The TCR contributes to tumor immune surveillance 5 by enabling T cells to recognize abnormal cells and triggering a cascade of signaling events that lead to T-cell activation and subsequent cancer cell lysis. T cells are molecularly defined by TCRs present on their cell surface.
However, the direct fusion of antigen recognition to cellular activation domains creates a synthetic activation signal that likely differs from the cellular activation signal propagated from an endogenous TCR-CD3 complex. The efficient single-chain design has demonstrated clinical efficacy as the backbone for the majority of CAR-T therapies to date. The group subsequently addressed these problems by engineering a single chain molecule that fused an antibody in scFv format onto the Immunoreceptor Tyrosine-based Activation Motifs (ITAM)-containing domain of CD3ζ 4. While they were able to demonstrate antigen specific T-cell activation through this chimeric antibody-TCR receptor, there were technical hurdles with the mispairing with the T-cell’s endogenous α and β TCR chains and having to express two synthetic molecules in the same cell. The first chimeric receptor design from Eshhar’s group replaced the antigen recognition variable regions of the alpha (α) and beta (β) TCR chains with the variable regions of an anti-SP6 antibody 3. The remarkable efficacy of anti-CD19-chimeric antigen receptor (CAR)-T cell therapy in both B-cell acute lymphoblastic leukemia (B-ALL) and lymphomas 1, 2 has demonstrated the clinical importance of genetically modified T-cells as a cancer therapy, and simultaneously exemplified Eshhar’s original vision to make a chimeric cell that combines the antibody specificity of a B-cell with the cytotoxic properties of a T cell 3. Moreover, in comparative studies with the clinically validated CD137 (4-1BB)-based CAR, CTL019, our anti-CD19-AbTCR shows less cytokine release and comparable tumor inhibition in a patient-derived xenograft leukemia model. By using the same anti-CD19 binding moiety on an AbTCR compared to a CAR platform, we demonstrate that AbTCR activates cytotoxic T-cell responses with a similar dose-response as CD28/CD3ζ CAR, yet does so with less cytokine release and results in T cells with a less exhausted phenotype. We demonstrate the ability of anti-CD19-AbTCR-T cells to trigger antigen-specific cytokine production, degranulation, and killing of CD19-positive cancer cells in vitro and in xenograft mouse models.
We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the γ and δ chains of the TCR as the effector domain. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T.
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