Immunotherapy on demand
Our frequent readers know that this site contains a peptide generator for designing simple, inexpensive and personalized cancer vaccines. Scientists believe that it is possible to use a system on the same principle, but much more effective.
Checkpoint inhibitors are not effective for many patients
Control point inhibitor immunotherapies are revolutionizing the treatment of cancer. However, even in the most sensitive cancers, a substantial proportion (50-80%) of patients have a low to no positive response. A surprising finding in the analysis of these patients was that one of the best correlates of response was the total number of neo-antigens in the tumor.
Basics of the new proposal
When information is transferred from DNA to RNA in cancer cells, errors occur frequently, resulting in the production of proteins that can be recognized by the immune system. Scientists at the Biodesign Institute at Arizona State University say these proteins, known as cancer-specific antigens, are important because they can be used to design vaccines that can treat or prevent tumor progression.
The common point of all cancer tumor mutations is the production of neo-antigens, or small fragments of proteins called peptides, formed inside a cancer cell, which the host's immune system had not yet never seen. These aberrant peptides, present only in cancer cells, can boost the immune system through a vaccine. They propose that mis-splicing and RNA transcription errors, particularly INDELs of MS in coding regions, in cancer cells could also be a source of neo-antigens.
These errors made by cancer cells can be used to develop a vaccine against some cancers
"In a cancer cell, it turns out that all levels of information transfer from DNA to RNA to protein become more prone to errors," said Johnston. "We proposed that these errors in cancer cells could also be the source of a cancer vaccine."
A "frame shift" or "splicing" error occurs when the DNA information of a gene is poorly processed during the fabrication of RNA, in a basic cellular process called transcription and splicing RNA.
For the most part, these alterations can be managed and cleaned by the cell, without ever being exposed to the immune system. As the cancer progresses, due to the increased number of errors, protein waste accumulates more rapidly, submerging the cell and aberrant proteins are exposed and recognized by the immune cell.
"These are overwhelming the quality control systems of a cell, generating errors in the RNA and proteins released by the cancer cell, which the immune system can respond to," said Johnston.
A new tool
To discover neo-antigens in tumors, Johnston's team has developed a new type of chip. They made fleas with the 200,000 possible neo-antigens for five common cancers, allowing them to simply search for antibodies present in the blood collected by patients. This is much simpler than the current practice of obtaining and sequencing tumor DNA, a starting point for the "personal cancer vaccines" that many companies are currently pursuing.
This set makes it possible to detect all possible predicted frame shift peptides that any tumor cell could potentially produce. They customized this chip, which contained nearly 400,000 peptides, and analyzed them with blood samples from cancer patients (and healthy control samples) to look for the peptides with the most reactive antibodies.
The basic idea is to make a vaccine containing multiple (up to 100) abnormal peptides.
Interest of this new type of immunotherapy
"Personal vaccines against cancer are complicated and expensive," said Johnston. "In addition, only about 40% of tumors have enough mutations in the DNA to make a vaccine. We have found that even cold tumors at the DNA level make many errors in the DNA. RNA: The peptides we generate are much more immunogenic than the point mutations used in personal cancer vaccines. More importantly, we can make standard vaccines for much cheaper therapeutic or even preventive vaccines. "
A vaccine that helps fight the development of resistance
It should be difficult for tumor cells to move away from the vaccine because these FSs are variants and not inherited mutations. In particular, if the FS antigen were produced in the RNA of an essential gene, the tumor cells would restrict the presentation of the MHC or create an immunosuppressive environment to evade an immune response.
In summary, scientists have discovered another class of neo-antigens that could be useful for developing different types of cancer vaccines. They have also created a matrix format for directly detecting immune responses to these tumor antigens.
What will happen to these works
Too often university laboratories stop their research when they can file a patent, in the very uncertain hope, that a large company will offer a golden bridge to buy that patent. This hope is often disappointed, simply because the patents resulting from academic research are not reproducible, but also because they do not respond to a large number of medical and regulatory issues. It is normally the role of biotech to solve these difficulties to make a process attractive for large companies. Our scientists are much more adept. They recently launched a large clinical trial of a pan-cancer prophylactic dog dog cancer vaccine funded by the Open Philanthropy Project. If that succeeds, Johnston is eager to move on to the first human clinical trials.
Regarding this web site, we could possibly design a peptide generator based on this principle. Please do not hesitate to contact us. "contact at padiracinnovation dot org"