Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma. (3rd June 2018)

• Record Type: Journal Article
• Authors: Suryadevara, Carter M.; Desai, Rupen; Abel, Melissa L.; Riccione, Katherine A.; Batich, Kristen A.; Shen, Steven H.; Chongsathidkiet, Pakawat; Gedeon, Patrick C.; Elsamadicy, Aladine A.; Snyder, David J.; Herndon, James E.; Healy, Patrick; Archer, Gary E.; Choi, Bryan D.; Fecci, Peter E.; Sampson, John H.; Sanchez-Perez, Luis
• Is Part Of: Oncoimmunology. Volume 7:Number 6(2018)
• Publication Date: 2018-06-03
• Subjects: glioma -- glioblastoma -- brain tumor -- immunotherapy -- lymphopenia -- temozolomide -- adoptive transfer -- chimeric antigen receptor; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2018.1434464
• Languages: English
• ISSNs: 2162-402X

Abstract

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 (TMZ SD ) and dose-intensified TMZ (TMZ DI ) in our murine model. Both regimens are clinically approved and provide similar efficacy. Only TMZ DI pretreatment prompted dramatic CAR proliferation and enhanced persistence in circulation compared to treatment with CARs alone or TMZ SD + CARs. Bioluminescent imaging revealed that TMZ DI + CARs induced complete regression of 21-day established brain tumors, which correlated with CAR abundance in circulation. Accordingly, TMZ DI + CARs significantly prolonged survival and led to long-term survivors. These findings are highly consequential, as it suggests that GBM patients may require TMZ DI 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 TMZ DI as a preconditioning regimen prior to CAR immunotherapy (NCT02664363).