Wednesday, May 18, 2022
5/18/2022
PROJECT SUMMARY CD4+ T cells respond to peptide antigens presented by MHCII molecules (pMHCII) using a 5-module molecular machines composed of a receptor module [the T cell receptor (TCR)], three signaling modules (CD3¿¿, CD3¿¿, CD3¿¿), and a coreceptor module (CD4). Drawing upon this blueprint, we designed a biomimetic 5-module chimeric antigen receptor (5MCAR) system composed of a chimeric receptor module, built with pMHCII and TCR components (CRMpMHCII), that assembles with the CD3 signaling modules and works with a surrogate coreceptor (ScoR) to generate signals in response to specific TCRs. As we recently reported (Kobayashi, et al., PNAS 2020), 5MCAR-CTLs can specifically target and kill pathogenic CD4+ T cells that express TCRs that bind the CRMpMHCII. Given that peripheral T cell lymphomas (PTCLs) represent a unique type of pathogenic T cell for which treatment options are limited, and patient prognosis is poor, we are motivated to ask if our 5MCAR technology can be developed into a patient-specific PTCL therapy. As PTCLs are often derived from transformed CD4+ ¿¿T cells and express a clonotypic TCR that represents a tumor-specific antigen, we consider them to be ideal targets for 5MCAR-CTLs. Accordingly, the goal of the current study is to establish a workflow whereby our 5MCAR technology is used to screen libraries of CRMpMHCII for mimotope CRMpMHCII that signal in response to the clonotypic TCR of a PTCL, and then use the identified mimotope CRMpMHCII to generate 5MCAR-CTLs for targeting the PTCL via its clonotypic TCR. When completed, the established workflow will provide a blueprint for adapting our 5MCAR technology into a personalized therapy to treat patients with PTCLs.
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