Abstract 1424: Preclinical development of TAC01-CD19, a CD19 specific T-cell Antigen Coupler (TAC) therapy for the treatment of CD19-positive B cell malignancies

Abstract

Abstract Background: The T cell antigen coupler (TAC) is a chimeric receptor co-opting the natural TCR receptor signaling complex to target tumor antigens in an MHC-independent manner (Helsen et. al., Nat. Comm. 2018). TAC engineered T cells mediate biological effects that are distinct from conventional chimeric antigen receptors (CARs) and may offer safety advantages due to greater target selectivity and no detectable off-target toxicity. Here, we present preclinical data of TAC01-CD19, an autologous CD19-specific TAC-T cell product candidate for clinical testing in patients with CD19-positive B cell malignancies Materials and Methods: T cells from healthy donors and lymphoma patients were engineered with a CD19-specific TAC using lentivirus. Anti-tumor activity, T cell expansion and persistence were measured in the CD19-positive NALM-6 and Jeko-1 mouse tumor xenograft models. We used flow cytometry to determine surface expression of CD19-TAC, cytokine production and in vitro T cell proliferation. Cytotoxicity was evaluated in vitro using luciferase-based killing assay. Results: Cytotoxicity was measured against multiple CD19 positive tumors cells (NALM6/Jeko-1/Raji) showing strong cytotoxicity in all cases. Treatment of established NALM-6 (acute lymphoblastic leukemia) and Jeko-1 xenografts (mantle cell lymphoma) with CD19 TAC-T cells resulted in clearance of tumors within a few weeks of T cell infusion. In vivo efficacy was tested across multiple donors, establishing consistent and reproducible anti-tumor efficacy. Monitoring of TAC T cells post-infusion revealed robust expansion that peaked in the peripheral blood 1-2 weeks post-infusion. Mice that cleared tumors following TAC-T cell treatment were resistant to subsequent challenge with fresh tumor cells demonstrating persistence of TAC-T cells. In contrast, treatment with control TAC-T had no impact on tumor growth. A histological examination of normal mouse tissues failed to detect TAC-T cell induced toxicity. Conclusion: The pre-clinical evaluation of TAC01-CD19 has demonstrated specific anti-tumor responses without signs of toxicity. Results were reproducible across multiple donors demonstrating the robustness of the CD19 TAC system. TAC01-CD19 is expected to enter clinical testing in patients with CD19-positive hematological malignancies in Q2 2019. Citation Format: Christopher W. Helsen, Danielle Hayes, Joanne Hammill, Criag Aarts, Andreas Bader, Donna Rill, Jonathan Bramson. Preclinical development of TAC01-CD19, a CD19 specific T-cell Antigen Coupler (TAC) therapy for the treatment of CD19-positive B cell malignancies [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 1424.