CAR-T therapies, which arm a patient’s own immune cells with cancer-fighting proteins, are currently used to treat some patients with blood cancers. But the technology has been hard to apply to other cancers, partly because of a lack of tumor-specific antigens for the T cells to target. Now, a research team at the University of Pennsylvania's Children’s Hospital of Philadelphia (CHOP) has developed a new type of CAR-T cell designed to fight solid tumors by targeting proteins inside cancer cells.
These “peptide-centric” CAR-T cells hunt down fragments of cancer-related proteins that are made accessible to the immune system by antigen-presenting MHC proteins. Such a CAR-T therapy selectively eliminated patient-derived neuroblastoma tumors in mice, the researchers reported in a new Nature study.
The discovery could open up a much broader range of therapeutic targets for cancer immunotherapy, the team said. Working with collaborators at Australia-based antibody discovery biotech Myrio Therapeutics, the CHOP scientists aim to move the CAR-T product into clinical trials in late 2022 or early 2023, said CHOP’s John Maris, M.D., senior author of the study and professor of pediatrics at Penn's Perelman School of Medicine, in a statement.
In solid tumors, most of the proteins responsible for driving tumor growth and survival reside in the nuclei of cancer cells, rather than on the cell surface, where they would readily be accessible to immune cells, including CAR-T cells. Tumor cells also reveal some fragments of intracellular proteins through MHC, which is known for its ability to present foreign objects to the immune system. However, low rates of mutations and MHC expression have made solid tumors difficult to target with immunotherapies.
Nevertheless, the CHOP team believed that some tumor-specific peptides from key oncoproteins could be targeted with synthetic peptide-centric (PC) CARs. The team focused its research on neuroblastoma, an aggressive form of pediatric cancer that has few mutations and is instead driven by abnormal gene-expression networks.
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By surveying a large genomic database of neuroblastoma samples, the researchers identified 7,608 peptides accessible to T cells. They narrowed the pool down to peptides that were unique to neuroblastoma, played essential roles in tumor growth and had strong binding ability with MHC.
An unmutated peptide derived from the PHOX2B gene emerged as the best hit. PHOX2B is neuroblastoma dependency gene, and its expression is routinely used in diagnosing neuroblastoma.
The team then engaged Myrio to select PHOX2B-directed PC-CAR constructs that could specifically bind to the related peptide-MHC complex.
In mice engrafted with patient-derived neuroblastoma tumors, treatment with the CAR-T cells led to complete tumor responses, the team reported. What’s more, the PC-CARs cells were able to target the same PHOX2B peptide on different MHC types.
The latest study from CHOP reflects a growing interest among immuno-oncology researchers in expanding CAR-T therapies to solid tumors. Penn, which collaborated with Novartis to develop the CAR-T treatment Kymriah, has an ongoing collaboration with Tmunity Therapeutics focused on CAR-T programs for solid tumors. These include a CHOP partnership with the Philadelphia biotech around a glypican 2 CAR-T therapy for neuroblastoma.
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In a Nature Cancer study published a year ago, a Penn team combined a PAK4 inhibitor, which blocks excessive growth of tumor-feeding blood vessels, with EGFR-targeted CAR-T cells and showed encouraging early results in mouse models of glioblastoma.
The new study expands the pool of potential targets for cancer immunotherapy, the researchers said.
“We are excited about this work because it allows us to now go after essential cancer drivers that have been considered ‘undruggable’ in the past,” Maris said in the statement. “We think that PC-CARs have the potential to vastly expand the pool of immunotherapies and significantly widen the population of eligible patients.”
In addition to moving a neuroblastoma CAR-T into the clinic, Myrio and CHOP plan to use the same approach to target other pediatric cancers, Myrio CEO Pete Smith said in a statement.