Nobel-Honored mRNA Tech Advancing Cancer Therapy

The 2023 Nobel Prize in Physiology or Medicine was awarded for discoveries that enabled the development of mRNA vaccines against COVID-19.

However, the pioneering contributions of Katalin Karikó, PhD, and Drew Weissman, MD, PhD—who, while both working at the University of Pennsylvania in Philadelphia in the mid-2000s, showed how chemical modifications to the mRNA backbone could alter the way that the molecule interacts with the innate immune system—have also paved the way for significant advancements in the treatment of cancer.

“They deserve a lot of credit for pushing the field [of mRNA therapeutics] forward when a lot of other people had basically given up on this whole strategy,” says Elad Sharon, MD, MPH, of the Dana-Farber Cancer Institute in Boston, MA.

Nucleoside-modified mRNA is now found in numerous clinical-stage development programs, including personalized cancer vaccines such as SW1115C3 (Stemirna Therapeutics), shared-antigen vaccines such as mRNA-5671 (Moderna), cytokine-encoding therapeutics such as mRNA-2752 (Moderna), antibody-encoding candidates such as BNT142 (BioNTech), and others.

“It's a platform technology,” says Rein Verbeke, PhD, of Ghent University in Belgium, “which has a lot of opportunities” in oncology.

The most clinically advanced such product, the individualized neoantigen vaccine mRNA-4157 (Moderna/Merck), previously showed potential as an adjuvant therapy for melanoma (Cancer Discov 2023;13:1278). The phase II data represented the first demonstration of antitumor efficacy in a randomized trial for an investigational mRNA cancer treatment.

Not all mRNA-based cancer therapeutics in trials today incorporate the chemical tweaks devised by Karikó and Weissman. For instance, the personalized vaccine autogene cevumeran (BioNTech) and the immune-stimulatory therapy CV8102 (CureVac) both rely on unmodified nucleoside platforms. It is possible that this form of mRNA, known to be more immunogenic than its modified counterpart, may offer advantages in specific therapeutic contexts in which enhanced immune activation is desirable.

As of now, however, modified mRNA remains the sole established technology that has produced marketable vaccine products—and many companies that once championed the unmodified approach have switched over in recent years.

Moreover, notes Verbeke, the contributions of Karikó and Weissman to the mRNA field extend beyond the one chemical alteration. They provided “new insights into how our immune system recognizes RNA, how this leads to an immune response, and how this is linked to the expression” of encoded sequences, he says.

Their findings, Verbeke adds, “will go into the record books as one of the most important discoveries of the last century.” –Elie Dolgin