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Written by Sister Xian | XI The human immune system can recognize and eliminate cells expressing exogenous non-self antigens, and all malignant tumors have non-synonymous mutations or other genetic changes, some of which may produce new "non-self" tables Position, which may trigger the body’s anti-tumor T cell response
.
In recent years, tumor immunotherapy has become an important tumor treatment after surgery, radiotherapy and chemotherapy
.
Cancer immunotherapy based on therapeutic vaccines or transduction of tumor infiltrating lymphocytes (TIL) targeting tumor neoantigens has shown good clinical effects [1,2]
.
In addition, the development of blood T cell engineering with tumor-reactive T cell receptor (TCR) has further expanded the scope of adoptive T cell therapy (ACT) [3, 4]
.
It is conceivable that the identification of clinically relevant tumor antigens and their homologous TCR is an important basis for this type of treatment
.
At present, autologous TIL or peripheral blood lymphocytes (PBL) amplified in vitro are usually used for the discovery of tumor antigens
.
However, the frequency of neoantigen-specific T cells in PBL and TIL is usually low, and studies have confirmed that neoantigens in PBL and TIL are inconsistent
.
In addition, despite some pioneering work in improving the detection of neoantigen reactivity in the blood, it is undeniable that the discovery of antigens in PBL is still extremely challenging
.
Although TIL has its advantages, traditional in vitro TIL expansion and culture methods have been shown to be distorted.
Therefore, the number of tumor-reactive lymphocytes may be underestimated and may also limit the verification of tumor epitopes
.
On November 15, 2021, Alexandre Harari's team from the University of Lausanne in Switzerland published an online article entitled Sensitive identification of neoantigens and cognate TCRs in human solid tumors on Nature Biotechnology, and developed a sensitive identification of rare tumor (new) antigens And the method of homologous TCR expressed by tumor-infiltrating lymphocytes-NeoScreen, and confirmed that the tumor antigen-specific TCR-transduced T cells identified by NeoScreen mediate the regression of tumors in xenograft mice derived from patients
.
Unlike traditional culture methods that rely solely on the growth factor interleukin (IL)-2, NeoScreen is based on early exposure of TIL derived from intact tumor fragments or isolated tumor cells to active autologous antigen presenting cells (APC) On the selective antigen (Figure 1)
.
The APCs selected in this study are CD40-activated (CD40-act) B cells because they are easier to obtain and expand from a small amount of blood than dendritic cells, and they are easy to be engineered by electroporation
.
At the same time, in order to optimize the effectiveness of APC, the researchers co-electroporated the immunostimulatory 4-1BB ligand (4-1BBL/CD137), OX40 ligand (OX40L/CD252) and IL-12 encoded by RNA on CD40-act B cells.
It has been remodeled
.
The researchers first verified the functionality of the NeoScreen method by using TIL from two tumor specimens
.
The traditional method of IL-2 amplification of TIL can easily identify the four new epitope reactions in the two specimens, but compared with the new epitope specific CD8 in TIL exposed to auto-engineered APC The frequency of T cells increased significantly
.
Subsequently, the researchers tested NeoScreen's ability to discover new tumor antigens in seven other patients
.
Researchers used the protein genomics NeoDisc to make predictions, using immunopeptidomics-based neoantigen recognition and prioritization, and only focused on non-synonymous somatic point mutations and tumor-associated antigen (TAA) candidates
.
Add once (1×) or twice (2×) engineered autologous APC loaded with neoantigens and/or TAA candidates during TIL stimulation, and compare NeoScreen amplified TIL with traditional cultured TIL to determine Whether there are antigen-specific cells (Figure 1)
.
The results showed that NeoScreen was able to identify 19 tumor epitopes in 7 patients, of which 10 epitopes were only found in the TIL amplified by NeoScreen
.
When using NeoScreen, the average number of tumor epitopes per patient is 3, compared to only 1 under the traditional method
.
Figure 1 Through NeoScreen, using IFNγ enzyme-linked immunospot (ELISpot), pMHC polymer and 4-1BB staining, researchers have verified 23 tumor antigens, including 15 new epitopes
.
Compared with traditional TIL culture methods, NeoScreen TIL has several orders of magnitude difference in the significant enrichment of new epitopes or TAA-responsive cells
.
It is worth noting that when only neoantigens are considered, NeoScreen is still significantly better than traditional strategies
.
In general, in the presence of tumor antigens, engineered APC allows neoantigen (and TAA) specific CD8 T cells to expand in large numbers in melanoma and ovarian cancer, lung cancer, and colon cancer, thereby establishing a high degree of Sensitive and reproducible tumor antigen recognition method
.
Furthermore, the researchers speculate that this new platform will be able to sensitively isolate relevant TCRs for personalized tumor antigens
.
The researchers used the up-regulation of pMHC multimers or 4-1BB to purify the tumor antigen-specific NeoScreen TIL, and perform TCRα and TCRβ batch sequencing on the isolated T cells
.
A single tumor epitope is recognized by one or more clonotypes and appears at different frequencies in NeoScreen TIL
.
