hence, the recognition of BTN3A activated by phosphoantigens can elicit cytotoxic effector functions of Vγ9Vδ2 T cells. In addition, stimulation through phosphoantigens and Interleukin (IL)-2 can upregulate the expression of FcγRIII (CD16) in circulating Vδ2 T cells [65], which when combined with therapeutic antibodies such as Rituximab or Obinutzumab can enhance the antibody dependent cellular cytotoxicity (ADCC) of Vγ9Vδ2 T cells and enhance their lytic activity on cancer cells, especially in hematological indications [66,67] and Neuroblastoma [68]. In another study, activated Vγ9Vδ2 T cells bound to Trastuzumab-treated breast cancer cells via CD16 and thereby exerted ADCC.…”

“…The capability of Vγ9Vδ2 T cells to undergo massive clonal expansion in infection settings is being exploited ex vivo using direct or indirect BTN3A agonists BrHPP or amino-bisphosphonates (such as zoledronic acid) in combination with IL-2. Many in vitro expansion protocols for γδ T cells have been established, opening the door for large-scale experiments, pre-clinical models and adoptive transfer studies [67,97] (Table 1). In the context of cancer therapy, it is now possible to highly enrich autologous cells by ex vivo expansion and re-infuse them into a cancer patient.…”

Battle of Thermopylae: 300 Spartans (natural Killer Cells Plus obinutuzumab) Versus the Immortal Warriors (chronic Lymphocytic Leukemia cells) of Xerxes’ Army

“…Intriguingly, both ibrutinib and venetoclax induce a significant increase in the frequency of γδ T cells [27], which are cytotoxic cells that share several NK-cell features such as CD16 expression and ADCC. In a very recent report, Hoeres et al demonstrated that both T and NK cells contribute to GA101-induced ADCC in an elegant and interestingly basic study [28].…”