Abstract
T cells engineered to express a tumor-specific αβ T cell receptor (TCR) mediate anti-tumor immunity. However, mispairing of the therapeutic αβ chains with endogenous αβ chains reduces therapeutic TCR surface expression and generates self-reactive TCRs. We report a general strategy to prevent TCR mispairing: swapping constant domains between the α and β chains of a therapeutic TCR. When paired, domain-swapped (ds)TCRs assemble with CD3, express on the cell surface, and mediate antigen-specific T cell responses. By contrast, dsTCR chains mispaired with endogenous chains cannot properly assemble with CD3 or signal, preventing autoimmunity. We validate this approach in cell-based assays and in a mouse model of TCR gene transfer-induced graft-versus-host disease. We also validate a related approach whereby replacement of αβ TCR domains with corresponding γδ TCR domains yields a functional TCR that does not mispair. This work enables the design of safer TCR gene therapies for cancer immunotherapy.
Highlights
T lymphocytes recognize cellular targets with extraordinary sensitivity and specificity
Mispairing between introduced and endogenous T cell receptor (TCR) chains produces autoreactive human T cells in vitro and causes graft-vs-host disease in mice (Bendle et al, 2010; Bunse, 2014), indicating that TCR gene transfer poses a non-theoretical risk of autoimmunity
As the potency of TCR gene therapy is augmented through combination with other immunotherapies, there may be a concomitant rise in mispairing-related serious adverse events
Summary
T lymphocytes recognize cellular targets with extraordinary sensitivity and specificity. The TCR - a heterodimer that is uniquely rearranged in each T cell during its development - is the sole determinant of T cell specificity (DembiCet al., 1986). Upon reinfusion into the patient, these engineered T cells mediate potent anti-tumor cytotoxicity (Park et al, 2011). This approach – termed TCR gene therapy – has demonstrated clinical responses for several malignancies (Johnson et al, 2009; Morgan et al, 2006; Davis, 2010; Parkhurst, 2011; Robbins et al, 2015, 2011), which may be bolstered in the future through combination with complementary immunotherapies like dendritic cell-based vaccination and checkpoint
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