Recently, mRNA technology has become very popular in the light of the COVID-19 pandemic, as the vaccines meant to prevent infection with the novel virus use it. While mRNA vaccines are a relatively new class of vaccines, it is worthy of note that they have been studied in the context of cancer immunotherapy for a long time. This innovative technology may yield promising results for people with occupational cancer, according to numerous medical studies.
Occupational cancer, regardless of the specific disease it refers to, generally has a dire prognosis, as it is generally detected in advanced stages when the person no longer responds well to treatment. There are multiple reasons that can justify the late detection of occupational cancer, one being the fact that the vast majority of people rarely experience symptoms when their disease is in the early phase. Furthermore, most occupational cancers have a long latency period, taking even several decades to develop, which causes patients to fail to make the connection between their disease and toxic exposure.
Every year, over 200,000 people die of occupational cancer1 worldwide, and half of these deaths are the consequence of asbestos exposure. Some of the most common occupational malignant diseases are lung cancer, mesothelioma, and colorectal cancer, all of which can be caused by exposure to asbestos that occurs in the workplace. Vaccines using mRNA technology may improve the prognosis of individuals with these cancers to a great extent by increasing their life expectancy, helping medical professionals detect malignant diseases earlier, and preventing cancer from recurring.
How Do mRNA Vaccines Work and What Is Their Role in Immunotherapy?
The messenger RNA, known as mRNA for short, acts as a series of genetic instructions for the cells2 and also serves as a code to make proteins, which are essential for the proper functioning of our body. Proteins have a major role in growth, defense against illness, and energy production. mRNA technology was created in a laboratory as a strand of mRNA that instructs the cells of the recipient to create fragments of protein based on the “non-self” DNA particularities of the target of the vaccine. When these protein fragments are recognized, the immune system activates itself in response and ultimately eliminates these proteins because they are perceived as being foreign.
Traditionally, mRNA vaccines are comprised of a messenger RNA synthesized by in vitro transcription3 with the aid of a bacteriophage RNA polymerase and a template DNA whose purpose is to encode the antigen of interest. Following administration and internalization by host cells, the mRNA transcripts are translated directly into the cytoplasm of the cell. The antigens are detected by the immune system, which stimulates it and subsequently activates it so that it can fight the abnormal cells. mRNA technology is actually the intermediate step between the protein-encoding DNA and the protein made by ribosomes, and it was found to be a very favorable alternative to conventional vaccines.
The concept of using vaccines for cancer immunotherapy dates back to 1891 when Dr. William Coley first attempted to stimulate the immune system3 of a patient in order to improve their condition. Accordingly, he administered intratumoral injections of inactivated Streptococcus pyogenes and Serratia marcescens to the patient, a combination that is known today as Coley’s toxin. Most cancer vaccines are meant to activate responses mediated by cells, such as those from cytotoxic T lymphocytes, that are able to clear or reduce tumor burden. However, mRNA vaccines were designed to target factors associated with growth or antigens that are specific to cancerous cells as a result of somatic mutations.
Vaccines that use mRNA technology have become a very promising approach in cancer immunotherapy. Shortly after the person receives the vaccine, it rapidly expresses tumor antigens in antigen-presenting cells, prompts antigen-presenting cells activation, and facilitates innate or adaptive immune system stimulation4. The most notable benefits and advantages of mRNA technology for cancer care include safe administration, fast development potentials, high potency, and cost-effective manufacturing. On the other hand, the use of mRNA vaccines in cancer immunotherapy has drawbacks, such as innate immunogenicity, instability, and inefficient in vivo delivery. Nevertheless, all of these disadvantages could be overcome with adequate mRNA structure changes, such as codon optimizations and nucleotide modifications, as well as with certain formulation methods, such as lipid nanoparticles and polymers.
mRNA Vaccines and Lung Cancer
Up to 4% of lung cancer cases are the result of occupational asbestos exposure5, and when asbestos exposure is the culprit behind it, the disease takes between 15 and 35 years to develop6. This is because the asbestos fibers that became embedded in the tissue of the lungs cause inflammation and scarring gradually, which may eventually give way to lung cancer. Perhaps the primary advantage of the administration of mRNA vaccines to lung cancer patients is safety, as these vaccines are non-replicating. Therefore, the natural RNA molecule cannot multiply, is active in the cytosol, and is also rapidly and completely degraded by RNases that cells, tissues, and biological fluids abound in. A vaccine using mRNA technology that encoded 5 non-small-cell lung cancer antigens7 conducted in the first and second phases of a clinical trial showed immune responses supporting the additional clinical investigation.
