Introduction
Basic mRNA pharmacology, limitations and advantages
Immunogenicity of mRNA and paradoxical effects in Cancer immunotherapy
Strategies to improve mRNA translation efficiency and overcome the innate immunogenicity
Five-prime cap (5’Cap) modification
Optimization of Untranslated regions (UTRs)
Codon optimization of open Reading frame (ORF)
Poly (a) tail modification
Nucleoside modified mRNA
Purification of IVT-mRNA
Utilizing the impact of type I IFN for improved mRNA vaccination
Self-amplifying mRNA vaccine, structure, advantages and deliveries
Delivery of mRNA Cancer vaccine
Ionizable lipid nanoparticles-based mRNA delivery system
Rationale for lipid nanoparticles to maximize deliver efficiency and immunogenicity
Mechanistic studies and additional functional modifications of LNPs
LNP mRNA vaccine from formulation to manufacturing
Polymer-based mRNA delivery system
Peptide-based mRNA delivery system
Other formulations used in mRNA delivery
Injection routes mRNA Cancer vaccines
Clinical overview of mRNA Cancer vaccines
NCT Number | Status | Phases | Disease | mRNA and Interventions | Formulation Type | Route | Combo | Sponsor (s) | Study Results |
---|---|---|---|---|---|---|---|---|---|
NCT03788083 | Recruiting | Phase 1 | Early-stage Breast Cancer | Trimix mRNA (mRNA encoding CD40L, CD70, acTLR4) | Synthetic naked mRNA | Intratumoral | NA | Universitair Ziekenhuis Brusse, eTheRNA immunotherapies | Not available |
NCT03394937 | Recruiting | Phase 1 | Melanoma (resected) | ECI-006: a. Trimix mRNA, b. mRNA encoding TAAs: tyrosinase, gp100, MAGE-A3, MAGE-C2, PRAME | Synthetic naked mRNA | Intranodal | Trimix mRNA + TAA | eTheRNA immunotherapies | ECI-006 is well tolerated. Vaccine-induced immune responses were detected in 4/10 and 3/9 patients treated with low (600 μg) and high dose (1800 μg). ECI-006 shown immunogenic in a portion of patients. |
NCT01066390 | Completed | Phase 1 | Stage III/IV Malignant Melanoma (Previously treated, unresectable) | TriMixDC-MEL a. DC electroporated with TriMix mRNAs, b. TAAs: MAGE-A3, MAGE-C2, tyrosinase, gp100 | DC-based | Autologous DC treatment (i.v. and i.d.) | Trimix mRNA + TAA | Universitair Ziekenhuis Brussel | Immunotherapy with TriMixDC-MEL is safe and immunogenic. Antitumor activity with durable disease control is observed. Antigen-specific CD8+T-cells were detected in the blood of 4 of 5 patients. |
NCT01676779 | Completed | Phase 2 | Melanoma (disease free following macrometastases) | TriMixDC-MEL a. DC electroporated with TriMix mRNAs b. TAAs: MAGE-A3, MAGE-C2, tyrosinase, gp100 | DC-based | Autologous DC treatment (i.v. and i.d.) | Trimix mRNA + TAA | Universitair Ziekenhuis Brussel | TriMixDC-MEL is tolerable (symptom: transient local skin reactions, flu-like symptom, post-infusion chills), and may improve the 1-year disease-free survival rate (71% disease free in treatment group vs 35% in control arm). |
NCT01302496 | Completed | Phase 2 | Stage III/IV Malignant Melanoma (Previously treated, unresectable) | TriMixDC-MEL and i.v. CTLA-4 inhibitor ipilimumab | DC-based | Autologous dc therapeutics (i.v. and i.d.) | Trimix mRNA + TAA + Checkpoint inhibitor | Bart Neyns|Vrije Universiteit Brussel|Universitair Ziekenhuis Brussel | T-cell stimulation were shown in 12/15 patients. Immune responses were stronger in patients with complete or partial response. Multifunctional CD8+ T-cell responses were detected either elicited by TriMixDC-MEL IPI or on subsequent pembrolizumab treatment, may provide a benchmark for the level of immune stimulation needed to achieve a durable clinical remission. |
