mRNA cancer vaccines are gaining traction as a promising avenue for cancer immunotherapy, spurred by the success of mRNA technology in combating the COVID-19 pandemic. These vaccines offer several advantages over traditional approaches, including cost-effective manufacturing, safe administration, high potency, and rapid development potential. However, challenges remain in optimizing mRNA structure, delivery methods, and adjuvant selection to maximize their effectiveness against cancer.
Neoantigen Discovery
Identifying suitable neoantigens is a critical step in developing mRNA cancer vaccines. Neoantigens, abnormal proteins unique to cancer cells, are recognized by the immune system as foreign entities. Recent research has focused on utilizing proteogenomic approaches to identify neoantigens, with studies revealing that many originate from RNA sources rather than DNA. Cancer/testis antigens (CTAs) are also being explored as potential targets, particularly in lung, bladder, and skin cancers. Studies have identified potential neoantigens for colorectal cancer (CRC) and breast cancer (BC), offering promising avenues for mRNA vaccine development in these areas.
Adjuvant Identification
While mRNA vaccines can stimulate the immune system on their own, the addition of adjuvants can further enhance their efficacy. Synthetic phosphonothioate-modified CPG oligodeoxynucleotides (CPG-ODNs) have shown promise as adjuvants, augmenting the antitumor effect of mRNA vaccines in melanoma-bearing mice. Similarly, virus-like vaccine particles (VLVPs) containing CpG oligonucleotides have been found to enhance antigen presentation and promote the proliferation of neoantigen-specific CD8+ T cells. TLR4 agonists like monophosphoryl lipid A (mPLA) and RIG-I agonists are also being investigated as potential adjuvants for mRNA cancer vaccines.
Delivery Materials
Effective delivery of mRNA vaccines to target cells is crucial for their function. Lipid nanoparticles (LNPs) are the predominant delivery method, but new approaches are being explored to improve efficacy and reduce inflammation-related side effects. Cationic lipid-assisted nanoparticles (CLANs) have shown promise in inducing dendritic cell (DC) maturation and activating antigen-specific T cells. Lipid/calcium/phosphate nanoparticles (LCP-NPs) engineered with mannose can facilitate the delivery of mRNA into DCs, triggering a cytotoxic T lymphocyte response. Targeted delivery to lymph nodes (LNs) is also being investigated to reduce side effects and enhance the immune response.
Synergistic Approaches: CAR-T Cells and mRNA Cancer Vaccines
The convergence of CAR-T cell therapy and mRNA cancer vaccines represents a promising development in cancer immunotherapy. mRNA technology offers a potential solution to overcome CAR-T cell manufacturing challenges by enabling the efficient and cost-effective generation of CAR-T cells within a patient's own body. Studies have demonstrated that mRNA-based injections can effectively elicit CAR-T cells in vivo, leading to disease regression in mouse models of prostate cancer, hepatitis B-induced hepatocellular carcinoma, and leukemia. CRISPR gene-editing tools are also being used to enhance CAR-T cell therapy by deleting the PD-1 gene locus, rendering them resistant to exhaustion.
Clinical Trials
Several clinical trials are underway to explore the potential of mRNA cancer vaccines. A phase I trial (NCT04161755) found that personalized mRNA vaccines can activate neoantigen-specific T cells and provide clinical benefits for patients with pancreatic ductal adenocarcinoma (PDAC). In a phase I trial (NCT03480152), a personalized mRNA vaccine containing validated neoantigens and mutations of driver genes evoked mutation-specific T-cell responses in patients with metastatic gastrointestinal cancer. A multicenter phase I trial (NCT03164772) studying mRNA vaccines in combination with immune checkpoint inhibitors (ICIs) for non-small cell lung cancer (NSCLC) showed promising progression-free survival rates. A collaboration between CARsgen and Moderna is exploring the combined potential of a Claudin18.2-specific CAR-T cell product and Moderna's investigational Claudin18.2 mRNA cancer vaccine.
Challenges and Future Prospects
Despite the progress, challenges remain in optimizing mRNA vaccine technology. These include the need for more comprehensive exploration of tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs), improving in vivo delivery efficiency, enhancing the stability of formulated mRNA vaccines, and developing effective combination therapies. Combination therapies involving mRNA vaccines and ICIs or CAR-T cell therapy hold great promise for augmenting the efficacy of cancer immunotherapy. Addressing these challenges will pave the way for the widespread adoption of mRNA cancer vaccines and improve outcomes for patients with various types of cancer.