By now, extensive research has been conducted on lung cancer markers, yet not a single clinically applicable marker was found. The initial approach to using RNA therapy to treat cancers is to locate appropriate targets at the RNA level to stop tumor cell growth indefinitely. In a recent study, Ali et al. revealed that specific long non-coding RNAs (lncRNA)8 that are heavily expressed throughout the cell division cycle in mice with lung cancer can be switched off by injecting lock nucleic acid-modified antisense oligonucleotides (LNA-ASO), resulting in a cure rate of 40–50% of lung cancers in mice.
Moreover, a study from March of 2021 published in the medical journal Molecular Cancer explored the present understanding of certain aspects of RNA-based therapeutics, such as modern platforms, modifications, and combinations with chemotherapy or immunotherapy, that have translational potential for the treatment of lung cancer. Researchers state that the main reason why the therapeutic approaches for cancer that are currently available often fail is the development of medication resistance linked to gene mutations, cancer stem cells, over expression of oncogenes, and deletion or inactivation of tumor suppressor genes.
Nonetheless, all of these obstacles in lung cancer treatment may be completely eliminated if oncologists make use of mRNA technology. By combining adoptive cell transfer therapy and self-delivering RNA interference9, down-regulating the expression of checkpoint proteins by damaging the mRNAs before their translation to proteins will occur. These combinations can also overcome drug resistance and enhance the effectiveness of chemotherapy or immunotherapy. The standard treatment for cancer, which includes surgery and chemotherapy, is far from the most efficient approach, particularly for tumors found in advanced stages, as the majority of the cancerous tumors display mutational diversity.
Instead of employing conventional targeted therapies, treatment with mRNA technology is potentially superior since it has a wide target range with improved drug-like properties for cancer therapies. Multiple approaches have been used to modulate gene function at the RNA level in malignant cells, including base editing, small molecules targeting RNA, the employment of synthetic antisense oligonucleotides, and exogenously expressed mRNAs. Thereby, RNA-based therapeutic approaches have emerged as a viable alternative to the conventional protein-based therapies that are challenging to pursue. These types of protein molecules can be adjusted by modulating mRNA levels or translation of proteins.
A clinical trial conducted on patients with stage IV non-small-cell lung cancer10 revealed the noteworthy benefits of immunotherapy comprised of protamine-protected, sequence-optimized mRNA (BI1361849 or CV9202) encoding six NSCLC-associated antigens, including New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1), MAGE-C1, MAGE-C2, survivin, 5T4, and Mucin-1), to prompt targeted immune responses in combination with local radiotherapy. The treatment was tolerated well, having only minor side effects. BI1361849 increased antigen-specific immune responses in most participants, whereas antigen-specific antibody levels and functional T cells were increased by 80% and 40% of patients. Likewise, another phase of a clinical trial also proved that CV9201 was well-tolerated and boosted immune response in stage IIIB/IV non-small-cell lung cancer patients. In conclusion, these results suggest the crucial nature of mRNA-based immunotherapy along with immune checkpoint inhibitors in the treatment of lung cancer.
mRNA Features in Mesothelioma Tumors
As a very aggressive cancer, mesothelioma develops on the outer lining of the lungs, and the only cause of this disease is asbestos exposure. Every year, approximately 3,000 people receive a mesothelioma diagnosis11 in the United States, most of whom were exposed to asbestos on the job during the last century.
The biggest issue emerging when studying new ways of treating or preventing mesothelioma is that being a fairly uncommon disease, it can be quite difficult to do thorough research. In general, due to their nature asbestos-induced carcinogenesis pathways are poorly understood, and that lack of understanding of the molecular alterations associated with mesothelioma severely impacts treatment development. Most doctors agree that any form or stage of mesothelioma should be investigated for treatment in a clinical study so that not only do people affected by it have the possibility to receive the best treatment available but also, it can potentially improve the treatment and outcome for future patients. However, at the clinical level, the function of immunotherapy in mesothelioma is very much at a crossroads.
