New Toolset by Yale Researchers Boosts Efficacy of CAR-T Cells Targeting Blood and Solid Cancers

Cancer researchers focused on improving the success of cancer immunotherapies introduced a new tool in a Yale study published Sept. 29 in Nature Chemical Biology.

In this study, Yale researchers outline how they designed a tool to engineer CAR-T—T cells bearing chimeric antigen receptors (CARs), a pioneering immunotherapy. The new toolset, called IDRs—Intrinsically Disordered Regions—were fused to the CAR-T cells to enhance their ability to detect and destroy the cancer cells, by effectively amplifying the low signals emitted by the antigens.

Most existing FDA-approved CAR-T cell therapies have limited effectiveness against cancers that do not express many cancer-signaling antigens. In the study, the researchers fused the IDR element (from proteins FUS, EWS, or TAF15) to the CARs to improve their cytotoxicity against cancer.

“We identified IDRs, though not previously associated with T cell signaling, as a novel toolset to build a CAR and improve its function, representing a breakthrough from the traditional approach of utilizing domains from T cell signaling proteins in CAR engineering,” says Xiaolei Su, PhD, senior author on the study, a member of Yale Cancer Center, and associate professor of cell biology at Yale School of Medicine.

They tested the efficacy of the IDRs in both cultured dishes and mouse models to validate them as a new modular toolset for improving the killing function of CAR-T cells against multiple tumors. In part, they found that:

• In culture dishes, the IDR-modified CAR-Ts showed substantially higher killing activity against cancer cells. They were particularly effective against those expressing low levels of target antigens (CD19, CD22, or HER2).

• In both the blood cancer and solid tumor mouse models, the FUS IDR CAR-T demonstrated improved anti-tumor effects. This effect can be explained by reduced exhaustion markers including PD1 and LAG3. The CAR-T cells engineered with FUS and TAF15 also improved effectiveness against the low-HER2 expressing colorectal cancers.

The study noted that IDRs exist in about half of human proteins, meaning there likely are many more opportunities to explore in engineering CAR in the future.

“In the future, we will screen more IDRs with diverse biochemical features to optimize CAR designs for personalized cancer targets. The same strategy can be used to engineer other immune receptors to improve their functions in targeting beyond-cancer diseases, including fibrosis, autoimmune, and infectious diseases,” says Su.

Funding for this research was supported by an American Cancer Society Research Scholar Grant 135926, the Charles H. Hood Foundation Child Health Research Awards, the Andrew McDonough B+ Foundation Research Grant, the Gilead Sciences Research Scholars Program in Hematology/Oncology, the Rally Foundation A Collaborative Pediatric Cancer Research Awards Program 22YIC53, the Yale SPORE in Skin Cancer DRP Award P50 CA121974, the Yale Cancer Center Pilot Award, the Yale DeLuca Pilot Award, the NIGMS MIRA program R35 GM138299, the Gabrielle’s Angel Foundation Medical Research Award, the Pershing Square Sohn Prize for Young Investigators in Cancer research, a National Cancer Institute R01 CA269779 grant, a NCI Exploratory/Developmental Research Grant R21 CA286364, a National Institutes of Health (NIH) Exploratory/Developmental Bioengineering Research Grants (EBRG) R21 CA294038, the NIH Director’s Transformative Research Award EB037112, the Human Frontier Science Program Early-Career Research Grant RGY0088/2021, the Yale Liver Center Pilot Award P30 DK034989, the Yale Lion Heart Pilot Grant, the Leslie Warner Postdoctoral Fellowship, the CRI-Irvington Postdoctoral Fellowship, the Yale College Dean’s Summer Research Fellowship, an American Cancer Society Research Scholar Grant RSG-23-1077564-01-CCB and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.