UCLA researchers from the Department of Medicine have developed a novel B cell-based assay to expand antigen-specific T cells, allowing for an efficient, patient-specific platform to generate tumor antigen-specific T cells.
BACKGROUND: Adoptive T cell therapies have emerged as a promising strategy for cancer immunotherapy, enabling the expansion of tumor-reactive T cells that can be used to eliminate malignant cancer cells. Existing methods rely on either non-specific polyclonal activation (using antibody-presenting beads or cytokines) or complex antigen-presentation platforms (such as dendritic cells or engineered artificial antigen-presenting cells). These approaches provide limited expansion efficiency due to low numbers of tumor-specific T cells and technical complexity. Additionally, current approaches often require additional sorting or enrichment steps to isolate tumor antigen-specific clones, which can result in significant T cell loss. There remains an unmet need for a streamlined, patient-specific method that can efficiently expand tumor antigen-specific T cells while minimizing cell loss and manufacturing complexity.
INNOVATION: UCLA researchers from the Department of Medicine have developed a novel B cell–mediated technology for the selective expansion of tumor antigen-specific T cells. In this novel technology, tumor-associated antigens are first identified through genomic and transcriptomic sequencing of patient-derived samples and then incubated with antibodies that bind the full-length protein. This process forms an antibody–antigen complex that can be internalized by autologous B cells. These complexes are then processed and presented as cell surface proteins that can activate CD8 and CD4 T cells that are highly specific to the tumor antigen. Cytokines and antigen-presentation enhancers can be also added to the system, driving the preferential expansion of antigen-specific cells while minimizing non-specific activation. Multiple antibody-tagged antigens can also be incorporated, widening the scope of tumor-specific clones that can be expanded. To further enrich antigen-specific populations, B cells loaded with antibody–antigen complexes are reintroduced several times, allowing them to function as renewable “growth-promoting factors” for T cells. The expanded T cell–B cell mixture can also be directly transfused back into the patient after removal of any free antigen, reducing cell loss and streamlining manufacturing. This innovation can revolutionize adoptive T-cell therapies by providing a scalable, patient-specific, and multiplexed platform for efficiently generating tumor antigen-specific T cells.
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ADVANTAGES:
DEVELOPMENT TO DATE: Researchers have shown that B cells can capture and cross-present a full-length, soluble tumor antigen to CD8 T cells with an antigen-specific TCR. They have shown that this increases activation, proliferation, and cytotoxicity of the CD8 T cell in vitro.
RELATED PAPERS (from the inventors only):
Ding L, Sun L, Bu MT, Zhang Y, Scott LN, Prins RM, Su MA, Lechner MG, Hugo W. Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors. Front Immunol. 2023 Jun 26;14:1176994. doi: 10.3389/fimmu.2023.1176994. PMID: 37435085; PMCID: PMC10330698.
KEYWORDS: tumor antigen-specific T cells; adoptive T cell therapy; autologous B cells; antibody–antigen complex; CR2 receptor uptake; MHC I/II presentation; IL-2; IL-7; IL-15; IFN-γ; neoantigen expansion; personalized immunotherapy