Several lines of evidence support the continued development of miRNA-based mesothelioma treatments.12 Numerous mRNAs have been shown to contribute to cancer hallmarks in cells, and altering their expression with miRNA mimics or inhibitors can reduce malignant pleural mesothelioma cell growth, invasion, and interaction with stromal and immune cells. Local distribution of miRNA mimics complexed with atelocollagen or encapsulated in (patient-derived) EVs, in addition to targeted systemic delivery by minicells, has immense potential for its treatment.
A recently published paper looking into clinical and immunological effects of mRNA vaccines in malignant diseases13 and the documented clinical studies that have been done until now, found the outcomes for mesothelioma studies to be inconclusive. Given the nature of the disease and the novelty of such treatment, assessing its efficiency through clinical trials might still take some time. But this does not mean that progress is not being made. There are ongoing studies that are expected to deliver results by 2023.14
mRNA Technology and Colorectal Cancer
As another malignant disease that can be caused by asbestos exposure, colorectal cancer affects nearly 150,000 people15 across the country every year. The disease is the third most common cancer in both men and women at the moment. Between 11% and 15% of colorectal cancer cases are occupational, meaning that they are the consequence of exposure to one or multiple toxic agents on the job. Fortunately, mRNA technology seems promising when it comes to colorectal cancer as well. At present, the second phase of a clinical trial concerning mRNA vaccines and colorectal cancer16 is ongoing at the University of Texas MD Anderson Cancer Center in Houston. Researchers explore the use of personalized mRNA vaccines for people with stage II and stage III colorectal cancer.
The team of international researchers is trying to determine whether mRNA technology could prevent colorectal cancer from recurring. While most people with colorectal cancer undergo surgery to have their malignant tumors removed, there are still cancerous cells in their bodies, which need to be destroyed. The malignant cells that stay in the body following surgery release DNA into the bloodstream, which is known as circulating tumor DNA.17 There is a test that can reveal with certainty whether a patient has circulating tumor DNA in their blood. The presence of these malignant cells in the body of a patient who underwent surgery for colorectal cancer is quite alarming, as the disease is likely to return sooner or later.
A 2020 study published in the medical journal Molecular Pharmaceutics18 examines immunogene therapy, which is a relatively novel way of treating colorectal cancer. Cytokine IL-15 has shown therapeutic anticancer potential because of the immune-stimulation properties it has. Nevertheless, conventional IL-15-based cancer gene therapy research has been carried out by using the plasmid DNA form, which typically has shortcomings such as weak delivery efficiency and backbone effect. Therefore, the study was conducted with regard to IL-15 immunogene therapy for colorectal cancer employing in vitro transcript mRNA.
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A protamine or liposome system (CLPP) was created to offer efficient condensation and delivery capacity for in vivo mRNA transportation. They demonstrated that the prepared CLPP system was able to deliver the IL-15-encoding mRNA into C26 cells with very high efficacy. The secretory expressed IL-15 cytokine by the C26 cells successfully led to lymphocyte stimulation and triggered anticancer cytotoxicity upon malignant cells in vitro. The results of this study proved the great therapeutic potential of the CLPP/mIL-15 complex for colorectal cancer immunogene therapy.
To sum up, mRNA technology may truly yield promising and hopeful results in terms of cancer immunotherapy. However, additional and extensive study is necessary for medical researchers to know exactly how and when to use these vaccines on cancer patients. Although we currently know only certain things about mRNA technology and how people with occupational cancer may benefit from it, we are undoubtedly witnessing a major breakthrough in the field of cancer immunotherapy with the ongoing COVID-19 pandemic and the continuous research concerning mRNA technology.
About the Author Responsible for the financial matters of the law firm and for case evaluation, Jonathan Sharp is the Director of Claims and the Chief Financial Officer at Environmental Litigation Group, P.C.19 Their attorneys and legal team have been seeking compensation on behalf of victims of toxic exposure, including occupational asbestos exposure, since 1990. Jonathan Sharp is also in charge of the management of firm assets, financial analysis, client relations, and the collection and proper distribution of the funds.
10. Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer