692535 event 1789133949 1789133980 Ching Shen (Sean) Chan
BME PhD Proposal Presentation

Date: 2026-09-22
Time: 3.00-5.00pm
Location / Meeting Link: Marcus Nanotechnology Research Center, Room 1117-1118

Committee Members:
Gabriel A. Kwong, PhD (Advisor); Philip Santangelo, PhD; Alexander Vlahos, PhD; Nicole Schmitt, MD, FACS; Rama Rao Amara, PhD


Title: Enhancing In Vivo CAR T Cell Therapy Through mRNA Delivery to Virus-Specific T Cells

Abstract:
Chimeric antigen receptor (CAR) T cell therapy uses an engineered receptor that combines an extracellular antigen-recognition domain with intracellular T cell signaling domains, redirecting T cells to recognize and eliminate tumor cells independent of MHC restriction. This approach has transformed treatment for relapsed and refractory hematologic malignancies. CD19- and BCMA-directed CAR T products produce high response rates in heavily pretreated patients, with a median response rate of 66.4% across trials leading to FDA approval. Despite this efficacy, only 20% to 30% of eligible patients ultimately receive CAR T therapy. This gap stems primarily from the cost and complexity of manufacturing: each product is generated individually through leukapheresis, viral transduction, and ex vivo expansion under GMP conditions, driving per-patient costs that typically exceed $400,000 and can surpass $1 million. These constraints have shifted recent interest in the field toward in vivo engineering, in which CAR constructs are delivered directly to T cells within the patient, removing the need for ex vivo manufacturing. Current delivery strategies, however, broadly target T cells irrespective of antigen specificity or activation state. Naive T cells, a substantial fraction of the endogenous repertoire, are comparatively poor cytotoxic effectors relative to effector and memory T cells. Broad activation of the remaining repertoire can also potentially cause toxicity and break self-tolerance by activating self-reactive T cell clones. Our lab previously developed lipid nanoparticles (LNPs) surface-functionalized with peptide-major histocompatibility complex (pMHC) class I molecules, termed antigen-presenting nanoparticles (APNs), to deliver mRNA in vivo to virus-specific T cells. APNs engage the T cell receptor directly, restricting cargo delivery to T cells of a defined antigen specificity while leaving the broader T cell repertoire unperturbed. In this thesis proposal, we adapt the APN platform for in vivo CAR T cell therapy. In Aim 1, we redirect influenza-specific T cells to express a BCMA-targeted CAR in a multiple myeloma rodent model, demonstrating both APN-mediated in vivo CAR generation and the antitumor efficacy of the resulting CAR T cells. Virus-specific T cells, however, occur at low frequency within the endogenous repertoire, which limits the number of CAR-expressing effector cells generated through direct in vivo transfection alone. In Aim 2, we will use APNs to expand the target T cell population prior to in vivo CAR transfection, increasing the effector-to-target ratio to improve therapeutic outcomes. In Aim 3, we will evaluate the tolerability of APN in a non-human primate model to assess the translational potential of this approach. Successful completion of these aims will establish APNs as a platform for in vivo CAR T cell engineering, providing a lower cost alternative to ex vivo CAR T cell therapy. 

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