mRNA melanoma vaccine revolution spurred by the COVID-19 pandemic

Cancer immunotherapy has transformed treatment for advanced melanoma and NSCLC through checkpoint blockade targeting PD-1, PD-L1, and CTLA-4, but cancer vaccines historically underperformed due to weak CD8+ T-cell induction, narrow T-cell repertoires versus heterogeneous tumors, and insufficient CD4+ and B-cell activation. mRNA vaccines, long in development but accelerated by the COVID-19 pandemic, address several of these issues. Global deployment improved manufacturing, delivery infrastructure, and understanding of immunogenicity and safety. Notably, mRNA vaccines can elicit neutralizing antibodies and robust CD8+ T-cell responses, supporting their promise as cancer vaccines. Several candidates, particularly for melanoma, have shown encouraging early clinical results. This review synthesizes lessons from COVID-19 mRNA vaccines and recent melanoma mRNA vaccine trials.

Historical development: Early in vivo gene transfer using IVT mRNA showed expression after intramuscular inoculation. Subsequent studies demonstrated mRNA encoding influenza hemagglutinin and CEA could induce CD8+ T-cell and antibody responses, respectively. Progress slowed due to mRNA thermal instability (limited room-temperature stability and cold-chain requirements) and innate immune activation via PRRs causing reactogenicity and reduced translation. Advances addressed these through purification and formulation, nucleoside modification, and sequence engineering. Optimization of transcripts: Innate sensors TLR7/8 recognize ssRNA rich in unmodified guanosine/uridine motifs, triggering type I IFN, degrading mRNA and causing injection-site reactions. Modified nucleotides (e.g., pseudouridine, m6A, m5C, s2U, m5U) reduce innate sensing and improve translation. 5′-end triphosphates in IVT mRNA activate PRRs; adding an m7G cap or anti-reverse cap analogs (ARCA) yields properly capped, translatable mRNA. Poly(A) tail optimization via polymerase methods, hydrolysis-resistant ATP analogs, or templated oligo(dT) improves stability and half-life. Sequence engineering: Codon usage should match target tissue/cell tRNA pools and delivery route; GC content and minimized secondary structures enhance stability and translation. UTR engineering (5′ Kozak/IRES for initiation; 3′ motifs like β-globin for stability or miR-122 sites for tissue specificity) tunes expression and safety. Purification and formulation: dsRNA byproducts activate TLR3/RIG-I; HPLC or cellulose-based methods remove dsRNA and reduce reactogenicity. Naked mRNA shows poor uptake and stability; protamine complexes improve delivery but with limited efficacy in trials (e.g., CV-9201). Lipid nanoparticles (LNPs) are now standard, stabilizing mRNA, enhancing APC uptake, enabling endosomal escape, and serving as adjuvants (e.g., IL-6 induction for Tfh maturation). LNPs can be targeted (e.g., CD5-directed LNPs to engineer T cells in vivo). Lessons from COVID-19: Rapid design-to-approval timelines were achieved for Pfizer/BioNTech and Moderna vaccines with strong efficacy, acceptable safety, and demonstrated T-cell responses (Th1-skewed CD4+; polyfunctional CD8+ detected with MHC-I tetramer/sorting), though reduced protection against variants like Omicron was observed. These data validate mRNA platforms’ immunogenicity and scalability. mRNA cancer vaccines: Approaches include TAAs (shared antigens; off-the-shelf; tolerance and autoimmunity risks) and TSAs (viral antigens or patient-specific neoantigens; personalized pipelines). NSCLC vaccines CV9201 and CV9202 were safe and immunogenic but did not improve survival. TSA-targeting includes viral (BNT113 for HPV E6/7) and driver (mRNA-5671 for KRAS) or personalized cocktails (e.g., mRNA-4650), with variable CD8+ induction highlighting prediction challenges. mRNA can encode immunostimulatory biologics (e.g., mRNA-2752 for OX40L/IL-23/IL-36γ) often given intratumorally to limit systemic toxicity. Melanoma focus: Melanoma has high mutational burden and is accessible for immunotherapy; CPI improves survival, and mRNA vaccines aim to augment responses. Preclinical B16F10 models showed multiepitope mRNA vaccines elicited strong CD4+/CD8+ responses and protected 60–80% of mice; lymph-node-targeting LNPs (113-O12B) improved efficacy (40% complete responses). Clinically, LNP-formulated vaccines include BNT111 (TAA cocktail; robust T-cell responses and responses with cemiplimab), and personalized vaccines BNT122 and mRNA-4157 (inducing neoantigen-specific T cells; promising efficacy signals in early trials). Non-coding RNA adjuvant CV8102, delivered intratumorally, increased T-cell infiltration and showed regressions alone or with CPI.

