Implications of High Tumor Burden on Chimeric Antigen Receptor T-Cell Immunotherapy

Importance: Chimeric antigen receptor (CAR) T-cell therapy has redefined the therapeutic landscape of several hematologic malignant tumors. Despite its clinical efficacy, many patients with cancer experience nonresponse to CAR T-cell treatment, disease relapse within months, or severe adverse events. Furthermore, CAR T-cell therapy has demonstrated minimal to no clinical efficacy in the treatment of solid tumors in clinical trials. Observations: A complex interplay between high tumor burden and the systemic and local tumor microenvironment on clinical outcomes of CAR T-cell therapy is emerging from preclinical and clinical data. The hallmarks of advanced cancers-namely, inflammation and immune dysregulation-sustain cancer progression. They negatively affect the production, expansion, antitumor activity, and persistence of CAR T-cell products. Understanding of CAR T-cell therapy, mechanisms underlying its failure, and adverse events under conditions of high tumor burden is critical for realizing the full potential of this novel treatment approach. Conclusions and Relevance: This review focuses on linking the efficacy and safety of CAR T-cell therapy with tumor burden. Its limitations relative to high tumor burden, systemic inflammation, and immune dysregulation are discussed. Emerging clinical approaches to overcome these obstacles and more effectively incorporate this therapeutic strategy into the treatment paradigm of patients with solid malignant tumors are also described.