Researchers develop new class of CAR-T cells that target previously untargetable cancer factors – ScienceDaily
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 inside cancer cells that are essential for tumor growth and survival. , but which have been historically impossible to achieve. Using the power of large datasets and advanced computational approaches, 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-CAR), a new class of modified T cells, stimulating an immune response that eradicates tumors.
The discovery, which was described today in Nature, opens the door to the treatment of a wider range of cancers with immunotherapy as well as to the application of each therapy to a greater proportion of the population.
“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 that can benefit from it,” said Mark Yarmarkovich, PhD, researcher at the laboratory. Husbands at Children’s Hospital of Philadelphia and first author of the article. “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 a more personalized approach to cancer treatment.”
The development of CAR T cell-based cancer immunotherapy marked a breakthrough in the treatment of leukemia, but the approach has not yet made significant progress against solid tumors due, at least in part, to lack of tumor-specific targets. In these cancers, most of the proteins responsible for tumor growth and survival are found 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 to the surface of tumor cells by presenting peptides on the major histocompatibility complex (MHC), which has evolved to present viral and bacterial peptides to the immune system. Cancer cells can also present intracellular proteins on the MHC, and if they are mutant peptides, they can be recognized as foreign. However, all pediatric cancers and many adult malignancies have few mutations and are instead due to other factors such as deregulated developmental pathways.
Neuroblastoma is an extremely aggressive pediatric cancer that is caused by changes in the expression of genes that promote uncontrolled tumor growth. Historically, neuroblastoma has been treated with chemotherapy, surgery, and radiation therapy, but patients often relapse with chemotherapy-resistant forms of the disease. In addition, the low mutational burden of cancer, combined with its low MHC expression, made targeting with immunotherapies difficult.
Despite these obstacles, the researchers hypothesized that some of the peptides presented on the surface of neuroblastoma tumor cells originate from proteins essential for tumor growth and survival and could be targeted with synthetic CARs. These PC-CARs would make it possible to directly target and kill tumor cells. The challenge was to differentiate tumor-specific peptides from other peptides of similar appearance or peptides that exist in normal tissues in order to avoid cross-reactivity and lethal toxicity.
To do this, the researchers removed MHC molecules from neuroblastoma cells and determined which peptides were present and in what abundance. They used a large set of genomic data that the Maris lab generated to determine which peptides were unique to neuroblastoma and not expressed by normal tissue. They prioritized peptides derived from genes essential to the tumor and exhibiting the characteristics required to engage the immune system. To eliminate any potential antigens that might cross-react with normal tissues, the researchers filtered the remaining tumor peptides against a database of MHC peptides on normal tissues, removing any peptide with a parent gene shown in the normal tissue.
Using this multi-omic approach, the researchers identified an unmutated neuroblastoma peptide that is derived from PHOX2B, a neuroblastoma dependency gene and a transcriptional regulator that has been previously identified and characterized at CHOP. The next major hurdle was the development of a PC-CAR that specifically recognized peptide only, which represents 2-3% of the peptide-MHC complex. In collaboration with the antibody discovery company Myrio Therapeutics, the researchers developed a PC-CAR targeting this peptide and showed that these PC-CARs recognized the tumor-specific peptide on different HLA types, which means that the treatment could be applied to patients of various genetic lines. .
Taking the research a step further, the team tested PC-CARs in mice and found that the treatment led to complete and targeted removal of neuroblastoma tumors.
“We are excited about this work because it now allows us to tackle critical factors in cancer that were considered ‘non-drug’ in the past. We believe that PC-CARS has the potential to dramatically expand the pool of immunotherapies and significantly expand the eligible patient population, ”said lead author John M. Maris, MD, pediatric oncologist and chair. Giulio D’Angio researcher on neuroblastoma at CHOP. “With 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 at the end of 2022 or early 2023.”