Intraperitoneal injection of in vitro expanded Vγ9Vδ2 T cells together with zoledronate for the treatment of malignant ascites due to gastric cancer

Abstract

Malignant ascites caused by peritoneal dissemination of gastric cancer is chemotherapy-resistant and associated with poor prognosis. We conducted a pilot study to evaluate the safety of weekly intraperitoneal injections of in vitro expanded Vγ9Vδ2 T cells together with zoledronate for the treatment of such malignant ascites. Patient peripheral blood mononuclear cells were stimulated with zoledronate (5 μmol/L) and interleukin-2 (1000 IU/mL). After 14 days culture, Vγ9Vδ2 T-cells were harvested and administered intraperitoneally in four weekly infusions. The day before T-cell injection, patients received zoledronate (1 mg) to sensitize their tumor cells to Vγ9Vδ2 T-cell recognition. Seven patients were enrolled in this study. The number of Vγ9Vδ2 T-cells in each injection ranged from 0.6 to 69.8 × 108 (median 59.0 × 108). There were no severe adverse events related to the therapy. Intraperitoneal injection of Vγ9Vδ2 T cells allows them access to the tumor cells in the peritoneal cavity. The number of tumor cells in the ascites was significantly reduced even after the first round of therapy and remained substantially lower over the course of treatment. IFN-γ was detected in the ascites on treatment. Computed tomography revealed a significant reduction in volume of ascites in two of seven patients. Thus, injection of these antitumor Vγ9Vδ2 T-cells can result in local control of malignant ascites in patients for whom no standard therapy apart from paracentesis is available. Adoptively transferred Vγ9Vδ2 T-cells do indeed recognize tumor cells and exert antitumor effector activity in vivo, when they access to the tumor cells.

2015 Guidance on cancer immunotherapy development in early‐phase clinical studies

“…Effector cells directly involved in the destruction of cancer cells and inhibition of their growth include CD8 + T cells, CD4 + T cells, γδ T cells, natural killer (NK) cells, and natural killer T (NKT) cells. These autologous cells collected from the peripheral blood or tumor in patients are in vitro processed and allowed to proliferate, and are subsequently infused into the patients . During in vitro preparation of these cells, antigen‐non‐specific or ‐specific stimulation by tumor antigens or autologous tumor cells may be provided.…”

Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug

“…In 9 clinical trials involving a total of 213 patients, adoptive transfer of Vγ2Vδ2 T cells has proven to be safe, does not require pretreatment with cytotoxic agents, and has resulted in a durable remission in a patient with metastatic clear cell renal cancer, complete and partial responses in patients with breast and cervical cancer, and stable disease in 50% of patients with advanced NSCLC . However, most patients progressed, underscoring the need for improvements in the efficacy of this therapy.…”

Quantum dot-based multiplexed imaging in malignant ascites: a new model for malignant ascites classification

“…In this regard, previous studies were mostly focused on searching for the optimal chemotherapy regimens against MA, including the paclitaxel with tegafur regimen, the combined intraperitoneal recombinant human endostatin and chemotherapy regimen, the catumaxomab regimen, the cediranib regimen, immunotherapy, and others. [29][30][31][32][33][34][35][36] However, the rate of complete remission with these regimens remains less than 30%.…”