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Nature Roundup: BioNTech CEO Shares Insights on Neoantigen Discovery
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Nature Roundup: BioNTech CEO Shares Insights on Neoantigen Discovery. Developing Personalized Cancer Vaccines!
Cancer cells can produce neoantigens that are only expressed in tumors due to genetic mutations.
These neoantigens can be recognized by the body’s T cells and attack the cancer cells that express them.
Because these neoantigens are not expressed in healthy tissues, they are one of the ideal targets for therapeutic cancer vaccines.
BioNTech, best known for its partnership with Pfizer to develop an mRNA Covid-19 vaccine, was working on developing mRNA-based cancer vaccines before developing a Covid-19 vaccine.
The company’s CEO and co-founder Dr. Ugur Sahin, as senior author, and partners recently published a review in Nature Reviews Drug Discovery , sharing insights into the discovery of neoantigens for personalized cancer vaccines .
Below article shares some of the highlights of this review with readers.
Basic principles of neoantigen presentation and recognition
Like other endogenous proteins expressed by cells, neoantigens expressed by cancer cells are degraded by the proteasome into small polypeptide chains.
These polypeptides form complexes with major histocompatibility type I (MHC-I) molecules, which are then presented on the surface of cancer cells.
They can be recognized by CD8 positive T cells.
Tumor-infiltrating immune cells, including dendritic cells, macrophages, and B cells, can act as antigen-presenting cells (APCs), ingesting neoantigens and presenting them to once-activated CD4 and CD8 memory-positive T cells.
Notably, neither cancer cells nor tumor-infiltrating APCs could directly activate naïve T cells. Activation of naive T cells is almost entirely accomplished by dendritic cells residing in lymph nodes.
These antigen-presenting cells take up soluble neoantigens from lymph, or from other antigen-presenting cells that migrate into lymph nodes, and present them to naive T cells.
Activated naive T cells are transformed into CD4- and CD8-positive memory T cells and effector T cells that recognize specific neoantigens.
Activation of naive T cells requires high levels of antigen-MHC complexes and co-stimulatory signals. Once switched to memory T cells, they can be activated by the presentation of neoantigens at much lower levels.
Activated memory T cells and effector T cells leave the lymph node and migrate into the tumor. In a favorable tumor microenvironment, they can recognize neoantigens expressed on the surface of cancer cells or by antigen-presenting cells in the tumor, and exercise many functions in controlling tumor growth. a function.
▲The mechanism of neoantigen presentation and activation of T lymphocytes (Image source: Reference )
The ultimate goal of cancer vaccines is to stimulate the production of new neoantigen-specific T cells, or to reactivate existing neoantigen-specific T cells, thereby promoting a sustained adaptive anticancer immune response until cancer cells are completely eliminated.
How to screen the neoantigens contained in cancer vaccines is one of the keys to the effectiveness of cancer vaccines .
Not all neoantigens are effective in stimulating the production of antigen-specific T cells, and the review authors divided neoantigens into three categories based on their ability to activate antigen-specific T cells.
Three types of neoantigens
According to the authors, different neoantigens act to stimulate anticancer immune responses in different clinical settings. Some neoantigens elicit potent anticancer immune responses in untreated patients and are often associated with better prognosis, while others are activated only after patients have been treated with immune checkpoint inhibitors Anticancer immune response.
The authors divided them into three broad categories based on their ability to elicit immune responses in different clinical settings.
Spontaneous generation of CD4- and CD8-positive T cells against neoantigens can also be found in untreated cancer patients.
These neoantigens have a guardian function, they can mediate early tumor rejection when the clinical symptoms of cancer are not yet obvious, or reduce tumor growth rate and inhibit the occurrence of metastasis.
Their main feature is that the expression of these neoantigens is sufficient to drive clinically meaningful anticancer immune responses in immunotherapy-naïve patients.
Guardian neoantigens can be divided into two categories, one is the neoantigens that are highly expressed in tumor cells and can bind to MHC proteins with high affinity and form stable complexes.
These features stimulate a potent cytotoxic T-cell response early in the appearance of orthotopic tumors, inhibiting the growth and metastasis of orthotopic tumors.
This type of antigen is difficult to find in humans, and the strongest evidence for it comes from mouse models.
The second type of guardian neoantigen can be recognized by pre-existing cross-reactive memory T cells.
This means that naive T cells have been activated by other antigens in the past to generate memory T cells, and these memory T cells express T cell receptors (TCRs) that can recognize neoantigens expressed by tumors.
For example, certain tumor neoantigens may be recognized by T cells that have been activated by viruses, the gut microbiome, and other pathogens.
Since the threshold for activating memory T cells is 50-fold lower than the threshold for activating naive T cells, this means that those T cells cannot activate naive T cells in the lymph node due to insufficient expression levels, weak affinity for MHC, or inability to form stable complexes Cellular neoantigens that may activate pre-existing cross-reactive memory T cells.
Guardian neoantigens control the natural progression of cancer and are associated with better outcomes in cancer patients who have not been treated with immunotherapy.
And immune checkpoint inhibitors or neoantigen vaccines may further enhance existing T cell responses.
One of its potential pitfalls, due to its early appearance in cancer, may be a prime target for cancer immune evasion.
