Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma

In this first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated with CARv3-TEAM-E T cells, which are chimeric antigen receptor (CAR) T cells engineered to target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well as the wild-type EGFR protein, through secretion of a T-cell–engaging antibody molecule (TEAM). Treatment with CARv3-TEAM-E T cells did not result in adverse events greater than grade 3 or dose-limiting toxic effects. Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants. (Funded by Gateway for Cancer Research and others; INCIPIENT ClinicalTrials.gov number, NCT05660369.)

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Glioblastoma is the most aggressive primary brain tumor, and the prognosis for recurrent disease is exceedingly poor with no effective treatment options. Chimeric antigen receptor (CAR) T cells represent a promising approach to cancer because of their proven efficacy against refractory lymphoid malignant neoplasms, for which they have become the standard of care. However, the use of CAR T cells in solid tumors such as glioblastomas has been limited to date, largely owing to the challenge in targeting a single antigen in a heterogeneous disease and to immunosuppressive mechanisms associated with the tumor microenvironment. 

In a previous clinical trial, we found that peripheral infusion of epidermal growth factor receptor (EGFR) variant III–specific CAR T cells (CART-EGFRvIII) safely mediated on-target effects in patients with glioblastoma. Despite this activity, no radiographic responses were observed, and recurrent tumor cells expressed wildtype EGFR protein and showed heavy intratumoral infiltration with suppressive regulatory T cells. To address these barriers, we developed an engineered T-cell product (CARv3-TEAM-E) that targets EGFRvIII through a second-generation CAR while also secreting T-cell–engaging antibody molecules (TEAMs) against wildtype EGFR, which is not expressed in the normal brain but is nearly always expressed in glioblastoma. We found in preclinical models that TEAMs secreted by CAR T cells act locally at the site where cognate antigen is engaged by the CAR T cells in the treatment of heterogeneous tumors. We also found in vitro that these molecules have the capacity to redirect even regulatory T cells against tumors. On the basis of these data, we initiated a first-in-human, phase 1 clinical study to evaluate the safety of CARv3-TEAM-E T cells in patients with recurrent or newly diagnosed glioblastoma. Here, we report the findings from a prespecified interim analysis involving the first three participants treated with this approach. [...]

Discussion

This study shows that antitumor CAR-mediated responses can be rapidly obtained in patients with glioblastoma, even in those with advanced, intraparenchymal cerebral disease. This finding contrasts with a previous report of a complete response that was observed in a patient with recurrent leptomeningeal disease who received treatment with 16 intracranial infusions of monospecific interleukin-13 receptor alpha 2 CAR T cells. It was hypothesized by the investigators of that study that the involvement of glioblastoma in the leptomeninges may have rendered the disease more responsive to intraventricular therapy. Our experience in the current study suggests that even a single dose of intraventricularly administered living drugs such as CAR T cells also have the capacity to access and mediate activity against infiltrative, parenchymal glioblastoma.

by Bryan D. Choi, M.D., Ph.D., Elizabeth R. Gerstner, M.D., Matthew J. Frigault, M.D., Mark B. Leick, M.D., Christopher W. Mount, M.D., Ph.D., Leonora Balaj, Ph.D., Sarah Nikiforow, M.D., Ph.D., Bob S. Carter, M.D., Ph.D., William T. Curry, M.D., Kathleen Gallagher, Ph.D., and Marcela V. Maus, M.D., Ph.D. NIH, National Center for Biotechnology Information |   Read more:

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[ed. Only three patients (so far) and it appears sustained treatments are needed to prevent recurrence (so far). But still, pretty interesting.]