ABSTRACT
Antibody-based therapeutics have experienced a rapid growth in recent years and are now utilized in various modalities spanning from conventional antibodies, antibody-drug conjugates, bispecific antibodies to chimeric antigen receptor (CAR) T cells. Many next generation antibody therapeutics achieve enhanced potency but often increase the risk of adverse events. Antibody scaffolds capable of exhibiting inducible affinities could reduce the risk of adverse events by enabling a transient suspension of antibody activity. To demonstrate this, we develop conditionally activated, single-module CARs, in which tumor antigen recognition is directly modulated by an FDA-approved small molecule drug. The resulting CAR T cells demonstrate specific cytotoxicity of tumor cells comparable to that of traditional CARs, but the cytotoxicity is reversibly attenuated by the addition of the small molecule. The exogenous control of conditional CAR T cell activity allows continual modulation of therapeutic activity to improve the safety profile of CAR T cells across all disease indications.
Subject(s)
Antigens, Neoplasm/immunology , Immunotherapy, Adoptive/methods , Methotrexate/administration & dosage , Neoplasms/therapy , Receptors, Chimeric Antigen/metabolism , T-Lymphocytes/drug effects , Animals , Cell Line, Tumor , Combined Modality Therapy/methods , Female , HEK293 Cells , Humans , Immunotherapy, Adoptive/adverse effects , Mice , Neoplasms/immunology , Primary Cell Culture , Receptors, Chimeric Antigen/immunology , Single-Domain Antibodies/immunology , Single-Domain Antibodies/metabolism , T-Cell Antigen Receptor Specificity/drug effects , T-Cell Antigen Receptor Specificity/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/transplantation , Xenograft Model Antitumor AssaysABSTRACT
CAR T-cell therapies hold great promise for treating a range of malignancies but are however challenged by the complexity of their production and by the adverse events related to their activity. Here we report the development of the CubiCAR, a tri-functional CAR architecture that enables CAR T-cell detection, purification and on-demand depletion by the FDA-approved antibody Rituximab. This novel architecture has the potential to streamline the manufacturing of CAR T-cells, allow their tracking and improve their overall safety.
