Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study

Abstract

BackgroundNot all non-small cell lung cancer (NSCLC) patients possess drug-targetable driver mutations, and response rates to immune checkpoint blockade therapies also remain unsatisfactory. Therefore, more effective treatments are still needed. Here, we report the results of a phase 2 clinical trial of adoptive cell therapy using zoledronate-expanded autologous Vγ9Vδ2 T-cells for treatment-refractory NSCLC.MethodsNSCLC patients who had undergone at least two regimens of standard chemotherapy for unresectable disease or had had at least one treatment including chemotherapy or radiation for recurrent disease after surgery were enrolled in this open-label, single-arm, multicenter, phase 2 study. After preliminary testing of Vγ9Vδ2 T-cell proliferation, autologous peripheral blood mononuclear cells were cultured with zoledronate and IL-2 to expand the Vγ9Vδ2 T-cells. Cultured cells (>1×109) were intravenously administered every 2 weeks for six injections. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), best objective response rate (ORR), disease control rate (DCR), safety and immunomonitoring. Clinical efficacy was defined as median PFS significantly >4 months.ResultsTwenty-five patients (20 adenocarcinoma, 4 squamous cell carcinoma and 1 large cell carcinoma) were enrolled. Autologous Vγ9Vδ2 T-cell therapy was administered to all 25 patients, of which 16 completed the foreseen course of 6 injections of cultured cells. Median PFS was 95.0 days (95% CI 73.0 to 132.0 days); median OS was 418.0 days (179.0–479.0 days), and best overall responses were 1 partial response, 16 stable disease (SD) and 8 progressive disease. ORR and DCR were 4.0% (0.1%–20.4%) and 68.0% (46.5%–85.1%), respectively. Severe adverse events developed in nine patients, mostly associated with disease progression. In one patient, pneumonitis and inflammatory responses resulted from Vγ9Vδ2 T-cell infusions, together with the disappearance of a massive tumor.ConclusionsAlthough autologous Vγ9Vδ2 T-cell therapy was well tolerated and may have an acceptable DCR, this trial did not meet its primary efficacy endpoint.Trial registration numberUMIN000006128

Chimeric Antigen Receptor beyond CAR-T Cells

“…As the major circulating γδ T population, Vδ2/Vγ9 T cells recognise phosphoantigens. Indeed, aminobiphosphonates (e.g., zoledronate) are broadly used for their ex vivo expansion [ 17 ]. Other γδ T cell subsets account for rarer populations, among which Vδ1 subsets confer residency in mucosal epithelia [ 18 ].…”

Bispecific Antibody PD-L1 x CD3 Boosts the Anti-Tumor Potency of the Expanded Vγ2Vδ2 T Cells

“…As the adoptive transfer of the expanded and purified Vg2Vd2 T cells has been shown a safe and well-tolerated therapy (20)(21)(22), we tested the concept of the combination of the purified Vg2Vd2 T cells with Y111 in the following study. Firstly, we investigated whether Y111 could bridge the expanded Vg2Vd2 T cells and tumor cells.…”

“…The adoptive transfer of Vg2Vd2 T cells could reduce the growth of NSCLC cell line-derived xenografts and prolong the survival of tumor-bearing mice (18,19). Yet, this immunotherapy failed in its efficacy evaluation of clinical trials during the past decades (20)(21)(22). Meanwhile, the landscape-changing "Magacurve" for advanced NSCLC showed the therapeutic successes of PD1/PD-L1 blockade (23), even though the monotherapy of anti-PD1/ PD-L1 mAb resulted in positive response of only~15-30% of NSCLC patients (24).…”

Bi-specific Antibody Y111, Targeting PD-L1 and CD3 Considerably Enhances the Therapeutic Efficacy of Adoptive Transferred Vγ2Vδ2 T Cells

“…The clinical response rates of non-small cell lung cancer (NSCLC) patients, which accounts for approximately 85% of lung cancers, to the current rst or second line treatment are still unsatisfying [13,14]. Although the adoptive transfer of Vγ2Vδ2 T cells could reduce the growth of lung cancer cell and prolong the survival of NSCLC-tumor bearing mice [15,16], this immunotherapy has be proved to be safe but only effective in stabilizing the cancer progress in clinical trials during the past decades [17][18][19]. Also, the landscape-changing "Magacurve" for advanced NSCLC has shown the therapeutic successes of PD1/PD-L1 blockade [20], the monotherapy of receiving anti-PD1/PD-L1 agents results in response only in a small proportion of NSCLC patients [21].…”