▲Characteristics of different types of neoantigens (Image source: Reference )
Not all neoantigen-specific T cells that arise spontaneously in patients are capable of killing cancer cells.
Some T cells targeting neoantigens were only reactivated after treatment with immune checkpoint inhibitors.
The review authors classified antigens recognized by these T cells as restricted neoantigens.
Restricted neoantigens still need to be highly expressed in tumors, bind with high affinity to MHC proteins and form stable complexes. They are able to predict the clinical benefit of immunotherapy.
In human cancers, however, only a small fraction of mutations generate guardian neoantigens or restrictive neoantigens that provoke spontaneous T cell responses.
The proteins produced by most gene mutations can also be presented by MHC molecules, but they cannot evoke a spontaneous T-cell response.
The authors call these antigens “ignored neoantigens” that are presented at levels not sufficient to activate naive T cells, but above the threshold for activation of memory T cells.
However, this does not mean that these neoantigens cannot contribute to killing tumors.
Studies have shown that among the cancer gene mutations found by next-generation sequencing in mice, 15-40% of the mutations can be used as vaccine antigens to stimulate strong anti-cancer effects. T cell responses.
The role of cancer vaccines is to make dendritic cells resident in lymph nodes present sufficient numbers of these neoantigens to activate naive T cells.
Taken together, guardian neoantigens and restrictive neoantigens are highly relevant targets that should be included in individualized cancer vaccines, especially for the treatment of early-stage disease or as adjuvant therapy.
Neglected neoantigens provide a rich and complementary source of targets for neoantigen vaccines.
All three types of neoantigens should be included in cancer vaccines containing multiple neoantigens, and the utility of different types of neoantigens should be evaluated in clinical trials.
Factors to Consider in Screening Candidate Neoantigens
The manufacture of individualized cancer vaccines first requires obtaining tumor tissue from patients and sequencing the genome of the cancer cells, discovering mutations present in the tumor genome, and then predicting the production of neoantigens and selecting which neoantigens to incorporate into the cancer vaccine.
Algorithms exist to rank candidate neoantigens that take into account multiple features of candidate neoantigens that have the potential to activate T cells or avoid immune escape in cancer cells.
▲ Design process and mode of action of neoantigen vaccines (Image source: Reference )
Binding and stability to MHC
The ability to bind to at least one class of MHC molecules is an essential requirement for T cell recognition. The authors point out, however, that the interaction between antigen-specific CD4 and CD8-positive T cells is critical for generating an effective anticancer immune response.
In mouse models, expression of only a single MHC-I neoantigen did not elicit an effective immune response, requiring the expression of at least one MHC-II neoantigen.
Therefore, individualized vaccines should include epitopes expected to bind to MHC-I and MHC-II.
In addition to the affinity to MHC, the stability of the neoantigen-MHC complex is equally important. More stable complexes may improve the odds of complex recognition by T cells.
Differences from wild-type sequences and similarity to pathogen-associated epitopes
The greater the difference between the neoantigen sequence and the wild-type sequence, the higher the probability of the emergence of high-affinity T cells.
The similarity of neoantigen epitopes to pathogen sequences may increase the likelihood that they will be cross-recognized by pre-existing T cells activated by common pathogens.
The prevalence and indispensability of genetic mutations
One of the hallmarks of a tumor is its heterogeneity, which means that a tumor is actually composed of clones of cells that carry different genetic mutations.
When selecting mutations, truncal mutations that appear in all clones may be preferred over branched mutations that appear only in some clones .
This could address the issue of tumor heterogeneity. Most cancer driver mutations appear early in tumor evolution and are therefore more likely to be present in all clones.
A major way of tumor immune escape is through gene mutation to reduce or eliminate the expression of antigens recognized by T cells.
If the expression of a neoantigen is required for tumor growth, it is less susceptible to immune escape due to loss of expression.
From this perspective, essential genes for loss of heterozygosity may be excellent targets for neoantigen vaccines. Loss of heterozygosity refers to the loss of one of the two alleles in the genome.
At this time, if the other allele produces a mutation that generates a neoantigen, the tumor cell cannot escape from the immune system by losing expression of the neoantigen.
Current genetics have provided 1600-2500 genes associated with cell survival that may facilitate the sequencing of candidate neoantigens.
▲The impact of tumor heterogeneity on neoantigen recognition (Image source: Reference )
Looking to the future
According to the authors, the field of neoantigen discovery has come a long way in the past decade, driven by next-generation sequencing, increased computing power, and advanced algorithms.
The clinicaltrials.gov website, which publishes clinical trial information, currently lists 61 clinical studies related to neoantigen vaccines .
Early clinical studies of neoantigen vaccines alone or in combination with PD-1 and PD-L1 inhibitors have also shown anticancer activity.
Ultimately, the authors point out, when the discovery of neoantigens matures, we can combine it with the use of genomic sequences to discover tumor resistance mechanisms, develop enhanced cancer vaccines against drug-resistant tumors based on the mutations that occur in tumors, and achieve long-term control of tumor growth.
 Lang et al., (2022). Identification of neoantigens for individualized therapeutic cancer vaccines. Nature Reviews Drug Discovery, https://doi.org/10.1038/s41573-021-00387-y
Nature Roundup: BioNTech CEO Shares Insights on Neoantigen Discovery
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