CAR T Cells Target Previously Untargetable Cancer Drivers

In a breakthrough for the treatment of aggressive solid cancers, researchers at the Children’s Hospital of Philadelphia (CHOP) have developed a new cancer therapy that targets proteins in cancer cells that are essential for tumor growth and survival, but have been historically impossible to achieve. Using large data sets and advanced computational approaches, the researchers were able to identify peptides that are presented on the surface of tumor cells and can be targeted with “peptide-centric” chimeric antigen receptors (PC-CARs), a new class of engineered T cells, which stimulate an immune response that eradicates tumors.

The discovery, described today in Nature, opens the door to treating a wider range of cancers with immunotherapy and to applying each therapy to a larger proportion of the population.

“This research is extremely exciting because it increases the possibility of targeting highly specific tumor molecules, expanding both the cancers that can be treated with immunotherapy and the patient population that can benefit,” said Mark Yarmarkovich, PhD, a researcher at the Maris Laboratory at Children’s Hospital of Philadelphia and first author of the article. “By using a multi-omics approach, we were able to identify peptides specific to neuroblastoma tumors, but this method can be used in any cancer, allowing for a more personalized approach to cancer treatment.”

The development of CAR T cell-based cancer immunotherapy represents a breakthrough in leukemia treatment, but the approach has not yet made significant progress against solid tumors, at least in part due to a lack of tumor-specific targets. In these cancers, most of the proteins responsible for tumor growth and survival are located in the nuclei of tumor cells, not on the cell surface, where they would generally be accessible to CAR T cells. Instead, fragments of these proteins can be presented on the tumor cell surface through the presentation of peptides on the major histocompatibility complex (MHC), which evolved to present viral and bacterial peptides to the immune system. Cancer cells can also present intracellular proteins on MHC, and if these are mutant peptides, they can be recognized as foreign. However, all childhood cancers and many adult malignancies have few mutations and are rather driven by other factors, such as dysregulated developmental pathways.

Neuroblastoma is an explosively aggressive pediatric cancer driven by gene expression modifications that promote uncontrolled tumor growth. Historically, neuroblastoma has been treated with chemotherapy, surgery, and radiation therapy, but patients often relapse with forms of the disease that are resistant to chemotherapy. In addition, the cancer’s low mutation burden, coupled with low MHC expression, have made it difficult to target with immunotherapies.

Despite these obstacles, the researchers hypothesized that some of the peptides presented on the surface of neuroblastoma tumor cells come from proteins essential for tumor growth and survival, which can be addressed with synthetic CARs. These PC-CARs could directly target and kill tumor cells. The challenge was to distinguish tumor-specific peptides from other similar peptides or peptides found in normal tissues to avoid cross-reactivity and lethal toxicity.

To do this, the researchers stripped the MHC molecules from neuroblastoma cells and determined which peptides were present and in what abundance. They used a large genomic dataset generated by the Maris lab to determine which peptides were unique to neuroblastoma and not expressed by normal tissues. They prioritized peptides derived from genes essential to the tumor and possessing characteristics necessary to activate the immune system. To eradicate potential antigens that could potentially have cross-reactivity with normal tissue, the researchers filtered the remaining tumor peptides against a database of MHC peptides on normal tissues, removing any peptide with a parent gene represented in normal tissue.

Using this multi-omics approach, the researchers identified an unmutated neuroblastoma peptide derived from PHOX2B, a neuroblastoma dependence gene and transcriptional regulator previously identified and characterized in CHOP. The next major hurdle was the development of a PC-CAR that specifically recognized only the peptide, which makes up 2-3% of the peptide-MHC complex. In collaboration with Myrio Therapeutics, an antibody discovery company, the researchers developed a PC-CAR targeting this peptide and showed that these PC-CARs recognized the tumor-specific peptide on different HLA types, meaning that the treatment can be applied to patients of different genetic lines. .

“We are excited about this work because it now enables us to target key cancer causes that were considered ‘non-curable’ in the past. We believe PC-CARS has the potential to greatly expand the pool of immunotherapies and significantly expand the population of eligible patients,” said senior author John M. Maris, MD, pediatric oncologist and Giulio D’Angio Chair. in Neuroblastoma Research at CHOP “Thanks to the accelerator grant we received through the Cell and Gen Therapy Collaborative at CHOP, we will move our PHOX2B PC-CAR to a clinical trial at CHOP in late 2022 or early 2023.”

The research was funded by the St. Baldrick’s Foundation, Stand Up to Cancer (SU2C), and the National Institutes of Health (NIH) through a Cancer Moonshot grant.

Reference: Yarmarkovich M, Marshall QF, Warrington JM, et al. Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs. Nature. 2021:1-8. doi: 10.1038/s41586-021-04061-6

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