Researchers discover deep links in structural biology that help improve CAR therapy

Chimeric antigen receptors (CARs) have opened an exciting new area of ​​therapeutic advancement for rare and difficult-to-treat cancers because they have the ability to deliver targeted therapies capable of killing tumor cells.

Peptide CARs (PC-CARs) rely on specific peptide “barcodes,” which are derived from proteins in the cell created by potentially cancer-causing oncogenes, and are designed to seek out and target cancer cells. These “barcodes” are displayed by human leukocyte antigens (HLA), which help the immune system distinguish its own proteins from foreign invaders, such as viruses.

However, HLAs are derived from the most “polymorphic” genes, with more than 25,000 alleles (fragments of DNA coding for proteins that perform essential functions) that can vary between them, making it difficult to design PC- CAR targeting specific genes. alleles associated with different cancers.

Now, researchers from two closely collaborating laboratories at Children’s Hospital of Philadelphia (CHOP) have solved a three-dimensional protein structure that explains how PC-CARs can recognize the “backbones” of these HLA complexes. The structural information will now allow researchers to understand how CARs recognize tumor-associated antigens among different polymorphic HLA alleles, opening more possibilities for designing precision medicine strategies for more complex and difficult-to-treat tumors.

The results were published online in the journal Scientific immunology.

“If CARs are not properly tailored to target specific alleles associated with certain cancers, there is a risk of inducing toxicity without providing any therapeutic benefit,” said lead author Nikolaos G. Sgourakis, Ph.D. , associate professor in the Center for Computational Medicine and Genomics at CHOP. “By examining their complex 3D structures, we can use these results to design CARs that can target multiple HLAs and increase the efficiency of therapeutic design.”

Previous CAR therapies could only target cancer-specific antigens on the surface of tumor cells, and most of these reside within the cells. However, researchers have discovered that these previously inaccessible targets are ultimately degraded into peptides, which can be expressed on the surface as “barcodes” and then targeted with therapy. Even so, with such variability in HLA alleles, CAR therapies might only be able to help a fraction of tumor patients, depending on which peptides are expressed on the surface of a tumor cell.

Given that HLAs contain more than 25,000 potentially mutated alleles, sifting through them one by one to find potential targets and design related CAR therapies is far too complex a task.

In this study, however, researchers used a combination of biochemical binding assays, molecular dynamics simulations, and structural and functional analyzes to determine that certain HLA classes exhibit cross-reactivity, meaning that different antigens can be recognized in the same way by PC-CAR therapy. In other words, although peptide “barcodes” may exhibit significant variability, the “backbone” of these HLAs is similar enough to be recognized by these therapies.

This work was carried out by a group of undergraduate and graduate students from the University of Pennsylvania and senior CHOP scientists from the Sgourakis lab.

CHOP was a pioneer in the development of PC-CAR. Study co-senior author John M. Maris, MD, a pediatric oncologist and Giulio D’Angio Chair in Neuroblastoma Research at CHOP, simultaneously published an updated article in the journal Nature on the development and effectiveness of PC-CARs, and patients are currently being recruited for clinical trials based on their HLA genotypes to further explore the effectiveness of PC-CARs in the treatment of rare and complex forms of cancer.

“For any CAR T cell therapy to be both safe and effective, we need to find “targets” that allow the T cells to detect the tumor. PC-CAR T cells target very specific targets that are only found on cancer cells and not on normal healthy cells. cells,” Maris said.

“This study essentially provides us with a model for how to integrate new knowledge about the structural biology of HLAs as well as PC-CARs into this exciting area of ​​new options for treating challenging cancers.”