Peeling Back the Layers of mRNA Technology: What is its Potential to Cure Cancer?

Special Section: Cancer Moonshot – Five Years and Rising

Peeling Back the Layers of mRNA Technology: What is its Potential to Cure Cancer?

Reem Yunis
Medable
@medableinc

herapies based on RNA molecules have been researched for decades, initially showing promise in animal models and some ultimately in clinical trials. Research on messenger RNA-based (mRNA) vaccines started in the 1990s when the first mRNA flu vaccine was tested in mice. Despite its promise, including the potential for delivering intact mRNA directly into cells, advancing mRNAs as a treatment modality still faces technical challenges.

A key hurdle is that mRNA molecules are unstable and break down rapidly, but advancements in nanotechnologies provided the solution. Lipid nanoparticles (LNPs) can encapsulate mRNA molecules and facilitate their entry into cells, where they are released and translated into proteins. These proteins then trigger an immune response.

By the start of the pandemic in March 2020, mRNA vaccine technology was, fortunately, proven safe and effective and thus ready for prime time. The success and safety of the COVID-19 mRNA vaccines have stimulated enthusiasm for additional mRNA vaccine efforts. The number of mRNA vaccine-related papers in PubMed spiked from 150 during the last 15 years (2005-2020) to more than 1,000 in one year (2021) and almost 750 in just the first four months of 2022.

The decades of mRNA vaccine research leading to the COVID-19 mRNA vaccine encompassed more than just infectious diseases. In fact, the research teams at Moderna and BioNTech (who partnered with Pfizer) had been intently working on mRNA vaccines for cancer for many years. There are currently 74 interventional clinical trials of cancer mRNA vaccines registered on ClinicalTrials.gov. FDA approval of the COVID-19 mRNA vaccine has created renewed expectations for cancer breakthroughs using mRNA vaccines for prevention and treatment. In February 2022, renewal of the Cancer Moonshot initiative provided $1.8 billion for cancer research over the next seven years with special attention on mRNA vaccines to prevent cancer.

Hopeful Progress

The simplicity yet versatility of mRNA vaccines makes them an attractive treatment modality for cancer. They operate much like an assembly line with sophisticated machinery. Once inside the cell, mRNA is rapidly translated to generate the protein for which they code. This protein is then called an antigen and elegantly presented by components of the immune system (MHC I/II) to the cytotoxic T cells to induce an antitumor response. This antitumor response is due to the careful selection of the antigen (the protein), making antigen selection core to the success of cancer mRNA vaccines. Fundamentally, tumor antigen-based mRNA vaccines are designed to have high tumor specificity and induce strong and controllable antitumor responses. Several classes of antigens, each with various pros and cons, are used for the development of cancer mRNA vaccines.

Early on, tumor-associated antigens (TAAs), which are proteins overexpressed in tumors, were attractive candidates. However, TAAs are also expressed in normal cells, therefore causing immunotolerance and rendering them less effective. Another class of mRNA antigens is the tumor-specific antigens (TSAs).

These are neoantigens that are not expressed in normal cells because they are the result of mutations arising in the genome of the tumor cells. Therefore, TSAs have strong tumor specificity and immunogenicity, and exhibit better efficacy than TAA-based approaches.

Advances in tumor genome sequencing and the personalized/precision medicine trend are driving the prevailing approach of using multi-neoantigen cancer mRNA vaccines. While this approach has some advantages, it currently takes a long time to prepare neoantigens: on average, 160 days. Unfortunately, this can reduce their effectiveness due to rapid changes in a patient’s tumor genome that may take place in the time it takes from screening to sequencing to vaccine creation. Therefore, improvements in techniques and predictive analytics for rapid screening, and identification of tumor neoantigens, are crucial for continued effective cancer mRNA vaccine development.