Platform and COVID-19 experience: Pfizer/BioNTech BNT162b2 provided 95% protection two months post two 30 µg doses and 83.7% at four months; Moderna mRNA-1273 provided 94.1% protection within 64 days and ~90% at six months. Adverse events were mostly self-limiting: Pfizer reported fever and fatigue in 3.8%; Moderna reported 38.1% moderate and 15.8% severe side effects after dose two. Protection decreased against Omicron (Pfizer 56% after second dose, 74% after third). Moderna induced strong Th1 CD4+ T-cell responses; polyfunctional CD8+ T cells were detected with MHC-I-based assays after mRNA vaccination, appearing earlier than CD4+ and antibody responses. Formulation and delivery advances: LNPs stabilize mRNA, target APCs, enable endosomal escape, and act as adjuvants via IL-6, enhancing Tfh and humoral responses. Targeted LNPs can direct payloads to specific cells (e.g., T cells) in vivo. HPLC or cellulose-based purification reduces dsRNA impurities and innate activation. Clinical trials in solid tumors and melanoma: - NSCLC mRNA vaccines: CV9201 induced antigen-specific T cells in 63% of subjects but did not improve progression-free or overall survival; CV9202 induced T-cell responses in 84% of subjects. - Immunostimulatory mRNA: mRNA-2752 (intratumoral OX40L/IL-23/IL-36γ) had one dose-limiting toxicity (cytokine release syndrome) among 30 patients at 8 mg, increased IFN-γ and TNF-α in tumor and plasma, with partial responses in 2/45 patients and 15/45 achieving stable disease. - Melanoma TAAs: BNT111 (NY-ESO-1, MAGE-C3, Tyrosinase, TPTE) induced CD4+ and/or CD8+ responses in 78% (39/50). In CPI-experienced patients receiving BNT111 plus cemiplimab, 35% (6/17) had partial responses and 12% (2/17) had stable disease; other cohorts reported partial responses and a complete metabolic remission. - Personalized neoantigen vaccines: BNT122 (autogene cevumeran) in PDAC induced de novo neoantigen-specific T cells in 8/16 patients, with longer recurrence-free survival in responders. mRNA-4157 was well tolerated and immunogenic in Phase 1; in a Phase 2 trial (KEYNOTE-942) adjuvant mRNA-4157 plus pembrolizumab reduced risk of recurrence or death by 44% versus pembrolizumab alone (HR 0.56; 95% CI 0.31–1.08); serious treatment-related adverse events occurred in 14.4% with combination versus 10% with pembrolizumab alone. Preclinical melanoma: Multiepitope mRNA vaccines protected 60–80% of mice against lethal B16F10 challenge; lymph-node-targeting LNPs achieved 40% complete responses in B16F10 models. Design considerations: Modified nucleosides (e.g., pseudouridine), ARCA capping, optimized poly(A) tails, codon/GC content, minimized secondary structure, and engineered UTRs collectively enhance stability and translation while reducing innate sensing.

The review argues that the COVID-19 pandemic catalyzed the maturation of mRNA vaccine technology—validating safety, scalability, and the capacity to induce multi-arm immunity (B cells, CD4+, CD8+ T cells). These attributes directly address historical shortcomings of cancer vaccines, particularly the need for potent CD8+ T-cell responses against heterogeneous tumors like melanoma. Advances in chemistry, purification, and LNP delivery mitigate prior barriers (instability, excessive innate activation), facilitating effective antigen presentation and adjuvanticity. Early clinical data in melanoma show robust T-cell immunogenicity for TAA-based BNT111 and clinically meaningful activity when combined with CPI; personalized neoantigen platforms (BNT122, mRNA-4157) induce de novo T-cell responses with signals for improved clinical outcomes (e.g., RFS in PDAC; reduced recurrence risk in melanoma). Nevertheless, translation from strong murine efficacy to humans remains incomplete, with lower CD8+ response magnitudes and variable clinical responses. Neoantigen selection accuracy is a bottleneck, as only a subset of predicted epitopes elicit CD8+ responses. The tumor microenvironment can limit vaccine-induced immunity at metastatic sites, underscoring the need for combination regimens (CPI, immunostimulants) and possibly self-amplifying RNAs or engineered antigens to boost responses. Overall, the synthesis supports mRNA vaccines as a promising adjunct in melanoma therapy, best leveraged in multimodal strategies.

mRNA vaccines have progressed substantially through nucleoside modification, optimized capping and poly(A) tails, sequence/UTR engineering, purification, and LNP formulation, overcoming key barriers of instability and innate reactogenicity. The COVID-19 experience accelerated platform validation and deployment, demonstrating robust immunogenicity and acceptable safety at scale. In melanoma, early-phase trials show strong T-cell immunogenicity and encouraging clinical activity, particularly in combination with checkpoint inhibitors, and personalized vaccines are advancing to late-stage evaluation. Future work should focus on amplifying cellular responses (e.g., self-amplifying RNAs, antigen/protein engineering), improving neoantigen selection (better in silico prediction and in vitro HLA-binding validation), and integrating vaccines within rational combination regimens to counter the suppressive tumor microenvironment. These directions may translate the platform’s biological promise into consistent clinical benefit across melanoma and other malignancies.

The review highlights several limitations: human CD8+ T-cell responses to mRNA vaccines are often of lower magnitude than in murine models, tempering efficacy in advanced disease; neoantigen prediction is imperfect, with only a fraction of selected epitopes eliciting effective CD8+ responses; even optimally designed vaccines may not overcome immunosuppressive tumor microenvironments at metastatic sites; and some mRNA immunostimulant strategies carry risks such as cytokine release syndrome. Additionally, TAA-targeted vaccines risk autoimmunity and are constrained by central/peripheral tolerance. Many efficacy data are early-phase or interim (some not yet peer-reviewed), limiting generalizability.