NCT03323398 | Recruiting | Phase 1/2 | Relapsed/ Refractory Solid Tumor Malignancies or Lymphoma | mRNA-2416 (mRNA encoding OX40L), alone (Phase I) or in combination with i.v. PD-L1 inhibitor, Durvalumab (Phase 2) | LNP | Intratumoral | mRNA LNP + Checkpoint inhibitor | ModernaTX, Inc. | Intratumoral mRNA-2416 is tolerable at all dose levels when dosed alone. Analyses of tumor post-treatment demonstrate increased OX40L protein expression, elevated PD-L1 levels and pro-inflammatory activity. |
NCT03739931 | Recruiting | Phase 1 | Dose Escalation: Relapsed/Refractory Solid Tumor Malignancies or LymphomaDose Expansion: Other solid tumors | mRNA-2752 (mRNA encoding OX40L, IL-23, IL-36Ƴ), alone (Phase I) or in combination with i.v. PD-L1 inhibitor, Durvalumab (Durva, Phase II) | LNP | Intratumoral | mRNA LNP + Checkpoint inhibitor | ModernaTX, Inc., AstraZeneca | Intratumoral mRNA-2752 given as monotherapy and in combination with PD-L1 inhibitor is tolerable at all dose levels studied, and administration can be associated with tumor shrinkage (52% Tumor reduction, 0.5 mg mRNA-2752 with durva in bladder carcinoma). Elevated IFN-γ, TNF-α, and PD-L1 levels were detected. |
Brand | NCT Number | Status | Phases | Disease | Antigen | mRNA | Formulation Type | Route | Combo | Sponsor (s) | Study Results |
---|---|---|---|---|---|---|---|---|---|---|---|
CV9201 | NCT00923312 | Completed | Phase 1/2 | Stage IIIB/IV NSCLC | MAGE-C1, MAGE-C2, NY-SEO-1, survivin, 5 T4 | mRNA | RNActive, (Protamine) | i.d. | NA | CureVac | CV9201 was well-tolerated and immune responses were detected after treatment. Median progression-free and overall survival were 5 and 10.8 months |
CV9202 | NCT03164772 | Recruiting | Phase 1/2 | NSCLC | NY-ESO-1, MAGE-C1, MAGE-C2, 5 T4, survivin, MUC1 | mRNA | RNActive, Protamine | i.d. | Durvalumab; Tremelimumab | CureVac | CV9202 was well-tolerated, and antigen specific immune responses were detected in majority of patients (84%) |
CV9103 | NCT00831467 | Completed | Phase I/2 | Prostate cancer | PSA, PSCA, PSMA, STEAP1 | mRNA | RNActive, Protamine | i.d. | NA | CureVac | CV9103 is well tolerated and immunogenic |
CV9104 | NCT01817738 | Terminated | Phase I/2 | Prostate cancer | PSA, PSCA, PSMA, STEAP1, PAP, MUC1 | mRNA | RNActive, Protamine | i.d. | NA | CureVac | Terminated due to insufficient activities |
BNT111 (Lipo-MERIT) | NCT02410733 | Active, not yet recruiting | Phase 1 | advanced melanoma | NY-ESO-1, MAGE-C3, tyrosinase, gp100 | mRNA | Lipo-MERIT, DOTMA (DOTAP)/ DOPE lipoplex | i.v. | NA | BioNTech | Not available |
IVAC | NCT02316457 | Active, not yet recruiting | Phase 1 | TNBC | 3 TAAs selected | mRNA | Lipo-MERTI, DOTMA(DOTAP)/DOPE lipoplex | i.v. | NA | BioNTech | Not available |
Not available | NCT01995708 | Active, not yet recruiting | Phase 1 | malignant melanoma | CT7, MAGE-A3, and WT1 mRNA-electroporated Langerhans cells (LCs) | dendritic cell (DC)-loaded mRNA | CT7, MAGE-A3, and WT1 mRNA-electroporated Langerhans cells (LCs) | i.d. | NA | Memorial Sloan Kettering Cancer Center | Not available |
Not available | NCT00204516 | Completed | Phase 1/2 | melanoma | TAA for melanoma (Melan-A, Mage-A1, Mage-A3, survivin, GP100, and tyrosinase) | naked mRNA | naked mRNA | i.d. | GM-CSF | The Norwegian Radium Hospital | Not available |
