Despite success in treating hematological malignancies, T cells expressing chimeric antigen receptors (CARs) have shown poor efficacy in solid tumor indications. The failure to initiate and elicit a complete TCR response is arguably a primary underlying factor preventing CAR-T cell success in solid tumor indications. Here, we present a novel T cell engineering platform: T Cell Receptor Fusion Constructs (TRuC™s), which target tumors independent of MHC. Unlike CARs, the constructs integrate into the TCR complex, harnessing the full potential of natural T cell activation, effector function and regulation. Here we describe preclinical evidence underscoring the efficacy of TRuC™-T cells re-programmed to target the solid tumor antigen mesothelin (TC-210).
TC-210 has shown robust anti-tumor activity in cellular assays and animal models of lung, ovarian and MPM cancers. In these studies, TC-210 was compared head-to-head against mesothelin-targeting CAR-T cells (MSLN CAR-T cells) bearing the same mesothelin binder expressed on TC-210. Mesothelin-dependent T cell activation, expansion and tumor clearance by TC-210 was faster than that observed with MSLN CAR-T cells. In a study using Renilla-luciferase-labelled MSLN-CAR T cells and TC-210, TC-210 migrated and accumulated at a faster rate in mesothelioma tumors than MSLN-CAR T cells. This migration pattern correlated with an increased level of chemokine receptors and number of TC-210 expressing these receptors, including CXCR3. TC-210 T cells also showed long-term functional persistence capable of preventing relapse in a mesothelioma model. Metabolic profiling of TC-210 versus MSLN-CAR T cells showed that the observed persistence may be related to the metabolic profile of TC-210 T cells. Unlike MSLN-CAR-T cells, TC-210 showed increased levels of oxidative phosphorylation and mitochondrial reserve, attributes associated with long-term memory T cells. Finally, systemic cytokine levels in animals treated with TC-210 were lower than those observed in MSLN CAR-T cell treated animals.
Together, these findings warrant the investigation of TC-210 in clinical trials as effective treatment for mesothelin-expressing tumors with potentially lower rates of adverse events.
Citation Format: Jian Ding, Holly Horton, Seema Shah, Adam Zieba, Janani Krishnamurphy, Thomas Ashhurst, Ashley V. Menk, Patrick Baeuerle, Nicholas J. King, Gregory Delogoffe, Robert Hofmeister, Daniel R. Getts. Preclinical evaluation of TC-210, a mesothelin-specific T cell receptor (TCR) fusion construct (TRuC™) T cells for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2307.