Written by: Aditi Venkatraman
Edited by: Ryan Lee
Edited by: Ryan Lee
Malignant tumors, despite being extensively studied, continue to be the second leading cause of death with 10 million deaths worldwide in 2020 (Sung et al. 2021). Apart from surgery and chemotherapy, which often lead to the regrowth of tumors, tumor immunotherapy is growing in popularity. Immunotherapy involves activating the host’s immune system in a way that targets the tumor microenvironment, causing the tumor to eventually shrink while also training the host’s body to fight against the cancer (Deng et al. 2022). One type of immunotherapy that is growing in popularity is the use of mRNA vaccines. During the COVID-19 pandemic, the importance of mRNA vaccines has been highlighted through their efficiency in increasing people’s immune responses against the virus, therefore decreasing death and hospitalization rates. These vaccines work by introducing a piece of mRNA corresponding to either a viral protein or signaling molecule and allowing the body’s cells to produce the protein coded by the mRNA. This then triggers an immune response in which specialized antibodies are released in order to target the particular foreign protein. Even after the foreign protein has been eliminated, the antibodies remain in preparation for future exposures (MedLinePlus. 2022). As a result of the focused research on mRNA vaccines over the duration of the pandemic, there has been significant progress in many key aspects of mRNA vaccines, including mRNA production, delivery systems, and antitumor immune strategies (Deng et al. 2022).
Current developments in mRNA vaccines involve a focus on developing more efficient ways of determining which protein the vaccine should encode for. To do so, researchers at Memorial Sloan Kettering Cancer Center examined tumors extracted from patients who had fully recovered from pancreatic cancer (Memorial Sloan Kettering Cancer Center. 2022). Here, a large number of immune cells, especially T cells, have been found. These T cells are triggered by signaling proteins called neoantigens that accumulate in the cancerous cells because of genetic mutations. Though neoantigens are present in all tumor cells, the body’s immune system often fails to recognize them, which allows the cancer cells to keep dividing. Because mRNA vaccines train the body’s immune system to respond against a particular protein, they can be used to train the immune system to target these neoantigens (Balachandran et al. 2017).
In order for the vaccine to be effective, it must be developed in a way that is personalized for the patient. Since each tumor may have different mutations and thus different neoantigens, whole exome sequencing is conducted on samples obtained from biopsies, surgery, or blood sampling in order to find the protein that should be targeted by the mRNA vaccine (Chen et al. 2021). Once injected into the bloodstream, the mRNA is taken up by antigen-presenting cells, where it undergoes antigen processing and enters the MHC presentation cascade to trigger CD8+ and CD4+ T cells. In addition, a humoral immune response can be activated by CD4+ T cells, which can induce antigen-specific B cells (Lorentzen et al). Now that the immune system has been trained to recognize the neoantigens, the immune system will be able to destroy cancer cells which express the same neoantigens, lowering the chances of the tumor coming back after it has been surgically removed (Memorial Sloan Kettering Cancer Center. 2022).
Currently, there are three main types of mRNA vaccines which have been tested through clinical trials: non-formulated, formulated, and mRNA-loaded dendritic cell vaccines. Non-formulated, or naked, vaccines are administered either intranodally or intradermally and avoid the requirement for antigen-presenting cell migration by enabling the delivery of antigens to antigen-presenting cells directly at the location of T-cell activation. In a recent phase 1 clinical trial, naked vaccines were administered for patients with varying stages of melanoma (III or IV); the vaccine encoded a unique tumor mutation marker with 10 of these neoantigens selected for each patient. Results showed that all patients developed immune responses against several encoded neoantigens. Formulated vaccines were developed in attempts to counter the destructive impact extracellular RNAses have on non-formulated mRNA. In order to protect the mRNA from being degraded, formulated vaccines often contain peptides and lipids that have proven to optimize mRNA preservation. So far, lipid nanoparticles, protamines, and lipoplex vaccines have been tested. All of these vaccines have shown to have positive impacts on patients, but only when administered with other immunotherapies. The last type of mRNA vaccine focuses on harnessing the functions of dendritic cells. Dendritic cells have a unique ability to initiate immunity and are also able to control and initiate the type of immune response. However, based on the clinical trials that have been conducted till date, mRNA-loaded dendritic cell vaccines have been observed to induce average T-cell immune responses and have low clinical efficacy (Lorentzen et al. 2022).
Most recently, Moderna and Merck shared preliminary results from their phase 2b trial, which focused on treating melanoma patients with Moderna’s mRNA cancer vaccine (mRNA-4157/V940) in conjunction with Keytruda, an anti-PD-1 therapy, which helps to disable a protein that helps tumors escape the immune system. During the trial, some patients out of the 157 were treated with just the anti-PD-1 therapy, while others were treated with both the vaccine and Keytruda every three weeks for around a year. They found that when a patient had their tumor surgically removed and was treated with both the mRNA vaccine and Keytruda, the risk of death or recurrence of the cancer was reduced by 44% (Byrne. 2022). The companies also announced that they will continue with Phase 3 next year and will expand their focus to additional tumor types.
