Prevention

Shot in the arm

Author: George Weiner
Date: 2020-12-15 

When my turn in line comes, I will have no hesitancy about rolling up my sleeve and getting a shot in the arm.  My position on the benefit and potential risk of receiving one of the new mRNA-based Covid-19 vaccines is based on over 30 years of studying how we can use the immune system to treat cancer.  I’d like to summarize how this experience has influenced my perspective on taking the vaccine. The idea of cancer immunotherapy is not new – indeed the first attempts to modulate the immune system to treat cancer date to the 1800s.  My involvement began in the early 1990s when my research group joined others around the world seeking new approaches to cancer immunotherapy.  We have made remarkable advances in some aspects of the field, however progress in development of cancer vaccines that can induce the immune system to reject an established cancer has been frustratingly slow.  The first attempts at cancer vaccines involved immunizing patients with tumor or tumor extracts to try and mimic the success of vaccines against infection.  This approach was a therapeutic bust despite multiple attempts to make it better including modifying the tumor cells, tumor extracts or proteins used in the vaccine or by mixing the vaccine with a variety of substances to gear up the immune response. We did learn a number of very important lessons about why inducing an effective immune response against a cancer is much more difficult than inducing such an immune response to prevent infection.  We now know there are three major obstacles to developing a successful therapeutic cancer vaccine. 

  1. Tumor masses have an abnormal “immune micro-environment” which turns off the immune system. This allows the cancer to avoid being rejected even in the face of an anti-cancer immune response.
  2. Every patient’s cancer is unique, so it is not possible to make a “one size fits all” vaccine against all cancers.
  3. Therapeutic cancer vaccines need to eliminate large numbers of malignant cells already in the body which takes a much stronger and different type of immune response than is needed for a vaccine designed to prevent infection. This is a biological reflection of the adage, “an ounce of prevention is worth a pound of cure”.

Several years ago, researchers went back to basic biology to think about possible ways to overcome these challenges.  As taught in basic biology classes, DNA in cells gets “transcribed” into strands of RNA.  This RNA serves as the messenger between the DNA and production of proteins, hence its name – messenger RNA or mRNA.  To use a metaphor that was not available when I was in school, think of each cell in the body as a 3-D printer.  The DNA is the operating system of the 3-D printer, the mRNA is the software instructions and the protein is the final product. Clever researchers realized it might be possible to reprogram the proteins made by cells by providing those cells with a novel mRNA.  To use our metaphor, this would be like downloading novel software that results in the 3-D printer producing something (in this case a protein) it has never made before.  In cancer, the selected mRNA could code for an abnormal protein found in the patient’s cancer cells but not in their normal cells.  Production by the cell of that abnormal protein, induced by the mRNA vaccine, could stimulate the immune system to recognize and fight the cancer. Many important lessons were learned from initial studies of mRNA-based cancer vaccines as well as researchers evaluating mRNA vaccines for other diseases.  Some forms of mRNA worked better than others.  The mRNA got into cells more effectively if it was enclosed in nanoparticles made up of lipids.  Nanoparticles containing mRNA were most stable if stored at very cold temperatures.  Importantly, clinical trials of this approach demonstrated mRNA-based vaccines could be administered safely.  In some cases, they induced the desired immune response.   Unfortunately, in most cancer trials, the strength of the anti-cancer immune response induced by mRNA was not strong enough to eliminate the cancer. While this work on mRNA-based vaccines was ongoing in tumor immunology, researchers interested in vaccines for infectious diseases also saw its potential.  Importantly, the three major hurdles to cancer vaccines did not represent obstacles for mRNA-based vaccines designed to immunize against most infectious organisms.

  1. The immune system of those being vaccinated is not suppressed.
  2. A single design of the vaccine could be used to treat the entire population (assuming enough of it could be manufactured).
  3. The vaccine is preventive, so even a relatively modest immune response could be highly effective.

From a safety point of view, mRNA-based vaccines have proven to be attractive whether they are designed to treat cancer or prevent infection.  The mRNA does not code for all the factors that drive a cancer cell to grow or allow a virus to multiply and spread.  In other words, there is no chance of an mRNA vaccine itself causing cancer or infection.  Furthermore, once injected, the mRNA is active for only a matter of days.  Normal cells that take up nanoparticles containing the mRNA fleetingly express the protein coded for by the mRNA.  Even though expression of the protein by normal cells is short lived, it is long enough to stimulate the immune system and leave behind a long-lasting immune response. Fast forward to the Covid-19 pandemic.  When we first learned about what we now know as Covid-19, researchers were at the ready.  They had already produced mRNA-based vaccines against a variety of cancers and against viruses related to the Covid-19 virus.  Within weeks, these researchers were able to synthesize the key mRNA from the Covid-19 virus (known as SARS-cov-2) spike protein, manufacture lipid nanoparticles containing this mRNA, and begin testing. This testing moved thoughtfully and safely, but quickly, through various phases going from laboratory and animal testing to large, randomized clinical trials in record time based on prior knowledge and the recognition of the need for speed.  The results have been nothing less than spectacular.  As with other mRNA-based vaccines, the Covid-19 vaccines appear to be safe.  They induce a robust immune response against the virus spike protein.  In contrast to mRNA-based cancer vaccines, the type of immune response the Covid-19 mRNA vaccines generates is incredibly effective and prevents Covid-19 infection in the vast majority of individuals. To summarize, the new Covid-19 mRNA vaccines are new and have been moved through the system in record time.  This was possible because they are based on solid biology and are similar to vaccines that have been tested in other settings for years.  Results of clinical trials to date show limited side effects and remarkable efficacy.  There is no reason to presume that they are likely to have unexpected long-term side effects.  Based on this background, I have no hesitancy in being immunized with one of the Covid-19 mRNA vaccines myself and encouraging my family members to do so as well. And, once I have newly developed immunity to Covid-19 coursing through my veins, I look forward to returning to a more normal life.  I look forward to a shot in the arm that our cancer research will get based on the knowledge and experience generated from the study of the Covid-19 and its vaccines, just as studies in cancer immunotherapy helped provide a foundation that contributed to the rapid development of the Covid-19 vaccine. So...here's to all of us getting a shot in the arm.

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