Abstract LB-340: Combinatorial platform for CART cell therapy for glioblastoma
Authors: Binder Zev A. , Yin Yibo , Thokala Radhika , O'Rourke Donald M. 
Published: August 2018

Introduction:

Our clinical program in chimeric antigen receptor T (CART) cell therapy has focused on targeting EGFR oncoproteins for glioblastoma (GBM). We have completed a phase I trial using CART cells directed to the EGFRvIII antigen and showed in situ uptake, proliferation, functional activation and antigen editing by CART cells in GBM tissue. This first clinical trial demonstrated two barriers to clinical efficacy. First, GBM heterogeneity was striking spatially and temporally, including the number of variants in EGFR. Second, CART cell therapy was associated with an adaptive anti-GBM response illustrated by an initial wave of CART activation followed by dramatic immunosuppression. These two features indicate that we need strategies to overcome GBM heterogeneity and the immunosuppressive tumor microenvironment (TME).

Methods:

We have used multiple CART variants, targeting both IL13Rα2 and EGFRvIII, in combination with selected immune checkpoint blockade inhibitors, to explore possible additive effects in both in vitro and in vivo GBM model systems on limiting the immunosuppressive GBM TME. Independently, we have developed a portfolio of CARTs with different binding specificities that target other homo- and heterodimers of EGFR oncoproteins, to address GBM heterogeneity.

Results:

Combination studies of CART cells with immune checkpoint blockade inhibitors revealed a non-homogenous response. Different CART structures and targets showed increased tumor killing activity with specific immune checkpoint blockade inhibition. Specifically, IL13Rα2-targeting CART cells had the best effect when paired with anti-CTLA4 treatment, while EGFRvIII-targeting CART cells had the largest effect when paired with anti-PD-1 treatment. In parallel to our combination therapy work, we have expanded our repertoire of CART constructs for targeting EGFR oncogenic alleles with extracellular domain mutations by utilizing antibody phage display technology. EGFR-targeting antibody sequences were incorporated into viral constructs and transduced into T cells. We have shown variable killing with these novel CART constructs in GSC/PDX models of GBM heterogeneity.

Conclusion:

Our initial experience with CART cells in GBM suggested that although a single intravenous infusion results in CART cell bioactivity in the brain, overcoming the adaptive changes in the local TME and addressing antigen heterogeneity may improve the clinical efficacy of CART-directed strategies. Our combination work showed that different CART constructs cooperate with immune checkpoint blockade inhibition differentially. This selective pairing suggests that a more personalized immunophenotypic assessment may result in higher efficacy therapeutic combinations. In addition, development of a broad portfolio of both selective and promiscuous CART constructs targeting EGFR in its various forms gives us the potential to cover a larger percentage of both the GBM tumor volume and regionally-specific tumor cells within a single GBM.

Citation Format: Zev A. Binder, Yibo Yin, Radhika Thokala, Donald M. O'Rourke. Combinatorial platform for CART cell therapy for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-340.