Multiple companies are pursuing mRNA-based medicines that harness the body's protein-making machinery to transform lab-synthesized nucleotides into cancer-associated antigens, in the case of vaccines, or immune-stimulating molecules, in the case of therapeutics. Several candidates from BioNTech and Moderna have shown promise in early-stage testing.

BioNTech, a leading developer of mRNA-based vaccines and immunotherapeutics for cancer, secured $325 million in private financing in June to advance its therapeutic pipeline and expand its manufacturing infrastructure. The money—which comes on top of a $270 million initial funding round last year and development deals with Genentech, Sanofi, and others—gives BioNTech the financial backing to compete with CureVac and Moderna, both of which have immune-stimulating oncology products in early-stage clinical testing (see Table).

Conceptually, mRNA-based immunotherapy offers several advantages over other technology platforms in terms of potency, pharmacokinetics, safety, and cost. The medicines harness the body's own protein-making machinery to transform strings of low-cost, easy-to-synthesize nucleotides into cancer-associated antigens, in the case of vaccines, or immune-stimulating molecules, in the case of therapeutics. Either way, the goal is the same: to induce antitumor immune responses, often as a complement to checkpoint inhibition or another immunotherapeutic strategy.

BioNTech's lead candidate, BNT122, is an individualized neoantigen vaccine under evaluation in two combination trials—one with the PD-L1 inhibitor atezolizumab (Tecentriq; Genentech), the other with the PD-1–targeted agent pembrolizumab (Keytruda; Merck). BioNTech makes its bespoke product by sequencing a patient's tumor, identifying up to 20 neoepitopes predicted to elicit T-cell immunoreactivity, codifying those sequences in a tailor-made DNA plasmid, and then reverse-transcribing mRNA molecules encapsulated in lipid nanoparticles.

The process takes about a month from biopsy to vaccine administration. Peptide-based neoantigen vaccines, in comparison, take at least twice as long to create.

The manufacturing may seem complex, but the therapeutic strategy is “pretty simple,” says Ryan Sullivan, MD, of Massachusetts General Hospital in Boston, MA, who is testing personalized mRNA vaccines from BioNTech and Moderna. “If you can generate more T cells that can recognize the tumor, that's a good thing.”

In phase I testing, BNT122 elicited T-cell responses in all 13 trial participants and produced objective responses in two of the five with metastatic lesions. When initial findings were published in 2017, the eight other participants, none of whom had active disease, had been recurrence-free for 1 to 2 years. Two years on, as of the last data analysis, “all of those patients are still metastasis-free,” says BioNTech's cofounder and CEO Ugur Sahin, MD.

“It is exciting because it is an on-demand, real-time production of a fully individualized drug tailored to the exome sequence of the tumor,” Sahin says. BioNTech also has antibodies, cell therapies, and small molecules in development, but its mRNA technologies, and especially its personalized vaccine program (in which Genentech is a partner), remain the company's top priority.

Moderna's analogous vaccine, mRNA-4157, similarly produced promising results when tested as a monotherapy for solid tumors in the adjuvant setting: As reported at the 2019 American Society of Clinical Oncology Annual Meeting in June, 11 of 13 patients remained disease-free for 6 to 17 months after vaccination. Plus, when the vaccine was given in combination with pembrolizumab to a different set of 20 patients, six recipients exhibited clinical responses, two of whom had previously relapsed on a checkpoint inhibitor. The highest vaccine dose was also safe and generated neoantigen-specific cytotoxic T cells.

In July, Moderna and development partner Merck launched a phase II trial of the vaccine–pembrolizumab combination in melanoma. The companies also upped the maximum number of mRNA-encoded neoepitopes from 20 to 34. As Tal Zaks, MD, Moderna's chief medical officer, points out, algorithms aren't flawless when picking the most immunogenic neoepitopes, so having more targets increases the likelihood of success. “We're playing a numbers game,” he says.

Moderna and Merck have also begun testing a shared-antigen vaccine, mRNA-5671, that encodes four mutant versions of KRAS commonly found in patients with colorectal, lung, and pancreatic cancers. BioNTech and CureVac have off-the-shelf mRNA vaccines of their own, but theirs include nonmutated antigens that are either overexpressed in tumors, restricted to the cell type turned cancerous, or expressed only in tumors and germ cells.

BioNTech's ready-made vaccine technology additionally takes advantage of a lipid carrier nanotechnology that protects RNA from degradation and mediates uptake of the encoded antigen by dendritic cells in lymphoid organs. Data on the first 41 patients to receive the company's melanoma vaccine, BNT111, suggest the approach is safe, with immune responses generated against at least one of the four encoded antigens in 81% of individuals. Notably, the vaccine also induced “extremely strong T-cell responses in these patients,” Sahin says, and half of those whose disease advanced despite prior PD-1 immunotherapy experienced tumor shrinkage or stable disease.

