Nature: New CAR-T therapy is expected to target various types of cancer

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Nature: New CAR-T therapy is expected to target various types of cancer

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Nature: New CAR-T therapy is expected to target various types of cancer.

The development of cancer immunotherapy represented by CAR-T has brought hope of curing leukemia and other hematological cancers, but this method has not yet achieved a substantial breakthrough in the treatment of solid tumors, partly because many solid tumors lack tumor specificity Sexual targets.

In these cancers, most of the proteins responsible for tumor growth and survival are buried deep in the cytoplasm or even the nucleus of tumor cells, not on the cell surface.

Neuroblastoma is the most common extracranial solid tumor in children , also known as the king of childhood cancers . This kind of cancer has almost no genetic mutations, but is driven by epigenetic disorders, so it lacks targets for immunotherapy, and it often recurs after conventional treatments such as radiotherapy, chemotherapy, and surgery.

On November 3, 2021, a research team from the Children’s Hospital of Philadelphia in the United States and University College London in the United Kingdom jointly published a research paper titled: Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs in the journal Nature .

The study used large data sets and advanced algorithms to identify that the neuroblastoma immune peptide group is rich in protein peptides that are essential for tumorigenesis, and focuses on human leukocyte antigen (HLA)-A*24:02 peptide found in the unmutated – QYNPIRTTF , the peptide derived from neuroblastoma dependent gene transcriptional regulatory factor and the core of PHOX2B , and may be ” peptide centered ” chimeric antigen receptor ( the PC-the CAR ) for Targeted therapy.

PC-CAR is a new type of engineered T cell that can stimulate the immune response to eradicate tumors in the body. These findings open the door to the treatment of a wider range of cancers through immunotherapy and the application of each therapy to a larger proportion of the population.

First, the research team conducted immunopeptidomic tests on 8 types of neuroblastoma cell-derived xenografts (CDX) and patient-derived xenografts (PDX) , and used three public data sets to screen and identify 13 Peptides derived from 9 unique genes expressed in neuroblastoma.

Then, according to the same method, they identified 56 peptides from 8 primary tumors of high-risk neuroblastoma.

In order to select those peptides with the highest potential as putative immunotherapy targets, they prioritized peptides based on pMHC binding affinity, HLA allele frequency, the degree of differential expression of parental genes, and the relative abundance of MHC relative to other peptides. , It is determined that PHOX2B is a highly specific tumor antigen for neuroblastoma and an ideal candidate for therapeutic targeting.

The use of synthetic peptide-centric receptors may induce immunogenic inert pMHCs to produce immunogenicity. At the same time, because high-affinity T cell receptors (TCR) were not found in multiple screenings , the research team continued to develop single-chain antibody-based CAR instead of PHOX2B’s engineered TCR.

In order to screen PHOX2B peptide-specific clones, they used the protein display platform ReD , which can select pMHC-binding single-chain antibodies in permeable bacterial cells by flow cytometry.  ReD produced 25 single-chain antibody conjugates.

In order to avoid the cross-reaction between normal tissues and pMHC, they developed an algorithm called sCRAP to predict potential cross-reactions and identified the clone 10LH with the highest specificity.

Cell experiments proved the effectiveness of sCRAP in pre-identifying non-targeting effects, effectively screening its functional consequences, and identifying molecules that have highly selective binding to tumor targets.

Finally, the research team tested the targeted killing potential of 10LH using a neuroblastoma model transplanted subcutaneously in immunodeficient mice. Model mice treated with 10LH- transduced CAR-T cells (10LH-PC-CAR) showed a complete tumor response. They also observed that CAR treatment induced a large up-regulation of MHC in tumors. This up-regulation may be due to effective IFN-γ release, indicating that the therapy can activate T cells at low antigen densities, thereby initiating a feedforward cascade, increasing MHC and antigen presentation.

Summary

this study proposes a method to identify tumor-specific antigens derived from non-mutant oncoproteins. The construction of ” peptide-centered ” chimeric antigen receptors ( PC-CAR ) for these tumor self-peptides can be effective Stimulating the immune system, showing excellent effects on neuroblastoma mouse models, completely eradicating tumors in mice.

These findings indicate that peptide-centric CARs may greatly expand the immunotherapy target library, opening the door to the treatment of a wider range of cancers through immunotherapy and the application of each therapy to a larger proportion of the population.

Original link:
https://www.nature.com/articles/s41586-021-04061-6

Nature: New CAR-T therapy is expected to target various types of cancer

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