By tracing the verified TCRβ sequence in the original tumor and NeoScreen amplified TIL, the researchers determined that the NeoScreen process did indeed result in a significant expansion of tumor antigen-specific TIL
.
The cumulative data of 50 clonotypes confirms NeoScreen's potential to recognize new antigens or TAA-specific new TCRs, which are not detected in traditional TILs
.
Finally, the researchers established an autologous tumor cell line and studied the anti-tumor reactivity of the validated tumor antigen-specific TCR revealed by NeoScreen
.
All NeoScreen-derived TCRs against neo-epitope or TAA are tumor-reactive.
It is worth mentioning that this is the first extensive proof that neo-antigen-specific TCRs always target autologous tumors
.
So can the TCR recognized by NeoScreen be used for personalized TCR-based ACT? The answer is gratifying
.
In the human IL-2 transgenic (hIL-2) NOG mouse model using patient-derived xenograft tumors, the researchers found that adoptive transplantation transduced peripheral blood T cells with tumor antigen-specific TCR from NeoScreen TIL to mediate in vivo Specific tumor regression (Figure 2)
.
This proves that the antigen-specific TCR identified by NeoScreen has anti-tumor reactivity in vitro and in vivo, and proves the feasibility of NeoScreen for TCR gene transduction therapy
.
Figure 2 In summary, this study uses engineered B cells to improve the sensitivity of antigen discovery at the initial stage of TIL growth for the first time, and has developed a highly sensitive method for tumor (neo) antigen screening-NeoScreen This method can generate the most extensive tumor antigen-reactive TCR so far
.
NeoScreen can not only increase the frequency of antigen-specific TCRs found by traditional methods, but it can also recruit additional TCR clonotypes and be newly detected with significantly improved sensitivity
.
NeoScreen can efficiently recognize tumor-specific antigens in melanoma, ovarian cancer, colorectal cancer, and lung cancer, and can isolate homologous tumor reactive TCRs with high sensitivity
.
This also shows that NeoScreen is of great value for the selection of relevant personalized target antigens for tumor vaccines and the isolation of tumor-responsive TCRs for the personalized engineering T cell therapy of solid tumors
.
Original link: https://doi.
org/10.
1038/s41587-021-01072-6 Platemaker: 11 References 1.
Tran, E.
et al.
Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer.
Science 344, 642–644 (2014) 2.
Chen, F.
et al.
Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors.
J.
Clin.
Invest.
129, 2056–2070 (2019) 3.
Sadelain, M.
, Rivière, I.
& Riddell, S.
Therapeutic T cell engineering.
Nature 545, 423–431 (2017).
4.
Rosenberg, SA & Restifo, NP Adoptive cell transfer as personalized immunotherapy for human cancer.
Science 348 , 62–68 (2015).
Reprinting instructions [Original Articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
.
In recent years, tumor immunotherapy has become an important tumor treatment after surgery, radiotherapy and chemotherapy
.
Cancer immunotherapy based on therapeutic vaccines or transduction of tumor infiltrating lymphocytes (TIL) targeting tumor neoantigens has shown good clinical effects [1,2]
.
In addition, the development of blood T cell engineering with tumor-reactive T cell receptor (TCR) has further expanded the scope of adoptive T cell therapy (ACT) [3, 4]
.
It is conceivable that the identification of clinically relevant tumor antigens and their homologous TCR is an important basis for this type of treatment
.
At present, autologous TIL or peripheral blood lymphocytes (PBL) amplified in vitro are usually used for the discovery of tumor antigens
.
However, the frequency of neoantigen-specific T cells in PBL and TIL is usually low, and studies have confirmed that neoantigens in PBL and TIL are inconsistent
.
In addition, despite some pioneering work in improving the detection of neoantigen reactivity in the blood, it is undeniable that the discovery of antigens in PBL is still extremely challenging
.
Although TIL has its advantages, traditional in vitro TIL expansion and culture methods have been shown to be distorted.
Therefore, the number of tumor-reactive lymphocytes may be underestimated and may also limit the verification of tumor epitopes
.
On November 15, 2021, Alexandre Harari's team from the University of Lausanne in Switzerland published an online article entitled Sensitive identification of neoantigens and cognate TCRs in human solid tumors on Nature Biotechnology, and developed a sensitive identification of rare tumor (new) antigens And the method of homologous TCR expressed by tumor-infiltrating lymphocytes-NeoScreen, and confirmed that the tumor antigen-specific TCR-transduced T cells identified by NeoScreen mediate the regression of tumors in xenograft mice derived from patients
.
Unlike traditional culture methods that rely solely on the growth factor interleukin (IL)-2, NeoScreen is based on early exposure of TIL derived from intact tumor fragments or isolated tumor cells to active autologous antigen presenting cells (APC) On the selective antigen (Figure 1)
.
The APCs selected in this study are CD40-activated (CD40-act) B cells because they are easier to obtain and expand from a small amount of blood than dendritic cells, and they are easy to be engineered by electroporation
.
At the same time, in order to optimize the effectiveness of APC, the researchers co-electroporated the immunostimulatory 4-1BB ligand (4-1BBL/CD137), OX40 ligand (OX40L/CD252) and IL-12 encoded by RNA on CD40-act B cells.