Clinical studies like these have shown promising results for patients impacted by malignant tumors, and researchers are still trying to find better and more efficient ways to identify the best neoantigens to target with the vaccines (Winstead. 2022). Though there is still a long way to go before mRNA vaccines become the preferred method of treatment for cancer, the pandemic has helped these vaccines become more accepted by both the scientific community and general public and has also led to the development of new and helpful information that will be critical for this kind of immunotherapy in the future.
References
Balachandran, V., Łuksza, M., Zhao, J. et al. (2017). Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, 512–516. https://doi.org/10.1038/nature24462
Byrne Jane. (2022). Moderna’s vaccine combined with Keytruda reduced melanoma recurrence by 44%: ‘The results are highly encouraging for the field of cancer treatment’. BioPharma-Reporter. https://www.biopharma-reporter.com/Article/2022/12/13/Moderna-s-vaccine-combined-with-Keytruda-reduced-melanoma-recurrence-by-44-The-results-are-highly-encouraging-for-the-field-of-cancer-treatment
Chen Z., Zhang S., Han N., et al. (2021). A Neoantigen-Based Peptide Vaccine for Patients With Advanced Pancreatic Cancer Refractory to Standard Treatment. Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.691605
Deng Z., Tian Y., Song J., An G., Yang P. (2022). mRNA Vaccines: The Dawn of a New Era of Cancer Immunotherapy. Frontiers in Immunology, 13. https://doi.org/10.3389/fimmu.2022.887125
Lorentzen C.L., Haanen J.B., Met O., Svane I.M. (2022). Clinical advances and ongoing trials of mRNA vaccines for cancer treatment. The Lancet Oncology, 23(10), E450-E458. 10.1016/S1470-2045(22)00372-2
MedLine Plus. (2022). What are mRNA vaccines and how do they work?https://medlineplus.gov/genetics/understanding/therapy/mrnavaccines/#:~:text=mRNA%20vaccines%20work%20by%20introducing,the%20virus%20by%20the%20vaccine
Memorial Sloan Kettering Cancer Center. (2022). MSK mRNA Pancreatic Cancer Vaccine Trial Shows Promising Results. https://www.mskcc.org/news/can-mrna-vaccines-fight-pancreatic-cancer-msk-clinical-researchers-are-trying-find-out
Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71(3), 209-249. https://doi.org/10.3322/caac.21660
Winstead Edward. (2022). Can mRNA Vaccines Help Treat Cancer?. National Cancer Institute. https://www.google.com/url?q=https://www.cancer.gov/news-events/cancer-currents-blog/2022/mrna-vaccines-to-treat-cancer&sa=D&source=docs&ust=1672696783457290&usg=AOvVaw20TGixUd6jxtFUs_X8Zl76
Current developments in mRNA vaccines involve a focus on developing more efficient ways of determining which protein the vaccine should encode for. To do so, researchers at Memorial Sloan Kettering Cancer Center examined tumors extracted from patients who had fully recovered from pancreatic cancer (Memorial Sloan Kettering Cancer Center. 2022). Here, a large number of immune cells, especially T cells, have been found. These T cells are triggered by signaling proteins called neoantigens that accumulate in the cancerous cells because of genetic mutations. Though neoantigens are present in all tumor cells, the body’s immune system often fails to recognize them, which allows the cancer cells to keep dividing. Because mRNA vaccines train the body’s immune system to respond against a particular protein, they can be used to train the immune system to target these neoantigens (Balachandran et al. 2017).
In order for the vaccine to be effective, it must be developed in a way that is personalized for the patient. Since each tumor may have different mutations and thus different neoantigens, whole exome sequencing is conducted on samples obtained from biopsies, surgery, or blood sampling in order to find the protein that should be targeted by the mRNA vaccine (Chen et al. 2021). Once injected into the bloodstream, the mRNA is taken up by antigen-presenting cells, where it undergoes antigen processing and enters the MHC presentation cascade to trigger CD8+ and CD4+ T cells. In addition, a humoral immune response can be activated by CD4+ T cells, which can induce antigen-specific B cells (Lorentzen et al). Now that the immune system has been trained to recognize the neoantigens, the immune system will be able to destroy cancer cells which express the same neoantigens, lowering the chances of the tumor coming back after it has been surgically removed (Memorial Sloan Kettering Cancer Center. 2022).
