Year: 2017
Type: conference-abstract
Abstract: The intent of this project is to develop T cells expressing an EphA2-specific chimeric antigen receptor (CAR) as an immunotherapy for diffuse intrinsic pontine glioma (DIPG) and glioblastoma (GBM). EphA2 is an attractive target given its high expression in GBM but not normal brain tissue. We previously generated an EphA2-specific CAR that exhibited potent antitumor activity in a glioma xenograft model. However, this CAR had a CH2CH3 spacer, which binds FC receptors and is not ideal for clinical development. We therefore generated a panel of EphA2-CARs with a short spacer region (SSR) lacking FC receptor binding sites, and a CD28.ζ, CD137.ζ, or CD28.CD137.ζ endodomain. T cell transduction efficiency ranged from 60–80%. CAR T cells only killed EphA2+ target cells (U373, A549), secreted IFNγ and IL2 in an antigen-dependent manner, and expanded for at least 14 days after repeat stimulations with EphA2+ tumor cells with no significant difference between CAR T-cell lines. In vivo, intratumoral injection of CD28.ζ and CD137.ζ CAR T cells in the U373 glioma model provided complete responses in 40–100% of mice at cell doses of 2x106, 5x105, or 1x105, but exhibited only transient antitumor activity at the lowest cell dose of 1x104. Comparing persistence of CD28.ζ and CD137.ζ CAR T cells after intratumoral injection in vivo revealed no significant difference. We demonstrate here that CD28.ζ and CD137.ζ EphA2-CAR T cells have similarly potent antitumor activity, and that including a second costimulatory domain does not improve effector function. We selected CD28.ζ EphA2-CARs for future clinical development since CD28.ζ CAR T cells do not persist long-term in humans. While our CAR’s scFV recognizes a cancer-specific conformational epitope, we are including an inducible suicide gene for clinical grade vector production. Limited T-cell persistence should further reduce the inherent risk of ‘on target/off cancer toxicity’ in a ‘first-in-human’ clinical study.
Source: Neuro-Oncology
Institution: Baylor College of Medicine
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2620093301