Cancer cell and T cell, illustration
Source: Roger Harris/Science Photo Library/Getty Images

In what they claim is a breakthrough for the treatment of aggressive solid cancers, researchers at Children’s Hospital of Philadelphia (CHOP) have developed a novel approach to targeting proteins inside cancer cells that are essential for tumor growth and survival, but which have historically been impossible to reach. By harnessing large data sets and advanced computational approaches, the researchers identified peptides presented on the surface of tumor cells that can be targeted with “peptide-centric” chimeric antigen receptors (PC-CARs)—a new class of engineered T cells—to stimulate an immune response that eradicates tumors. Tests showed that a neuroblastoma peptide-targeting PC-CAR completely and selectively eliminated neuroblastoma tumors in mice.

The scientists suggest that their discoveries could open up new opportunities for treating a broader range of tumor types using immunotherapy, and for applying each therapy across a greater proportion of the population. Clinical trials with the technology are projected to by early 2023. “This research is extremely exciting because it raises the possibility of targeting very specific tumor molecules, expanding both the cancers that can be treated with immunotherapy and the patient population who can benefit,” said Mark Yarmarkovich, PhD, an investigator in the laboratory of John M. Maris, MD, pediatric oncologist and Giulio D’Angio Chair in Neuroblastoma Research at CHOP. “By using a multi-omics approach, we were able to identify peptides specific to neuroblastoma tumors, but this method could be used in any cancer, allowing for a more personalized approach to cancer treatment.”

Yarmarkovich is first author, and Maris senior author, of the team’s published paper in Nature, which is titled, “Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs the paper,” in which the authors concluded, “We expect that the methods presented here will facilitate the discovery of tumor-specific targets in other human cancers with high unmet need …”

The development of CAR T cell-based cancer immunotherapy has represented a breakthrough in the treatment of leukemia, but this therapeutic approach has not yet made significant strides against solid tumors. This is due, at least in part, to a lack of tumor-specific targets. In these types of cancer, most of the proteins responsible for tumor growth and survival are 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 may 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. If cancer cell intracellular proteins presented on MHC are mutant peptides, they may then be recognized as foreign. “… most cancer driver proteins reside in the cytoplasm or nucleus of the cell, where they are accessible to the immune system only through presentation of peptides on the major histocompatibility complex (MHC),” the team noted. “T cell recognition of mutation-derived pMHC neoantigens as non-self is the basis of curative responses achieved through immune checkpoint blockade and complete remissions using adoptive transfer of tumor-infiltrating lymphocytes (TILs) …” However, all pediatric cancers, and many adult malignancies have few mutations. Rather, they are driven by other factors, such as dysregulated developmental pathways.

Neuroblastoma is an explosively aggressive pediatric cancer that is driven by modifications of gene expression that promote uncontrolled tumor growth. “Neuroblastoma is a pediatric cancer that harbors few mutations and is instead driven by epigenetically deregulated transcriptional networks,” the team explained.

Historically, neuroblastoma has been treated using chemotherapy, surgery, and radiation therapy, but patients often relapse with forms of the disease that are chemotherapy resistant. Additionally, the low mutational burden of the cancer, combined with its low MHC expression, have made it difficult to target with immunotherapies. “These tumors are low in mutational burden and MHC expression, making neuroblastoma both a challenging tumor to target with MHC-based immunotherapies and an ideal model for addressing the major problems currently hindering the wider advancement of cancer immunotherapies,” the authors continued.

Despite these obstacles, the researchers hypothesized that some of the peptides presented on the surface of neuroblastoma tumor cells come from proteins that are essential for tumor growth and survival and could be targeted with synthetic CARs. “We hypothesized that a subset of the immunopeptidome consists of tumor-specific peptides derived from essential oncoproteins and that these can be targeted using synthetic peptide-centric CARs (PC-CARs).”

Such PC-CARs would allow for direct targeting and killing of tumor cells. The challenge was differentiating tumor-specific peptides from other, similar looking peptides or peptides that exist in normal tissues, to avoid cross-reactivity and lethal toxicity. To do so, the researchers stripped the MHC molecules off neuroblastoma cells and determined which peptides were present, and their abundance.

They used a large genomic dataset that the Maris lab has generated to determine which peptides were unique to neuroblastoma and not expressed by normal tissues. The team then prioritized peptides that were derived from genes essential to the tumor and had characteristics required to engage the immune system. To weed out any potential antigens that might 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 pinpointed an unmutated neuroblastoma peptide that is derived from PHOX2B, a neuroblastoma dependency gene and transcriptional regulator that was previously identified and characterized at CHOP. The team then worked in collaboration with antibody-discovery company Myrio Therapeutics, to develop PC-CARs that specifically recognized just this peptide—which makes up 2–3% of the peptide-MHC complex. Subsequent experiments confirmed that the resulting PC-CARs recognized the tumor-specific peptide on different HLA types, indicating that if used as a treatment, they could potentially be applied to patients of diverse genetic lineages.

Taking the research a step further, the team tested the PC-CARs in neuroblastoma-bearing mice and found that the treatment led to complete and targeted elimination of their neuroblastoma tumors. “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,” said Maris. “We think that PC-CARS have the potential to vastly expand the pool of immunotherapies and significantly widen the population of eligible patients. Thanks to the Acceleration grant we received through the Cell and Gene Therapy Collaborative at CHOP, we will bring our PHOX2B PC-CAR to a clinical trial at CHOP in late 2022 or early 2023.”

Concluding in their published paper, the authors wrote, “These methods have resulted in PC-CARs that can induce potent tumor killing across multiple HLA alleles in neuroblastoma and provide a roadmap for addressing the major challenges of therapeutic targeting of intracellular oncoproteins … These data suggest that peptide-centric CARs have the potential to vastly expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and widen the population of patients who would benefit from such therapy by breaking conventional HLA restriction.”

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