Peripheral T cell lymphomas are typically aggressive with a poor prognosis. Unlike other hematologic malignancies, the lack of target antigens to discriminate healthy from malignant cells has limited the efficacy of immunotherapeutic approaches. The T cell receptor expresses one of two highly homologous chains [T cell receptor β-chain constant (TRBC) domains 1 and 2] in a mutually exclusive manner, making it a promising target. We previously described an antibody with unique TRBC1 specificity (Jovi-1). Here we demonstrate specificity redirection by rational design using structure-guided computational biology to generate a TRBC2-specific antibody (KFN). This permitted the generation of paired reagents (chimeric antigen receptor-T cell) specific for TRBC1 and TRBC2, with preclinical evidence to support their efficacy in T cell malignancies.
Adoptive T cell therapy aims to achieve lasting tumour clearance, requiring enhanced engraftment and survival of the immune cells. Cytokines are paramount modulators of T cell survival and proliferation. Cytokine receptors signal via ligand-induced dimerization, and this principle has been hijacked utilising non-native dimerization domains. A major limitation of current technologies resides in the absence of a module that recapitulates the natural cytokine receptor heterodimeric pairing. To circumvent this, we created a new engineered cytokine receptor able to constitutively recreate receptor-heterodimer utilising the heterodimerization domain derived from the IgG1 antibody (dFab_CCR). We found that the signal delivered by the dFab_CCR-IL2 proficiently mimics the cytokine receptor heterodimerization, with transcriptomic signatures similar to that obtained by the activation of IL2 native receptor. Importantly, we found that this dimerization structure is agnostic, efficiently activating signaling through four cytokine receptor families. Using a combination of in vivo and in vitro screening approaches, we characterized a library of 18 dFab_CCRs co-expressed with a clinically relevant solid tumor-specific GD2 CAR. Based on this characterization we suggest that the co-expression of either the common beta-chain GMCSF or the IL18 dFab_CCRs is optimal to improve CAR T cell expansion, engraftment, and efficacy. Our results demonstrate how the Fab dimerization is efficient and versatile in recapitulating a cytokine receptor heterodimerization signal. This module could be applied for the enhancement of adoptive T cell therapies, and therapies based on other immune cell types. Furthermore, these results provide a choice of cytokine signal to incorporate with adoptive T cells therapies.
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