Precision immunotherapy for solid tumors: overcoming challenges by targeting tumor-associated carbohydrate antigens 4421

Description Directing cell-based immunotherapies against tumor-associated carbohydrate antigens (TACAs) presents a promising strategy to overcome challenges in cancer immunotherapy, particularly for solid tumors, which often exhibit on-target/off-tumor toxicity. Several glycans are TACAs that are selectively found on cancer cells and contribute to immune evasion and metastasis. By employing a multidisciplinary approach to design chimeric antigen receptors (CARs) that recognize and target a broad range of glycoantigens on cancer cells, we can enhance specificity and minimize off-tumor toxicity. This work proposes two key aims: (1) Characterize human-derived single-chain variable fragments (scFvs) specific to a variety of tumor-associated glycans to develop CARs with optimal affinity, selectivity, and configuration, and (2) Generate and evaluate CAR-natural killer (CAR-NK) cells targeting these glycans expressed on the surface of cancer cells, measuring immune activation, proliferation, cytokine release, and cancer cell killing. By applying this approach to various glycan antigens, we aim to demonstrate the efficacy of glycan-directed CAR therapies in targeting and eliminating tumor cells, laying the groundwork for broader applications in glycan-targeted cancer immunotherapy and establishing a framework for precision immunotherapy using TACA targets to advance the clinical applicability of CAR-NK cells in solid tumors. Funding Sources Supported by NIH R25GM125597; NIH T32GM138826 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)