Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma

Abstract

Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for B-cell malignancies but has failed in some solid tumors clinically. Intracerebral tumors may pose challenges that are even more significant. In order to devise a treatment strategy for patients with glioblastoma (GBM), we evaluated CARs as a monotherapy in a murine model of GBM. CARs exhibited poor expansion and survival in circulation and failed to treat syngeneic and orthotopic gliomas. We hypothesized that CAR engraftment would benefit from host lymphodepletion prior to immunotherapy and that this might be achievable by using temozolomide (TMZ), which is standard treatment for these patients and has lymphopenia as its major side effect. We modelled standard of care temozolomide (TMZSD) and dose-intensified TMZ (TMZDI) in our murine model. Both regimens are clinically approved and provide similar efficacy. Only TMZDI pretreatment prompted dramatic CAR proliferation and enhanced persistence in circulation compared to treatment with CARs alone or TMZSD + CARs. Bioluminescent imaging revealed that TMZDI + CARs induced complete regression of 21-day established brain tumors, which correlated with CAR abundance in circulation. Accordingly, TMZDI + CARs significantly prolonged survival and led to long-term survivors. These findings are highly consequential, as it suggests that GBM patients may require TMZDI as first line chemotherapy prior to systemic CAR infusion to promote CAR engraftment and antitumor efficacy. On this basis, we have initiated a phase I trial in patients with newly diagnosed GBM incorporating TMZDI as a preconditioning regimen prior to CAR immunotherapy (NCT02664363).

Keywords

• glioma
• glioblastoma
• brain tumor
• immunotherapy
• lymphopenia
• temozolomide
• adoptive transfer
• chimeric antigen receptor