Other classes of antigens include immunomodulatory molecules, tumor-suppressor genes, and combinations of mRNA cancer vaccines with checkpoint inhibitors. All hold tremendous promise and are being evaluated as rapidly as possible but depend upon essential funding for scientific research and clinical trials. The Cancer Moonshot can address that.

The advancement of mRNA vaccines was, in part, achieved due to breakthroughs in mRNA delivery carriers. Delivery carriers are carefully evaluated for safety, stability, load capacity, and adjuvant effect, as well as their ability to reach target cells, present antigens, and activate immune cells. The predominant delivery mechanisms used for cancer mRNA vaccines are liposomes and their derivatives. Liposomes can bind and deliver the mRNA to immune cells, which then induce antigen-specific immune responses. LNPs are gaining ground as the delivery carriers of mRNA vaccines because of their size, structural stability, and longer half-life.

Where Are We on the Road to Cancer Treatment and Prevention?

The field of cancer mRNA vaccines has come a long way since the immune response to liposome-containing mRNA was first shown in 1995. This proof-of-concept study study set the stage for mRNA-based cancer vaccine technology.

Following this and other advancements, the first phase 1 clinical trial was reported in 2002. This study showed that autologous dendritic cells (DCs) transfected with mRNA encoding a protein–prostate-specific antigen (PSA)–induced T-cell response in all metastatic prostate cancer patients. In 2009, a metastatic melanoma feasibility phase 1/2 study of an mRNA vaccine encoding several TAAs given to 21 patients induced an immune response showing positive outcomes, with one patient showing complete response.

To date, numerous cancer mRNA vaccines have been tested in clinical trials. Several have gained regulatory approval, including Bacillus Calmette-Guérin (BCG) for the treatment of non-muscle-invasive bladder cancer; sipuleucel-T for the treatment of metastatic prostate cancer; and talimogene laherparepvec for the treatment of advanced melanoma. Two prophylactic cancer vaccines were also approved, marking a significant step toward cancer prevention for millions of people: HPV, known to cause cervical and head and neck cancer, and hepatitis B virus, known to cause liver cancer. In 2021, FDA issued a fast-track designation of BNT111, a melanoma vaccine, in a phase 2 clinical trial for late-stage metastatic melanoma patients using an mRNA encoding four TAAs prevalent in melanoma, in combination with an immune checkpoint inhibitor. This combination treatment has been shown to induce persistent and strong antigen-specific immune responses against melanoma cells, effectively extending life for patients.

At the 2022 American Association for Cancer Research (AACR) conference, researchers shared promising results of their CAR-T cell + mRNA vaccination therapy in which six out of the 14 patients’ tumors either disappeared or shrunk considerably. This extends the use of CAR-T therapy from blood cancers to solid tumors and showcases the promise of combination approaches and value of clinical trials.

Cancer Moonshot Now Less of a Long Shot

Therapeutic vaccines represent viable active immunotherapy for cancers by harnessing the power of a patient’s own immune system. The diversity and flexibility in the choice of mRNA approaches allow encoding separately or in combination for both antigenic and immunomodulatory molecules that subsequently induce and regulate both the adaptive and innate immune responses. They are safe because they do not carry the risk of integrating in the host genome, are transiently expressed in cells, noninfectious, and well tolerated because they do not induce autoimmunity. Further, mRNA vaccines are relatively easy to control, and their cell-free production eliminates the risk for biological contamination, rendering them safe and economical for rapid mass production.

Fully and rapidly realizing the potential of mRNA-based prevention and treatment also requires the application of new, equally innovative research models like decentralized clinical trials (DCTs). As more researchers adopt DCTs that leverage digital technologies and reduce traditional trial participation burdens, we will see better population representation and richer, real-world data for accelerated time to market of drugs that work for every biology.

Together, DCTs and mRNA technology can expedite breakthrough cancer vaccine approvals and bring personalized, life-saving treatments to patients faster so we can achieve the longshot promise of the Cancer Moonshot initiative.

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