The Power of γ9δ2 T Cells: A Game-Changer in CD19-Positive Cancer Therapy

The treatment landscape for CD19-positive hematological malignancies has witnessed remarkable advancements in the last two decades. Notably, the emergence of CD19-targeting therapies, such as chimeric antigen receptor (CAR) T cell therapy and bispecific antibodies, like blinatumomab, has transformed the prognosis for patients suffering from cancer.  Blinatumomab, as the first T cell-engaging bispecific antibody (bsAb) in clinical use, has garnered considerable attention for its efficacy in treating patients with relapsed and refractory B cell-acute lymphoblastic leukemia (ALL). Its mechanism of action involves bringing cancerous B cells and functional T cells into close proximity, thereby facilitating the elimination of the cancer cells by the T cells. This off-the-shelf treatment has significant advantages over the autologous CD19-CAR T cell therapy, but it does have its limitations. The most prominent drawback of blinatumomab is its rapid clearance from circulation and short serum half-life, necessitating continuous intravenous infusion for up to 4 weeks per cycle, a burden for both patients and physicians. However, an innovative alternative to the continuous infusion of blinatumomab has emerged by engineering of αβ T cells to secrete blinatumomab. This strategy compensates for rapid blood clearance, supports long-term efficacy, and drastically reduces treatment burden. In an animal study, blinatumomab-secreting αβ T cells have demonstrated their superiority over conventional CD19-CAR T cell therapies in terms of limiting leukemia escape, making them an exciting prospect in the realm of CD19-targeted therapy.

A new study led by Dr. Shang-Ju Wu, Dr. Chien-Ting Lin, Dr. Cheng Hao Liao, and Dr. Chun-Ming Lin from National Taiwan University Hospital and ManySmart Therapeutics in Taiwan explored the potential of utilizing γ9δ2 T cells as vehicles for the delivery of blinatumomab to target CD19-positive hematological malignancies. This novel approach has the potential to revolutionize CD19-targeted therapy by offering a balance of advantages and disadvantages, as well as providing broader applications for cancer treatment.

The authors considered γ9δ2 T cells which constitute a small portion of peripheral blood T cells in healthy individuals possess innate immune functions that enable them to kill stressed or transformed cells without the need for co-stimulation. Their unique T cell receptors (TCRs) distinguish between normal and transformed cells by recognizing isopentenyl pyrophosphate (IPP)/butyrophilin 3A complexes on the target cells, making them highly attractive for cancer immunotherapy. Additionally, γ9δ2 T cells do not cause graft-versus-host disease, making them suitable for allogeneic applications and, potentially, off-the-shelf therapies. Their innate cytotoxicity, independent of human leukocyte antigen expression on tumor cells, offers an advantage over conventional αβ T cells.

The researchers genetically modified γ9δ2 T cells for blinatumomab secretion. The genetic engineering of γ9δ2 T cells to express blinatumomab through a retroviral vector was successful. The engineered γ9δ2 T cells secreted functional blinatumomab, demonstrating their capacity to deliver the therapeutic payload. This innovation addresses a significant limitation of blinatumomab-secreting αβ T cells, which cannot be easily applied in allogeneic settings. In contrast, γ9δ2 T cells hold promise for allogeneic applications without the risk of graft-versus-host disease, thus positioning themselves as potential universal, off-the-shelf therapy. The authors’ results demonstrated the potential utility of blinatumomab-secreting γ9δ2 T cells in both cell culture and mouse models. The first experiment showed that ex vivo expanded γ9δ2 T cells can effectively serve as effector cells for blinatumomab in eliminating ALL cells from bone marrow, thus extending the survival of tumor-implanted mice. Furthermore, these γ9δ2 T cells exhibited a memory phenotype, which suggests their potential for prolonged in vivo survival, supporting a weekly dosing schedule for adoptive γ9δ2 T cell therapy.

They also evaluated the cytotoxicity of blinatumomab-secreting γ9δ2 T cells, confirming their ability to kill CD19+ tumor cells effectively. The data show that γ9δ2 T cells induced substantial killing of tumor cells when applied alone, and their cytotoxicity was further enhanced when combined with zoledronic acid, which increases IPP to levels capable of sensing tumor cells to γ9δ2 T cells, offering a potential dual-targeting strategy that can improve therapeutic efficacy. The application of this novel approach to solid tumors is another compelling facet of this study. The results indicate that blinatumomab-secreting γ9δ2 T cells can effectively target solid tumor cells when coupled with appropriate CD19 gene transfer. This expands the potential applications of this innovative therapy beyond hematological malignancies, especially in view that authors have established an approach to bring γ9δ2 T cells into solid tumor.

Taken together, the study by Dr. Shang-Ju Wu and colleagues provided a number of significant findings with their novel approach to CD19-targeted therapy, utilizing γ9δ2 T cells as vehicles for the delivery of blinatumomab. The off-the-shelf nature of blinatumomab-secreting γ9δ2 T cells, combined with their potential dual-targeting capabilities, positions them as an important advancement in the field of cancer immunotherapy and offer a compelling case for further exploration and development of this novel treatment modality, which could revolutionize the treatment landscape for CD19-positive hematological malignancies and extend its potential to solid tumor applications. Further research and clinical trials are warranted to realize the full potential of blinatumomab-secreting γ9δ2 T cells as a transformative therapy in the fight against cancer.