It has been remodeled
.
The researchers first verified the functionality of the NeoScreen method by using TIL from two tumor specimens
.
The traditional method of IL-2 amplification of TIL can easily identify the four new epitope reactions in the two specimens, but compared with the new epitope specific CD8 in TIL exposed to auto-engineered APC The frequency of T cells increased significantly
.
Subsequently, the researchers tested NeoScreen's ability to discover new tumor antigens in seven other patients
.
Researchers used the protein genomics NeoDisc to make predictions, using immunopeptidomics-based neoantigen recognition and prioritization, and only focused on non-synonymous somatic point mutations and tumor-associated antigen (TAA) candidates
.
Add once (1×) or twice (2×) engineered autologous APC loaded with neoantigens and/or TAA candidates during TIL stimulation, and compare NeoScreen amplified TIL with traditional cultured TIL to determine Whether there are antigen-specific cells (Figure 1)
.
The results showed that NeoScreen was able to identify 19 tumor epitopes in 7 patients, of which 10 epitopes were only found in the TIL amplified by NeoScreen
.
When using NeoScreen, the average number of tumor epitopes per patient is 3, compared to only 1 under the traditional method
.
Figure 1 Through NeoScreen, using IFNγ enzyme-linked immunospot (ELISpot), pMHC polymer and 4-1BB staining, researchers have verified 23 tumor antigens, including 15 new epitopes
.
Compared with traditional TIL culture methods, NeoScreen TIL has several orders of magnitude difference in the significant enrichment of new epitopes or TAA-responsive cells
.
It is worth noting that when only neoantigens are considered, NeoScreen is still significantly better than traditional strategies
.
In general, in the presence of tumor antigens, engineered APC allows neoantigen (and TAA) specific CD8 T cells to expand in large numbers in melanoma and ovarian cancer, lung cancer, and colon cancer, thereby establishing a high degree of Sensitive and reproducible tumor antigen recognition method
.
Furthermore, the researchers speculate that this new platform will be able to sensitively isolate relevant TCRs for personalized tumor antigens
.
The researchers used the up-regulation of pMHC multimers or 4-1BB to purify the tumor antigen-specific NeoScreen TIL, and perform TCRα and TCRβ batch sequencing on the isolated T cells
.
A single tumor epitope is recognized by one or more clonotypes and appears at different frequencies in NeoScreen TIL
.
By tracing the verified TCRβ sequence in the original tumor and NeoScreen amplified TIL, the researchers determined that the NeoScreen process did indeed result in a significant expansion of tumor antigen-specific TIL
.
The cumulative data of 50 clonotypes confirms NeoScreen's potential to recognize new antigens or TAA-specific new TCRs, which are not detected in traditional TILs
.
Finally, the researchers established an autologous tumor cell line and studied the anti-tumor reactivity of the validated tumor antigen-specific TCR revealed by NeoScreen
.
All NeoScreen-derived TCRs against neo-epitope or TAA are tumor-reactive.
It is worth mentioning that this is the first extensive proof that neo-antigen-specific TCRs always target autologous tumors
.
So can the TCR recognized by NeoScreen be used for personalized TCR-based ACT? The answer is gratifying
.
In the human IL-2 transgenic (hIL-2) NOG mouse model using patient-derived xenograft tumors, the researchers found that adoptive transplantation transduced peripheral blood T cells with tumor antigen-specific TCR from NeoScreen TIL to mediate in vivo Specific tumor regression (Figure 2)
.
This proves that the antigen-specific TCR identified by NeoScreen has anti-tumor reactivity in vitro and in vivo, and proves the feasibility of NeoScreen for TCR gene transduction therapy
.
Figure 2 In summary, this study uses engineered B cells to improve the sensitivity of antigen discovery at the initial stage of TIL growth for the first time, and has developed a highly sensitive method for tumor (neo) antigen screening-NeoScreen This method can generate the most extensive tumor antigen-reactive TCR so far
.
NeoScreen can not only increase the frequency of antigen-specific TCRs found by traditional methods, but it can also recruit additional TCR clonotypes and be newly detected with significantly improved sensitivity
.
NeoScreen can efficiently recognize tumor-specific antigens in melanoma, ovarian cancer, colorectal cancer, and lung cancer, and can isolate homologous tumor reactive TCRs with high sensitivity
.
This also shows that NeoScreen is of great value for the selection of relevant personalized target antigens for tumor vaccines and the isolation of tumor-responsive TCRs for the personalized engineering T cell therapy of solid tumors
.
Original link: https://doi.
org/10.
1038/s41587-021-01072-6 Platemaker: 11 References 1.
Tran, E.
et al.
Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer.
Science 344, 642–644 (2014) 2.
Chen, F.
et al.
Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors.
J.
Clin.
Invest.
129, 2056–2070 (2019) 3.
Sadelain, M.
, Rivière, I.
& Riddell, S.
Therapeutic T cell engineering.
Nature 545, 423–431 (2017).
4.
Rosenberg, SA & Restifo, NP Adoptive cell transfer as personalized immunotherapy for human cancer.
Science 348 , 62–68 (2015).
Reprinting instructions [Original Articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
