SUMMARY:
Researchers from UCLA’s Department of Microbiology, Immunology and Molecular Genetics have developed methods for generating self-modulating CAR-T cells which retain robust anti-tumor function whilst having reduced adverse side effects relating to cytokine release syndrome.
BACKGROUND:
The immunotherapy approach of T-cell engineering to express chimeric antigen receptors (CARs) for greater specificity has proven successful in some hematological malignancies, most famously B-cell leukemia and lymphoma. However, one of the barriers immediately limiting the adoption of engineered CAR-T cell therapy is the phenomenon of cytokine release syndrome. Cytokine release syndrome (CRS) refers to a rapid and dramatic increase of cytokines in the blood of patients who have been treated with CAR-T cell therapy. This rapid increase in cytokine levels can cause fever, rash, rapid heartbeat, low blood-pressure, and trouble breathing, and the severity can range from mild to life-threating. Furthermore, the exact magnitude and timing of CRS is difficult to predict as various underlying factors can confound the patients who are highest at risk. To combat this challenge, Dr. Yvonne Chen’s group engineered CAR-T cells that constitutively release single-chain variable fragments (scFvs) that can inhibit cytokine signaling, yielding “self-modulating” CAR-T cells that can prevent or ameliorate CRS while retaining robust anti-tumor efficacy.
INNOVATION:
UCLA researchers led by Dr. Yvonne Chen in the Department of Microbiology, Immunology and Molecular Genetics have developed a novel approach for the generation of self-modulating CAR-T cells that can prevent severe cytokine release syndrome, a serious side effect often seen following CAR-T administration. These self-modulating CAR-T cells co-express a tumor-targeting CAR with an scFv that can bind to cytokines or cytokine receptors implicated in CRS. Dr. Yvonne Chen’s team have shown that the engineered self-modulating CAR-T cells retain robust anti-tumor function both in vitro and in vivo. Preliminary testing has also shown that in mouse models of human tumor xenografts, the self-modulating CAR-T cells efficiently eliminate established tumor xenografts while lowering toxicities associated with CRS caused by CAR-T therapy. Taken together, self-modulating CAR-T cells could ameliorate CRS and enhance the safety of CAR-T cell therapy.
POTENTIAL APPLICATIONS:
• Immunotherapy for both solid tumors and hematological cancers
• Reduction of CRS symptoms in high-risk patients
ADVANTAGES:
• No reduction in the anti-tumor efficacy of CAR-T cells
• Chemistry connecting the CAR to the scFv is universal, allowing for a modifiable platform with other scFvs
• A platform for treatment of autoimmune diseases such as rheumatoid arthritis since the tested scFvs are derived from antibodies that have also been used to treat autoimmune diseases
DEVELOPMENT-TO-DATE:
Proof-of-concept CAR-T cells have been engineered with this approach and shown robust antitumor effects in in vitro and in vivo experiments. Further validation with humanized NSG-SGM3 mouse models showed efficacy at reducing CRS symptoms compared to alternative approaches.