Targeted Therapy of Intracellular Oncoproteins by Peptide-centered CAR T Cells

Posted by beauty33 on December 27th, 2021

Researchers at the Children\'s Hospital of Philadelphia (CHOP) have made a breakthrough in the treatment of aggressive solid cancers, and they have developed a new cancer treatment that targets proteins within tumor cells that are essential for tumor growth and survival, but this has not been possible before. Using the power of large data and advanced computational methods, researchers can identify peptides on the surface of tumor cells and can target \"peptide-centric\" chimeric antigen receptors (PC-CARs): a new design of T cells that stimulates the immune response to eliminate tumors.

The findings, published in Nature, open the door to the treatment of a wider range of cancers with immunotherapy and the application of each therapy in a larger proportion of the population.

\"This research is very exciting because it improves the possibility of targeting very specific tumor molecules, expanding the cancers that can be treated with immunotherapy and the patient population that can benefit,\" said Dr. Mark Yarmarkovich, a researcher in the Maris laboratory at Philadelphia Children\'s Hospital and lead author of the paper. “By using a multi-omics approach, we are able to identify peptides specific to neuroblastoma tumors, but this approach can be used in any cancer, thus providing a more personalized approach to cancer treatment.\"

The development of CAR-T cell-based cancer immunotherapy marks a breakthrough in leukemia therapy, but this approach has not yet made significant progress in the treatment of solid tumors, at least in part due to the lack of tumor-specific targets. In these cancers, most of the proteins responsible for tumor growth and survival are in the nucleus of tumor cells, rather than on the cell surface, where CAR-T cells usually have access to them. In contrast, fragments of these proteins may be presented on the surface of tumor cells through 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 these are mutant polypeptides, they may be recognized as foreign proteins. However, all childhood cancers and many adult malignancies have few mutations but are driven by other factors such as dysregulated developmental pathways.

Neuroblastoma is an explosively aggressive childhood cancer driven by alterations in gene expression that promotes uncontrolled tumor growth. Historically, treatments for neuroblastoma have been chemotherapy, surgery, and radiotherapy, but patients frequently relapse in the form of chemo resistant disease. In addition, the low mutational burden of cancer, coupled with its low MHC expression, makes it difficult for immunotherapy to target therapy.

Despite these obstacles, the investigators hypothesize that some peptides on the surface of neuroblastoma cells come from proteins that are essential for tumor growth and survival and can be targeted by synthetic CARs. These PC-CARs can directly target and kill tumor cells. The challenge we face is to distinguish tumor-specific peptides from other seemingly similar peptides or peptides present in normal tissue to avoid cross-reactivity and lethal toxicity.

To this end, the researchers isolated MHC molecules from neuroblastoma cells and determined which peptides were present and in which abundance. They used a large genomic dataset generated in the laboratory to determine which peptides were unique to neuroblastoma and not expressed by normal tissue. They preferentially select peptides extracted from tumor-essential genes that have features required to participate in the immune system. To eliminate any potential antigens that may cross-react with normal tissues, the researchers filtered the remaining tumor peptides with the MHC peptide database of normal tissues to remove any peptides containing maternal genes in normal tissues.

Using this multi-omics approach, the investigators identified an unmutated neuroblastoma peptide from PHOX2B, a neuroblastoma-dependent gene and transcriptional regulator that has been previously identified and described in CHOP. The next major hurdle is the development of a PC-CAR that recognizes only the peptide, which accounts for 2–3% of the peptide-mhc complex. In collaboration with Myrio Therapeutics, an antibody discovery company, the researchers developed a PC-CAR against this peptide and showed that these PC-CARs can recognize tumor-specific peptides of different HLA types, which means that this treatment can be applied to patients with different genetic lineages.

In further studies, the team tested PC-CARs in mice and found that this treatment could completely and specifically eliminate neuroblastoma.

\"We are excited about this work because it allows us to now track the basic cancer drivers that used to be considered \'non-medicable\'. We believe that PC-CARS has the potential to greatly expand the immunotherapy pool and significantly expand the eligible patient population,\" said corresponding author John M. Maris, MD. \"Due to our accelerated grant through the Cell and Gene Therapy Collaboration Project of CHOP, we will conduct a clinical trial of PHOX2B PC-CAR at CHOP at the end of 2022 or early 2023.\"

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