mRNA Therapies

Messenger ribonucleic acid (mRNA) vaccines are a relatively new class of vaccines that have shown great promise in the immunotherapy of a wide variety of infectious diseases and cancer. In the past 2 years, SARS-CoV-2 mRNA vaccines have contributed tremendously against SARS-CoV2, which has prompted the arrival of the mRNA vaccine research boom, especially in the research of cancer vaccines. Compared with conventional cancer vaccines, mRNA vaccines have significant advantages, including efficient production of protective immune responses, relatively low side effects and lower cost of acquisition. In this review, we elaborated on the development of cancer vaccines and mRNA cancer vaccines, as well as the potential biological mechanisms of mRNA cancer vaccines and the latest progress in various tumour treatments, and discussed the challenges and future directions for the field.

Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity, especially in genetic alteration and microenvironment. Conventional therapeutic strategies for pancreatic cancer usually suffer resistance, highlighting the necessity for personalized precise treatment. Cancer vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting, minimal nonspecific effects, broad therapeutic window, low toxicity, and induction of persistent immunological memory. Multiple conventional vaccines based on the cells, microorganisms, exosomes, proteins, peptides, or DNA against pancreatic cancer have been developed; however, their overall efficacy remains unsatisfactory. Compared with these vaccine modalities, messager RNA (mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment, and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic cancer. This review summarizes the current progress on pancreatic cancer vaccines, highlights the superiority of mRNA vaccines over other conventional vaccines, and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.

Abstract Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years, but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used alone. In this study, an oncolytic virus (rVSV-LCMVG) that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T cells. By transforming the immunosuppressive tumor microenvironment into an immunosensitive one, in B16 tumor-bearing mice, combination therapy showed superior antitumor effects than monotherapy. This occurred whether the OV was administered intratumorally or intravenously. Combination therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8+ T cells to the TME to trigger antitumor immune responses. Pretreatment with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment, down-regulating the expression of PD-1, and restoring effector T-cell function. To offer a combination therapy with greater translational value, mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells. The combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged survival. This study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens, in terms of synergistic efficacy and mechanism.

In recent years, the use of messenger RNA (mRNA) in the fields of gene therapy, immunotherapy, and stem cell biomedicine has received extensive attention. With the development of scientific technology, mRNA applications for tumor treatment have matured. Since the SARS-CoV-2 infection outbreak in 2019, the development of engineered mRNA and mRNA vaccines has accelerated rapidly. mRNA is easy to produce, scalable, modifiable, and not integrated into the host genome, showing tremendous potential for cancer gene therapy and immunotherapy when used in combination with traditional strategies. The core mechanism of mRNA therapy is vehicle-based delivery of in vitro transcribed mRNA (IVT mRNA), which is large, negatively charged, and easily degradable, into the cytoplasm and subsequent expression of the corresponding proteins. However, effectively delivering mRNA into cells and successfully activating the immune response are the keys to the clinical transformation of mRNA therapy. In this review, we focus on nonviral nanodelivery systems of mRNA vaccines used for cancer gene therapy and immunotherapy.

COVID-19 vaccines were developed and approved rapidly in response to the urgency created by the pandemic. No specific regulations existed at the time they were marketed. The regulatory agencies therefore adapted them as a matter of urgency. Now that the pandemic emergency has passed, it is time to consider the safety issues associated with this rapid approval. The mode of action of COVID-19 mRNA vaccines should classify them as gene therapy products (GTPs), but they have been excluded by regulatory agencies. Some of the tests they have undergone as vaccines have produced non-compliant results in terms of purity, quality and batch homogeneity. The wide and persistent biodistribution of mRNAs and their protein products, incompletely studied due to their classification as vaccines, raises safety issues. Post-marketing studies have shown that mRNA passes into breast milk and could have adverse effects on breast-fed babies. Long-term expression, integration into the genome, transmission to the germline, passage into sperm, embryo/fetal and perinatal toxicity, genotoxicity and tumorigenicity should be studied in light of the adverse events reported in pharmacovigilance databases. The potential horizontal transmission (i.e., shedding) should also have been assessed. In-depth vaccinovigilance should be carried out. We would expect these controls to be required for future mRNA vaccines developed outside the context of a pandemic.

