IMMU-17. CAR T CELLS TARGETING THE INTEGRIN ALPHAVBETA3 EXHIBIT ROBUST ANTI-TUMOR RESPONSES AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND GLIOBLASTOMA (GBM)

Abstract

Effective therapies for DIPG and GBM are lacking. CD19 chimeric antigen receptor (CAR) T cells are highly effective in patients with refractory B-cell malignancies. We aim to develop novel CARs for high-grade gliomas. The integrin complex alphavbeta3 was selected as a CAR-T cell target due to its expression on gliomas and their vasculature, yet with minimal expression throughout normal tissues, vessels and organs. Indeed, a majority of DIPG and GBM cell lines express surface α vβ 3. Second-generation CAR-T cells expressing an anti-α vβ 3 scFv and either a CD28 or 4-1BB co-stimulatory domain and CD3zeta were constructed. Transduced healthy, donor-derived T cells exhibited high level CAR expression, efficient expansion, and representative populations of memory subsets including central, effector, and stem cell-like memory CAR-T cells. α vβ 3.28z and α vβ 3.BBz CAR-T cells exhibited antigen-specific in vitro cytotoxicity and cytokine production against DIPG and GBM cell lines. Both CARs mediated rapid and robust anti-tumor responses in NSG mice bearing orthotopic DIPG or GBM tumors. 5/13 α vβ 3.28z and 0/14 α vβ 3.BBz treated animals died without detectable disease within 2 weeks of infusion suggesting different toxicity profiles and is consistent with faster CAR-T cell expansion in CD28-versus 4-1BB-containing CD19 CAR-T cells seen clinically. Our results demonstrate that α vβ 3.BBz CAR-T cell therapy may be both highly effective and safe in DIPG and GBM patients. Due to the restricted nature of α vβ 3 expression in normal tissues, the robust responses seen in tumor-bearing mice, and the slower kinetics of α vβ 3.BBz CAR-T cell expansion, a first-in-human clinical trial is being planned.