By Dr. Sope Olugbile
Medical Oncology
Hartford HealthCare Cancer Institute
The COVID-19 pandemic has caused unprecedented health and economic devastation across the globe. Unfortunately, the people at the highest risk for severe diseases and death include the elderly and those with pre-existing conditions like diabetes and cancer.
But the rapid development, approval and deployment of effective vaccines has brought hope of a return back to normalcy in the coming months. Two of the approved vaccines, manufactured by Pfizer-BioNTech and Moderna, are based on a new technology that uses genetic information in the form of messenger RNA (called mRNA). Given its success in battling COVID-19, the hope is that the same concept will be deployed in developing more effective immunotherapies for cancers.
For centuries, the immune system has been suspected to have the capacity to control cancers. Early signs were based on reports of partially effective Coley’s vaccines, a toxin concoction that contained heat-killed bacteria. In the modern era, however, infusion of cytokines (proteins naturally produced by the body to fight infections and cancers, such as interferon and interleukins) were shown to cause tumor shrinkage in patients with melanoma and kidney cancers. And a more elaborate approach that involves infusion of immune cells initially obtained from resected tumor was used to eradicate tumors in a handful of patients.
More recently approved medications, including immune checkpoint inhibitors (such as Pembrolizumab and Nivolumab) and CAR-T cells (engineered immune cells initially obtained from patients), have demonstrated remarkable, long-lasting clinical benefits for patients with different tumor types, including melanoma, lung cancer, bladder cancer and leukemia. But many of the most common cancer types — breast, prostate and pancreatic cancers — do not respond remarkably well to any of these immunotherapies for now. Because of this, there is ongoing global effort to further develop even more effective therapies for cancer patients, especially those with advanced and metastatic diseases.
When compared with conventional chemotherapy, immunotherapies are better tolerated as they are less likely to cause significant side effects. In those who respond to them, the benefits often tend to last much longer. One potential additional advantage is in prevention of cancers. In the near future, it is theoretically possible to develop “preventive” cancer vaccines for individuals at highest risk for specific type of cancers and those with pre-cancer lesions.
These are all possible given the robustness and versatility of the immune system, which promptly identifies anything foreign, including infectious agents and cancers, and rolls out a plan to neutralize it. Just as it eradicates infections like flu after a few days, the immune system initially recognizes the tumor as foreign and tries its best to generate a counterattack toward eliminating the cancer cells.
This effort, however, is thwarted by different mechanisms deployed by the tumor to ensure a weak and ineffective response. So an effort to negate this suppression of the immune response by the tumor and to generate much stronger effective immune attack directed against the tumor may improve outcomes of cancer patients.
Development of such effective cancer vaccines has been hampered over the past few decades by various obstacles. Unlike viruses entirely foreign to the body, cancer cells share many similarities with normal cells. They also tend to “hide” and frequently change their weakest links from the immune system. As they grow within the body, they also propagate a “territory” that curtails the potency of immune cells capable of eradicating tumor cells.
Most of the currently available vaccines and vaccine technologies generate mostly antibodies against the target infections (for example, flu). It is, however, believed that cancers and other infections like HIV and tuberculosis for which the development of effective vaccines have been challenging will require generation of immune cells referred to as T cells for their eradication. One approach that now appears very promising is using genetic information based on optimized mRNA vaccine technology.
Unlike previously available technologies, mRNA vaccine uses the body’s own “manufacturing” system to generate targets for the immune system. Rather than producing the targets in the laboratory, the “recipe” in the form of information instructs the body to “prepare the meal” by manufacturing the proteins that the tumor had effectively been hiding from the immune system.
Once the protein is released from the cells into which mRNA is injected, the immune system will be able to generate much stronger and hopefully more effective response. The anti-tumor immune cells can then be circulated to different parts of the body where tumors are located and hopefully eradicate them. Given that mRNA vaccine is just “recipe information,” it will enable incorporation of entire tumor proteins (rather than fragments) and enable incorporation of multiple of such targets within an injection.
And, compared to DNA vaccine that it might be integrated into human genome, mRNA vaccines undergo one-step conversion, referred to as translation, that only lasts a few days because they’re rapidly degraded by the body and thus pose no risk of being a permanently incorporated into the human gene. There is also less risk of contamination and allergies given that the mRNA manufacturing process does not require growth within cells (compared to, for example, the annual influenza shot that are grown in eggs).
The efforts toward mRNA vaccine development were initially hampered by their instability as they are rapidly degraded after injection with only limited amount being eventually delivered into the cells. Several recent advances, including coating them with lipid nanoparticles, have now mitigated this and ensure delivery of large amount of the genetic material into the cells.
Further refinement in the purification process — that ensures induction of more precise immune response, rather than non-specific innate immune response — together with state-of-the-art manufacturing techniques now allows for rapid, inexpensive and large scale production of mRNA. In fact, in the case of COVID-19, the first dose of vaccine was available for clinical trial within a few weeks of publication of the genetic information of SARS-CoV-2 (the virus that causes COVID-19).
The development of vaccines against infectious diseases has improved the median survival across the globe over the past 100 years. In fact, it is estimated that they save about 6 million lives every year and have greatly improved economic productivity of the global population (less time spent being treated for infection) and reduced overall healthcare cost (less money spent treating infections).
In the near future, it is hoped that equally effective treatment strategies including immunotherapies will positively impact the lives of close to two million new cases of cancers diagnosed every year in the US. Given its precision (it will only express the specified protein for which the “recipe” information is provided), ability to generate robust immune response and its flexibility (the backbone is the same, only the information inserted needs to be changed), mRNA vaccines hold lots of promises for future cancer treatment and even possibly prevention as well.
There are, however, still several challenges ahead. That tumors share many similarities with normal cells make its interactions with the immune system a bit more complicated when compared with infections that entirely foreign to be the body. Furthermore, the capacity of tumors to ‘evolve’ over time within the same individual through the acquisition of new genetic abnormalities within an environment that tames effective immune response is another obstacle.
So, unlike SARS-CoV-2 (the virus that causes COVID-19) that has only one to two dozen proteins, cancer cells contain around 20,000 different genes and the identification of the most critical one(s) for potent immune response is still yet to be fully determined.
There is great optimism that immunotherapies will be able to save many of the 600,000 lives lost every year to cancers. The mRNA vaccines appear to be one of the most promising approaches given its flexibility and the robustness of the immune response it induces. Further research, however, is needed given the complexity of the interactions between cancer and the immune system.
Just like in the case of COVID-19 pandemic for which effective vaccines were developed within one year after its discovery, focused and committed public-private partnership may lead to the development and deployment of effective vaccines in the near future.
Dr. Sope Olugbile is a Medical Oncologist with the Hartford HealthCare Cancer Institute.