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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 .
Lack of tumor-specific 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 child of the most common extracranial solid tumor, also known as the king of childhood cancer
2021 Nian 11 Yue 3 days, Children's Hospital of Philadelphia and University College London research team at the JointNaturepublished a journal entitled: Cross-HLA Targeting of intracellular oncoproteins with Peptide-Centric CARsresearch papers
.
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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 The unmutated peptide found on QYNPIRTTF , which is derived from neuroblastoma-dependent genes and the core transcription regulator PHOX2B , and can be carried by the " peptide-centric " chimeric antigen receptor ( PC-CAR ) Targeted therapy
.
.
PC-CAR is a new type of engineered T cell that can stimulate the immune response, thereby eradicating 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
PC-CAR is a new type of engineered T cell that can stimulate the immune response, thereby eradicating tumors in the body
First, the research team conducted immunopeptidomic tests on 8 types of neuroblastoma cell-derived xenografts ( CDX ) and patient-derived xenografts ( PDX ), using three public data sets to screen and identify 13 Peptides derived from 9 unique genes expressed in neuroblastoma .
First, the research team conducted immunopeptidomic tests on 8 types of neuroblastoma cell-derived xenografts ( CDX ) and patient-derived xenografts ( PDX ), using 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 immunogenicity of immunogenic inert pMHCs .
At the same time, since no high-affinity T cell receptor ( TCR ) was found in multiple screenings , the research team continued to develop single-chain antibody-based CAR instead of PHOX2B 's engineered TCR
The use of synthetic peptide-centric receptors may induce immunogenicity of immunogenic inert pMHCs .
At the same time, since no high-affinity T cell receptor ( TCR ) was 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
Finally, the research team tested the targeted killing potential of 10LH using a
neuroblastoma model transplanted subcutaneously in immunodeficient mice .
10LH transduced CAR-T cells ( 10LH the PC-CAR- model mice treated) showed complete tumor response, they also observed CAR therapy-induced tumors MHC large upregulated
.
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
.
Finally, the research team tested the targeted killing potential of 10LH using a
neuroblastoma model transplanted subcutaneously in immunodeficient mice .
10LH transduced CAR-T cells ( 10LH the PC-CAR- model mice treated) showed complete tumor response, they also observed CAR therapy-induced tumors MHC large upregulated
.
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
.
In 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 ) against these tumor self-peptides can be effective Stimulating the immune system, showing excellent effects on neuroblastoma mouse models, completely eradicating tumors in mice
.
The construction of " peptide-centered " chimeric antigen receptors ( PC-CAR ) against 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
.
.
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