Currently, there are three main types of mRNA vaccines which have been tested through clinical trials: non-formulated, formulated, and mRNA-loaded dendritic cell vaccines. Non-formulated, or naked, vaccines are administered either intranodally or intradermally and avoid the requirement for antigen-presenting cell migration by enabling the delivery of antigens to antigen-presenting cells directly at the location of T-cell activation. In a recent phase 1 clinical trial, naked vaccines were administered for patients with varying stages of melanoma (III or IV); the vaccine encoded a unique tumor mutation marker with 10 of these neoantigens selected for each patient. Results showed that all patients developed immune responses against several encoded neoantigens. Formulated vaccines were developed in attempts to counter the destructive impact extracellular RNAses have on non-formulated mRNA. In order to protect the mRNA from being degraded, formulated vaccines often contain peptides and lipids that have proven to optimize mRNA preservation. So far, lipid nanoparticles, protamines, and lipoplex vaccines have been tested. All of these vaccines have shown to have positive impacts on patients, but only when administered with other immunotherapies. The last type of mRNA vaccine focuses on harnessing the functions of dendritic cells. Dendritic cells have a unique ability to initiate immunity and are also able to control and initiate the type of immune response. However, based on the clinical trials that have been conducted till date, mRNA-loaded dendritic cell vaccines have been observed to induce average T-cell immune responses and have low clinical efficacy (Lorentzen et al. 2022).
Most recently, Moderna and Merck shared preliminary results from their phase 2b trial, which focused on treating melanoma patients with Moderna’s mRNA cancer vaccine (mRNA-4157/V940) in conjunction with Keytruda, an anti-PD-1 therapy, which helps to disable a protein that helps tumors escape the immune system. During the trial, some patients out of the 157 were treated with just the anti-PD-1 therapy, while others were treated with both the vaccine and Keytruda every three weeks for around a year. They found that when a patient had their tumor surgically removed and was treated with both the mRNA vaccine and Keytruda, the risk of death or recurrence of the cancer was reduced by 44% (Byrne. 2022). The companies also announced that they will continue with Phase 3 next year and will expand their focus to additional tumor types.
Clinical studies like these have shown promising results for patients impacted by malignant tumors, and researchers are still trying to find better and more efficient ways to identify the best neoantigens to target with the vaccines (Winstead. 2022). Though there is still a long way to go before mRNA vaccines become the preferred method of treatment for cancer, the pandemic has helped these vaccines become more accepted by both the scientific community and general public and has also led to the development of new and helpful information that will be critical for this kind of immunotherapy in the future.
References
Balachandran, V., Łuksza, M., Zhao, J. et al. (2017). Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, 512–516. https://doi.org/10.1038/nature24462
Byrne Jane. (2022). Moderna’s vaccine combined with Keytruda reduced melanoma recurrence by 44%: ‘The results are highly encouraging for the field of cancer treatment’. BioPharma-Reporter. https://www.biopharma-reporter.com/Article/2022/12/13/Moderna-s-vaccine-combined-with-Keytruda-reduced-melanoma-recurrence-by-44-The-results-are-highly-encouraging-for-the-field-of-cancer-treatment
Chen Z., Zhang S., Han N., et al. (2021). A Neoantigen-Based Peptide Vaccine for Patients With Advanced Pancreatic Cancer Refractory to Standard Treatment. Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.691605
Deng Z., Tian Y., Song J., An G., Yang P. (2022). mRNA Vaccines: The Dawn of a New Era of Cancer Immunotherapy. Frontiers in Immunology, 13. https://doi.org/10.3389/fimmu.2022.887125
Lorentzen C.L., Haanen J.B., Met O., Svane I.M. (2022). Clinical advances and ongoing trials of mRNA vaccines for cancer treatment. The Lancet Oncology, 23(10), E450-E458. 10.1016/S1470-2045(22)00372-2
MedLine Plus. (2022). What are mRNA vaccines and how do they work?https://medlineplus.gov/genetics/understanding/therapy/mrnavaccines/#:~:text=mRNA%20vaccines%20work%20by%20introducing,the%20virus%20by%20the%20vaccine
Memorial Sloan Kettering Cancer Center. (2022). MSK mRNA Pancreatic Cancer Vaccine Trial Shows Promising Results. https://www.mskcc.org/news/can-mrna-vaccines-fight-pancreatic-cancer-msk-clinical-researchers-are-trying-find-out
Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71(3), 209-249. https://doi.org/10.3322/caac.21660
Winstead Edward. (2022). Can mRNA Vaccines Help Treat Cancer?. National Cancer Institute. https://www.google.com/url?q=https://www.cancer.gov/news-events/cancer-currents-blog/2022/mrna-vaccines-to-treat-cancer&sa=D&source=docs&ust=1672696783457290&usg=AOvVaw20TGixUd6jxtFUs_X8Zl76
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