Abstract 3592: Pharmacological intervention to temporally stimulate or inhibit ICAM-1 targeting CAR-T cells
Authors: Vedvyas Yogindra , McCloskey Jaclyn , Yang Yanping , Min Irene M. , Jin Moonsoo M. 
Published: August 2018

Gene-engineered adoptive T cell therapies have recently been approved by the FDA. We have previously published data utilizing this technology to target intercellular adhesion molecule-1 (ICAM-1), a broad tumor biomarker. Using an affinity modified version of the physiological ligand of ICAM-1,leukocyte function-associated antigen-1 (LFA-1) I-domain, we have shown efficient clearance of a human metastatic anaplastic thyroid cancer (ATC). We were able to visualize and quantify the bio-distribution of CAR-T cells with a PET gene reporter, somatostatin receptor 2 (SSTR2) (Park et. al, Scientific Reports 7, Article number: 14366, 2017). To expand on this platform, we now want to control the activity of our CAR-T cells by exploiting these features using two FDA approved drugs. First, a somatostain analogue, Lanreotide, has been approved for treating Acromegaly and we have recently observed that Lanreotide can activate SSTR2-transduced T cells via calcium release. Second, Lovastatin, a drug clinically used for lowering cholesterol levels, was found to bind the LFA-1 I-domain and inhibit LFA-1 binding to ICAM-1. We hypothesized that in addition to our I-domain CAR-T cell, systemic use of Lanreotide will stimulate CAR-mediated tumor killing while systemic use of Lovastatin will inhibit CAR-mediated tumor killing.

In-vitro testing involved effector to target (E:T) assays performed in the presence and absence of Lovastatin or Lanreotide. ICAM-1(+) ATC target cells or ICAM-1(-) 293T off-target cells were utilized, both of which were transduced with GFP-Firefly Luciferase (GFP/Fluc) for quantification. Effector T-cells derived from healthy donor PBMCs were either transduced with our I-domain CAR-T cell construct that contains SSTR2, or were left nontransduced. Similar assays were translated in-vivo using a previously established solid tumor model with GFP/Fluc ATC ICAM-1(+) cells. Luminescence was used to track tumor progression and regression throughout both in-vivo and in-vitro experiments. [Ga68] DOTA-TOC was administered via IV injections to visualize the bio-distribution of the CAR-T cells using SSTR2 via PET/CT.

Both in-vitro and in-vivo experiments showed Lovastatins ability to compromise I-domain CAR-mediated tumor killing while Lanreotide expedited the rate of I-domain CAR-mediated killing. We report here that Lovastatin inhibits the interaction of our I-domain CAR with ICAM-1 that is present on our target tumor cells and compromises tumor killing. In addition, we have shown a unique phenomena where we can activate SSTR2-transduced CAR-T cells using Lanreotide. The ability to control CAR-T cell activity is an essential tool when addressing adverse effects and/or less than robust treatment outcomes. This will be crucial when translating our adoptive T cell therapy to the clinic.

Citation Format: Yogindra Vedvyas, Jaclyn McCloskey, Yanping Yang, Irene M. Min, Moonsoo M. Jin. Pharmacological intervention to temporally stimulate or inhibit ICAM-1 targeting CAR-T cells [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 3592.