Synthetic mRNA technologies represent a versatile platform that can be used to develop advanced drug products. The remarkable speed with which vaccine development programs designed and manufactured safe and effective COVID-19 vaccines has rekindled interest in mRNA technology, particularly for future pandemic preparedness. Although recent R&D has focused largely on advancing mRNA vaccines and large-scale manufacturing capabilities, the technology has been used to develop various immunotherapies, gene editing strategies, and protein replacement therapies. Within the mRNA technologies toolbox lie several platforms, design principles, and components that can be adapted to modulate immunogenicity, stability, in situ expression, and delivery. For example, incorporating modified nucleotides into conventional mRNA transcripts can reduce innate immune responses and improve in situ translation. Alternatively, self-amplifying RNA may enhance vaccine-mediated immunity by increasing antigen expression. This review will highlight recent advances in the field of synthetic mRNA therapies and vaccines, and discuss the ongoing global efforts aimed at reducing vaccine inequity by establishing mRNA manufacturing capacity within Africa and other low- and middle-income countries.

TPS9107 Background: Vaccine therapies stimulate the immune system to attack cancer cells (active immunotherapy), whereas checkpoint inhibitors block immune inhibition (passive immunotherapy). Several PD-1 and PD-L1 blocking antibodies are approved for NSCLC. This study combines active and passive immunotherapies to determine if the addition of a mRNA vaccine can enhance the activity of checkpoint blockade. The vaccine BI 1361849 (comprising 6 mRNAs encoding for selected tumor-associated antigens: MUC1, survivin, NY-ESO-1, 5T4, MAGE-C2 and MAGE-C1) is combined with 1 or 2 checkpoint inhibitors (durva [anti-PD-L1] ± treme [anti-CTLA-4]). Methods: This ongoing Phase 1/2, open-label study (NCT03164772) evaluates the safety and efficacy of BI 1361849 when administered with durva (Arm A) or durva + treme (Arm B) in NSCLC patients. In arm A, an initial dose-evaluation phase follows a 3+3 design to determine the dose of durva (1500 or 750 mg) to be given with the vaccine. Arm B uses the durva dose from Arm A, with the addition of 75 mg treme. In the expansion phase, 20 patients are treated in each arm. To aid in the evaluation of immune responses, there is an additional control group (n = 10), which receives the checkpoint inhibitors only. Study treatment is administered over 12 (28-day) cycles. Durva (x 12 doses) and treme (x 4 doses) are administered intravenously every 28 days. The vaccine is administered on 1 to 3 days over each of the 12 cycles using a device that provides a needle-free intradermal administration. The primary endpoint is safety/tolerability per CTCAE, including dose-limiting toxicity during dose evaluation. Secondary endpoints are progression-free survival and objective response rate at 8 and 24 weeks, disease control rate, response duration, and overall survival, with tumor response evaluated by RECIST and immune-related RECIST. Exploratory objectives include effects on tumor microenvironment and evaluation of immune responses. Enrollment opened 20Dec2017. Clinical trial information: NCT03164772.

Breast cancer represents the most prevalent cancer among women globally, constituting approximately 30% of newly diagnosed female malignancies and serving as the second leading cause of cancer-related mortality, accounting for 11.6% of deaths. Despite notable advancements in survival rates and quality of life for breast cancer patients over recent decades-achieved through interventions such as surgery, chemotherapy, radiotherapy, and endocrine therapy-there remains an urgent need for novel therapeutic strategies. This necessity arises from challenges associated with recurrence, metastasis, and drug resistance. The COVID-19 pandemic has accelerated the development of Messenger RNA (mRNA) vaccines at an unprecedented pace, and as a novel form of precision immunotherapy, mRNA vaccines are increasingly being recognized for their potential in cancer treatment. mRNA vaccines efficiently produce antigens within the cytoplasm, specifically activating the immune system to target tumor cells while minimizing the risk of T-cell tolerance. Therefore, mRNA vaccines have emerged as a promising approach in cancer immunotherapy. This review systematically examines the principles, mechanisms, advantages, key targets, and recent progress in mRNA vaccine therapy for breast cancer. Furthermore, it discusses current challenges and suggests potential directions for future research.

