211. CD2, the First Identified T cell Co-Stimulator, Demonstrates More Effective Chimeric Antigen Receptor Activity Over CD28 and 4-1BB
Year: 2015
Type: article
Abstract: CD2, first identified as T11 sheep erythrocyte receptor protein, was originally classified as the trigger for an alternative T cell activation pathway and later as a costimulatory molecule that synergized with CD3 activation. Co-stimulation of T cells with CD2 augments CD3-mediated signaling cascades, IL-2 production, and proliferation. The field dedicated to the development of novel second- and third-generation chimeric antigen receptors (CARs) has focused on the inclusion endodomains from CD28 superfamily and TNFRSF members as costimulation, but the use of CD2/SLAM family of costimulatory molecules has not been explored. Here, we report the development of an anti-mesothelin (SS1) chimeric antigen receptor co-stimulated with the endodomain of CD2 juxtaposed to the CD3z activation domain (SS1CD2z). Human T cells modified with SS1CD2z demonstrate comparable cytotoxicity of tumor cell lines in vitro as SS1z, SS1BBz, and SS128z. SS1CD2z T cells proliferation similar to SS128z and better than SS1BBz in vitro. SS1CD2z T cells exhibit a calcium flux in response to antigen that is half the amplitude of the response seen for SS128z, while no calcium flux is observed for SS1BBz. Similarly, all three CARs exhibit differential signaling profiles, consistent with the signaling of CD28 superfamily, TNFRSF, and CD2/SLAM superfamily pathways. Luminex analysis revealed that IL-2 production is superior among SS128z and SS1CD2z, while SS1BBz T cells produce less. IFNγ production is comparable between all CAR groups. Importantly, SS1CD2z cells produce minimal quantities TNFα similar to SS1BBz cells; contrary to SS128z cells, which produce large quantities of the neurotoxic cytokine. SS1CD2z T cells exhibited a fast and durable anti-tumor response against a subcutaneous mesothelioma xenograft model, while both SS128z and SS1BBz T cells lagged in terms of response rate. These results suggest that CAR co-stimulation via CD2 can produce potent antitumor activity, T cell proliferation and favorable cytokine profiles. Exploration of other CD2/SLAM superfamily members for CAR co-stimulation could be beneficial to cancer patients and the cellular therapy community.
Source: Molecular Therapy
Authors: Avery D. Posey, Carl H. June
Institution: University of Pennsylvania
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W2566469602