Additionally, BioNTech, Moderna, CureVac, and a smaller company called eTheRNA Immunotherapies all have immunostimulatory cocktails of therapeutic mRNAs in phase I development. These include some combination of mRNA sequences that encode proinflammatory cytokines, T-cell costimulators, and/or noncoding RNA molecules that activate immune pathways.

The most advanced candidate is Moderna's mRNA-2416, which encodes the costimulatory ligand OX40L that's normally expressed on antigen-presenting cells and binds activated T cells and natural killer cells to promote antitumor activity. After evaluating safety in 28 patients with various cancers, the company announced plans in January to commence a phase II study in advanced ovarian cancer.

Moderna chose that indication after observing the regression of injected lesions in two patients in the phase I study. Neither response met RECIST criteria, says Zaks, but “those lesions shrinking gave us enough interest to take this into a phase II study.”

For now, only mRNA-2416 and the personalized vaccines from BioNTech and Moderna have advanced to mid-phase clinical testing—although the lack of data has not dampened enthusiasm for mRNA-based immunotherapeutics. “We can see a whole bunch of applications that leverage this technology to wake up the immune system,” Zaks says. –Elie Dolgin

mRNA-BASED CANCER MEDICINES IN CLINICAL DEVELOPMENT
CompanyCompany partnerProduct namemRNA(s) includedIndicationPhase
Vaccines BioNTech Genentech RO7198457 (BNT122) Individualized neoantigens Melanoma II 
 BioNTech  BNT111 NY-ESO-1, tyrosinase, MAGE-A3, and TPTE Melanoma 
 BioNTech  BNT114 Personalized combination of shared antigens Triple-negative breast cancer 
 BioNTech  BNT113 Antigens encoding HPV16 E6 and E7 HPV-driven head and neck cancer 
 Moderna Merck mRNA-4157 Individualized neoantigens Melanoma II 
 Moderna Merck mRNA-5671 Mutant KRAS Colorectal, lung, and pancreatic cancers 
 CureVac Boehringer Ingelheim CV9202 NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC1 Lung cancer 
Therapeutics BioNTech Sanofi SAR441000 (BNT131) IL12, IFNα, GM-CSF, IL15 Solid tumors 
 Moderna  mRNA-2416 OX40L Ovarian cancer II 
 Moderna  mRNA-2752 OX40L, IL23, and IL36γ Solid tumors and lymphoma 
 Moderna AstraZeneca MEDI1191 IL12 Solid tumors and lymphoma 
 CureVac  CV8102 Undisclosed noncoding RNA to stimulate TLR-7/8 and RIG-I pathways Liver cancer, superficial tumors (melanoma, squamous cell carcinoma of the skin, head and neck cancers, and adenoid cystic carcinoma) 
 eTheRNA  TriMix caTLR4, CD40L, and CD70 Breast cancer 
 eTheRNA  ECI-006 TriMix, plus tyrosinase, gp100, MAGE-A3, MAGE-C2, and PRAME Melanoma 
mRNA-BASED CANCER MEDICINES IN CLINICAL DEVELOPMENT
CompanyCompany partnerProduct namemRNA(s) includedIndicationPhase
Vaccines BioNTech Genentech RO7198457 (BNT122) Individualized neoantigens Melanoma II 
 BioNTech  BNT111 NY-ESO-1, tyrosinase, MAGE-A3, and TPTE Melanoma 
 BioNTech  BNT114 Personalized combination of shared antigens Triple-negative breast cancer 
 BioNTech  BNT113 Antigens encoding HPV16 E6 and E7 HPV-driven head and neck cancer 
 Moderna Merck mRNA-4157 Individualized neoantigens Melanoma II 
 Moderna Merck mRNA-5671 Mutant KRAS Colorectal, lung, and pancreatic cancers 
 CureVac Boehringer Ingelheim CV9202 NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC1 Lung cancer 
Therapeutics BioNTech Sanofi SAR441000 (BNT131) IL12, IFNα, GM-CSF, IL15 Solid tumors 
 Moderna  mRNA-2416 OX40L Ovarian cancer II 
 Moderna  mRNA-2752 OX40L, IL23, and IL36γ Solid tumors and lymphoma 
 Moderna AstraZeneca MEDI1191 IL12 Solid tumors and lymphoma 
 CureVac  CV8102 Undisclosed noncoding RNA to stimulate TLR-7/8 and RIG-I pathways Liver cancer, superficial tumors (melanoma, squamous cell carcinoma of the skin, head and neck cancers, and adenoid cystic carcinoma) 
 eTheRNA  TriMix caTLR4, CD40L, and CD70 Breast cancer 
 eTheRNA  ECI-006 TriMix, plus tyrosinase, gp100, MAGE-A3, MAGE-C2, and PRAME Melanoma