UCLA researchers in the Department of Microbiology, Immunology & Molecular Genetics have developed novel engineering methodologies for CAR molecules that overcome the tonic signaling process that leads to T cell exhaustion and poor therapy efficacy.
Background: Immunotherapy has become a highly effective method to combat cancer that enhances a patient’s immune system to attack tumors with high specificity. One such immunotherapy utilizes chimeric antigen receptor (CAR) T cells that recognize unique surface antigens of cancer cells. CAR therapy has found remarkable success in the treatment of lymphoma using CD19 antigens, with high and lasting remission rates. Unfortunately, other non-CD19 CAR-T cell therapies have not shown similar rates of therapeutic efficacy for lymphomas or solid tumors. The unique therapeutic efficacy of CD19 is stipulated to be due to the lack of tonic signaling (i.e., CAR signaling in the absence of antigen binding). Modifying tonic signaling through CAR-T cell engineering platform can produce effective cancer therapies of validated cancer targets.
Innovation: UCLA researchers in the Department of Microbiology, Immunology & Molecular Genetics have developed novel engineering methodologies for CAR molecules that can tune the intensity of CAR tonic signaling and achieve significantly improved in vivo anti-lymphoma efficacy. Tonic signaling directly impacts the metabolism and anti-tumor efficacy of CAR-T cells. When tonic signals are low, there is robust effector function upon antigen stimulation while CAR-T cells are not prematurely exhausted. Tonic signaling can be modulated through alternations of the CAR’s ligand-binding domain and protein conformation. UCLA researchers have shown that the sequence and structure of the CAR have tunable impacts on tonic signaling and CAR-T cell metabolism. Additionally, the anti-tumor function can be altered through the tuning of tonic-signaling intensity and basal T-cell activation. A second novel breakthrough from UCLA researchers is a torsional linker containing a CAR to further enhance intracellular signaling. This engineering framework may provide a novel methodology for the development of other CAR constructs to increase efficacy in solid tumors that have proven otherwise unsuccessful in the clinic.
Applications:
- Cancer immunotherapy
- Treatment for B-cell malignancies
- Potential platform for new chimeric antigen receptors
Advantages:
- Torsional linker that links a CAR to the cytoplasmic region and the primary intracellular signaling domain.
- Superior tumor-cell killing
State of Development: In vitro and in vivo characterizations of CARs were completed and compared in efficacy against other current clinical therapies.
Related Papers (from the inventors only): Rational Tuning of CAR Tonic Signaling Yields Superior T-Cell Therapy for Cancer. Ximin Chen, Mobina Khericha, Aliya Lakhani, Xiangzhi Meng, Emma Salvestrini, Laurence C. Chen, Amanda Shafer, Anya Alag, Yunfeng Ding, Demetri Nicolaou, Junyoung O. Park, Yvonne Y. Chen. (2020)