Armored CARs to overcome sialylation mediated resistance in Multiple Myeloma

Description

Chimeric Antigen Receptor T (CAR-T) cell therapy has revolutionized the treatment of refractory B-cell malignancies. Nevertheless, in multiple myeloma (MM), despite a high rate of initial response, these responses tend not to be durable, important contributory factors including intrinsic cancer cell resistance and immune suppression within the tumor microenvironment (TME). Emerging evidence highlights the role of sialic acids—terminal glycan structures known to mask antigens and inhibit immune activation—as key drivers of these therapeutic challenges. Our preliminary findings reveal that sialic acids coat critical CAR targets, including CD38 and BCMA, as well as the adhesion molecule ICAM-1, thereby diminishing the efficacy of CAR-T and NK cells directed against these antigens. Treatment with neuraminidase (Neu), an enzyme that cleaves sialic acids, enhanced CAR target recognition, strengthened immune synapse formation, and reversed immune suppression, resulting in increased cytotoxicity of CAR-T and NK cells . Building on these preliminary data, the aim of this project is to significantly enhance CAR immunotherapy for MM by engineering CAR-T and CAR-NK cells to express Neu. CAR-NK cells, known for their innate immune capabilities and important immune modulatory effects, are expected to synergize with CAR-T cells, delivering a robust and sustained antitumor response. This strategy promises to improve the detection of CAR targets, counteract immune evasion mechanisms, and foster durable remissions. We will evaluate the antitumor efficacy of Neu-engineered CAR-T and CAR-NK cells both individually and in combination in preclinical MM models. Single-cell phenotypic and genotypic profiling will provide critical insights into the mechanisms driving therapeutic success. This innovative approach has the potential to redefine CAR-based therapies, overcoming current limitations and offering new hope for patients with multiple myeloma.