ABSTRACT: Cancer remains a major global health challenge, with conventional treatments like chemotherapy and radiotherapy often hindered by significant side effects, lack of specificity, and limited efficacy in advanced cases. Among emerging therapeutic strategies, mRNA vaccines have shown remarkable potential due to their adaptability, rapid production, and capability for personalized cancer treatment. This review provides an in-depth analysis of messenger RNA (mRNA) vaccines as a therapeutic approach for cancer immunotherapy, focusing on their molecular biology, classification, mechanisms, and clinical studies. Derived from reported literature and data on clinicaltrials.gov, it examines studies on mRNA vaccines encoding tumor-specific antigens (TSAs), tumor-associated antigens (TAAs), immunomodulators, and chimeric antigen receptors (CARs) across various cancer types. The review highlights the ability of mRNA vaccines to encode TSAs and TAAs, enabling personalized cancer treatments, and classifies these vaccines into non-replicating and self-amplifying types. It further explores their mechanisms of action, including antigen presentation and immune activation, while emphasizing findings from clinical studies that demonstrate the potential of mRNA vaccines in cancer therapy. Despite their promise, challenges remain in enhancing delivery systems, improving immunogenicity, and addressing tumor heterogeneity. Overcoming these obstacles will require further investigation to fully harness the potential of mRNA vaccines in personalized cancer treatment.

Abstract Vaccine therapies stimulate the immune system to attack cancer cells (active immunotherapy), whereas checkpoint inhibitors block immune inhibition (passive immunotherapy). BI 1361849 (formerly CV9202) is a cancer vaccine comprising 6 mRNA constituents, each of which encodes for one of the non-small cell lung cancer (NSCLC) associated antigens: MUC1, survivin, NY-ESO-1, 5T4, MAGE-C2, and MAGE-C1. Durvalumab (durva) is a checkpoint inhibitor that blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1 (PD-1). Several PD-1 and PD-L1 blocking antibodies are approved for NSCLC. Tremelimumab (treme) is an anti-cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) blocking antibody. Targeting both the CTLA-4 and PD-1 checkpoint pathways provides the potential for additive or synergistic effects. This study combines active and passive immunotherapies to determine if the addition of a mRNA vaccine, BI 1361849, can enhance the activity of checkpoint blockade. This ongoing phase 1/2, open-label study (NCT03164772) evaluates the safety and efficacy of BI 1361849 when administered with durva (Arm A) or durva + treme (Arm B) in patients with NSCLC. In Arm A, an initial dose evaluation phase follows a 3+3 design to confirm the dose of durva (full dose 1500 mg or de-escalated 750 mg, if needed) to be given with the vaccine. Arm B uses the dose established in Arm A, with the addition of 75 mg treme. In the expansion phase, 20 patients are treated in each arm. To aid in the evaluation of immune responses, there is an additional control group (n=10), in which patients receive the checkpoint inhibitor(s) only. Study treatment is administered over 12 cycles (28 days each). Durva (x 12 doses) and treme (x 4 doses, Arm B only) are administered intravenously every 28 days. The vaccine is administered as a total of 14 doses (of the 6 components) during the 12 cycles, using a device that provides a needle-free intradermal administration. The primary endpoint is assessment of safety and tolerability, including evaluation of dose-limiting toxicities. Secondary endpoints include progression-free survival and objective response rate at 8 and 24 weeks, disease control rate, response duration, and overall survival, with tumor response evaluated by RECIST 1.1 and immune-related RECIST. Exploratory objectives include effects on tumor microenvironment and evaluation of immune responses. Enrollment opened 20 December 2017. As of 27 June 2018, 2 patients are enrolled; enrollment is ongoing. Citation Format: Joshua Sabari, Kristen Aufiero Ramirez, Paul Schwarzenberger, Toni Ricciardi, Mary Macri, Aileen Ryan, Ralph Venhaus. Phase 1/2 study of mRNA vaccine therapy + durvalumab (durva) ± tremelimumab (treme) in patients with metastatic non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B209.