NA | NCT01278940 | Completed | Phase 1/2 | melanoma | TAA-transfected DC | dendritic cell (DC)-loaded mRNA | DC loaded mRNA | i.d. or i.n. | IL-2 | Oslo University Hospital | Not available |
AVX701 | NCT01890213 | Completed | Phase 1 | Stage III CRC | an alphavirus replicon (VRP) encoding the protein (CEA) | SAM | VRP | i.m. | NA | AlphaVax | Not available |
AVX701 | NCT00529984 | Completed | Phase 1/2 | Advanced or metastatic CEA expressing solid tumor | an alphavirus replicon (VRP) encoding the protein (CEA) | SAM | VRP | i.m. | NA | AlphaVax | Five-year survival for patients with stage IV and stage III cancer was 17, 75%, respectively. All patients shown CEA-specific humoral immunity. CEA-specific, IFNγ-producing CD8 + granzyme B + TCM cells were increased. So, VRP-CEA induces antigen-specific effector T cells while decreasing Tregs, suggesting favorable immune modulation. |
Brand | NCT Number | Status | Phases | Disease | Antigen /mRNA | Formulation Type | Route | Combinations | Sponsor/Collaborators | Study Results |
---|---|---|---|---|---|---|---|---|---|---|
IVAC MUTANOME, RBL001/RBL002 | NCT02035956 | Completed | Phase 1 | Advanced Melanoma | Neo-Ag/TAA (mRNA) | naked mRNA | ultrasound- guided i.n. | NA | BioNTech | 60% of the 125 selected neoepitopes elicited a T- cell response. The vaccination was very well tolerated. |
RO7198457 | NCT03289962 | Recruiting | Phase 1 | Melanoma, NSCLC, Bladder Cancer, CRC, Breast Cancer etc. | Neo-Ag (mRNA) | Lipo-MERIT | i.v. | Atezolizumab (infusion) | BioNTech, Genentech | RO7198457 combined with atezolizumab was generally well tolerated; RO7198457 in combination with atezolizumab induced the release of pro-inflammatory cytokines and peripheral T-cell responses in the majority of patients |
NCT04267237 | Recruiting | Phase 2 | NSCLC | Neo-Ag (mRNA) | Lipo-MERIT | i.v. | Atezolizumab | Hoffmann-La Roche | NA | |
NCT03815058 | Recruiting | Phase 2 | Advanced Melanoma | Neo-Ag (mRNA) | Lipo-MERIT | i.v. | Pembrolizumab (infusion) | BioNTech, Genentech | NA | |
NCT04486378 | Recruiting | Phase 2 | Stage II and III CRC (surgically resected) | Neo-Ag (mRNA) | Lipo-MERIT | i.v. | NA | BioNTech | NA | |
NCT04161755 | Recruiting | Phase 1 | Pancreatic Cancer (surgically resected) | Neo-Ag (mRNA) | Lipo-MERIT | i.v. | Atezolizumab, FOLIFIRINOX | Memorial Sloan Kettering Cancer Center, Genentech | NA | |
mRNA-4157 | NCT03313778 | Recruiting | Phase 1 | Mono-: resected solid tumors; Combo: unresectable solid tumor | Neo-Ag (mRNA) | LNP | i.m. | Pembrolizumab (infusion) | Moderna, Merck | mRNA-4157 is safe and well tolerated at all tested dose levels. Clinical responses were observed when dosing combined with Pembrolizumab. Neoantigen-specific T cells have been detected |
NCT03897881 | Recruiting | Phase 2 | Complete Resection of High-Risk Melanoma | Neo-Ag (mRNA) | LNP | i.m. | Pembrolizumab (infusion) | Moderna, Merck | Not available | |
mRNA-5671/Merck V941 | NCT03948763 | Recruiting | Phase 1 | CRC, NSCLC, pancreatic cancer | KRAS mutations: G12D, G12V, G13D, G12C (mRNA) | LNP | i.m. | Pembrolizumab (infusion) | Moderna, Merck | Not available |
Not available | NCT03468244 | Recruiting | Phase 1 | Advanced Esophageal Squamous Carcinoma; Gastric Adenocarcinoma; Pancreatic Adenocarcinoma; Colorectal Adenocarcinoma | Neo-Ag (mRNA) | lipopolyplex | s.c. | NA | Changhai Hospital, Stemirna Therapeutics | Not available |