Facts and hopes: CAR-T cell therapy and Immune contexture in Non-Hodgkin Lymphoma

Abstract The genetic reprogramming of T cells with chimeric antigen receptors (CARs), specifically targeting CD19 in B-cell malignancies or B cell maturation antigen (BCMA) for plasma cell tumors has achieved remarkable success. CAR-T cell therapy represents a revolutionary strategy in personalized cancer care, leveraging the immune system's precision to target cancer cells with unprecedented efficacy. However, challenges persist with resistance and relapse occurring in hematological malignancies. Understanding the intricate mechanisms governing response and resistance is crucial, emphasizing factors such as pharmacokinetics, product attributes, and tumor biology. This review focuses on biomarkers associated with CAR-T cell therapy in Mature B-cell Non-Hodgkin lymphoma (B-NHL) malignancies, underscoring the importance of pre-existing tumor immune contexture. Previous findings highlight strong correlation between early peak-levels of CAR-T cells post- treatment initiation and treatment response. Maintaining an optimal CAR-T cell to tumor burden ratio is essential for sustained responses. Systemic and tumor immune contexture impacts therapy outcomes, revealing pre-existing immunity's role in CAR-T cell efficacy. The mechanistic impact of CAR-T cells was investigated using pre- and post- treatment biopsies, revealing specific markers associated with treatment response in refractory large B-cell lymphoma (LBCL), across patients receiving CAR T-cell therapy in the second- and third-line setting, supporting precision medicine in developing next-generation cell therapies for hematological malignancies. The evolution of the tumor microenvironment (TME) with therapy lines was also demonstrated, supporting earlier intervention with CAR T cell therapy. Ongoing translational efforts, including single-cell omics analysis, aim to uncover additional factors that impact outcomes to develop more potent treatments.