Glioblastoma (GBM) is the most common and most malignant primary brain tumor, presenting significant treatment challenges due to its heterogeneity, invasiveness, and resistance to conventional therapies. Despite aggressive treatment protocols, the prognosis remains poor, with a median survival time of approximately 15 months. Recent advancements in mRNA vaccine technology, particularly the development of lipid nanoparticles (LNPs), have revitalized interest in mRNA-based therapies. These vaccines offer unique advantages, including rapid production, personalization based on tumor-specific mutations, and a strong induction of both humoral and cellular immune responses. mRNA vaccines have demonstrated potential in preclinical models, showing significant tumor regression and improved survival rates. Early-phase clinical trials have indicated that mRNA vaccines are safe and can induce robust immune responses in GBM patients. Combining mRNA vaccines with other immunotherapeutic approaches, such as checkpoint inhibitors, has shown synergistic effects, further enhancing their efficacy. However, challenges such as optimizing delivery systems and overcoming the immunosuppressive tumor microenvironment remain. Future research should focus on addressing these challenges and exploring combination therapies to maximize therapeutic benefits. Large-scale, randomized clinical trials are essential to validate the efficacy and safety of mRNA vaccines in GBM therapy. The potential to reshape the tumor microenvironment and establish long-term immunological memory underscores the transformative potential of mRNA vaccines in cancer immunotherapy.

BACKGROUND: Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis and low survival rates. Standard treatments, such as surgery and radiotherapy, are limited by tumor infiltration and resistance. To review current vaccine strategies for GBM, including peptide, virotherapy, cell-based, and genetic vaccines, with a focus on mRNA vaccines. METHODS: Relevant literature on GBM vaccines and immunotherapy was reviewed to summarize design, mechanisms, and potential clinical applications. RESULTS: Cancer vaccines aim to activate the immune system to target tumor cells. mRNA vaccines are promising due to their flexibility, rapid production, and strong immune activation, though clinical investigation is ongoing. CONCLUSION: Vaccine-based therapies, particularly mRNA vaccines, hold potential for personalized GBM treatment, but further studies are needed to confirm efficacy and optimize use.

Vaccines escape some of the controls required for human drugs (without scientific justification). However, mRNA vaccines, which represent a new class of vaccine, should be subject to more controls than conventional vaccines because they are based on several new technologies. Conventional vaccines could be replaced by mRNA vaccines and anti-cancer "vaccines" (actually therapies) are being announced. Moreover, mRNA vaccines can be considered as pro-vaccines (the injected substance is not the active substance). The WHO tried unsuccessfully to regulate these new products in 2022. mRNA vaccines are not subject to regulation as gene therapy products (GTP) although they correspond to the definition of GTP and although for the EMA therapeutic mRNAs are considered as gene therapy products. Moreover, Moderna and BioNTech expected their products to be regulated as gene therapies. Therefore, anti-covid mRNAs are subject to the EMA's human drug regulations, which also apply to vaccines; there is even an EMA document that requires pharmacokinetic testing for DNA vaccines. The exclusion of anti-Covid mRNAs from the regulation of gene products is not justified by the regulatory agencies, which allows these products to avoid numerous controls, in particular concerning specific toxicity, integration in the genome, transmission in the germ line, toxicity linked to the expression of structurally altered proteins, reproductive toxicity, repeated toxicity and excretion in the environment.

mRNA-based gene therapy drugs and preventive vaccines have become a hot topic of development. The technical principle is that mRNA delivered to the body cells can be expressed through the translation mechanism of host cells to produce therapeutic proteins or immunogenic proteins, which have therapeutic effects on the body or stimulate the body to produce immune effects. mRNA vaccines have many advantages over traditional vaccines, such as their safety, flexibility, rapid production and low cost. mRNA vaccines are therefore proposed as a new frontier in vaccination. in this review, the main key technologies based on mRNA drug design, such as in vitro transcription (IVT), nucleotide and cap and tail structure modification, were reviewed, followed by a brief introduction to mRNA purification methods and delivery systems. Several novel mRNA drugs are also briefly described. Finally, the latest research directions and possible challenges of mRNA are mentioned, aiming to provide support for the development of mRNA gene therapy drugs and vaccines.