グローバル規模で増大するがんの負担

がんとそれに関連する死亡率の負担は、人口の高齢化と、がんの主要危険因子の有病率と分布の変化によって、世界中で急速に増大しています。2040年には2,840万人ががんと診断されると予測されています。これは、2020年から47%の上昇となります。

最も診断数が多いがんは、現在は肺がんを抜いて女性の乳がんになっています。推定では2020年には230万人（11.7％）が新たに乳がんに罹患するとされており、次いで肺がん（11.4％）、大腸がん（10.0％）、前立腺がん（7.3％）、胃がん（5.6％）となっています。がん治療における重要な進歩のひとつとして、チェックポイント阻害薬などの免疫療法があります。この画期的な前進にもかかわらず、免疫療法はすべてのがんに効く万能薬となっていません。これは、すべての腫瘍タイプが免疫療法の薬に反応するわけではないためです。それに、対抗機構が腫瘍の免疫回避や増殖につながる可能性すらあります。

現在、米国食品医薬品局によって承認されているmRNAがんワクチンは現在ありません。しかし、チェックポイント阻害薬ペムブロリズマブ（メルク社）との組み合わせにおける治験用ワクチンmRNA-4157-P201（モデルナ社）は、完全切除後の高リスク黒色腫における補助療法として画期的治療薬に指定されました。mRNA ワクチンがCOVID-19で成功したことから、研究者はmRNAワクチン技術ががん細胞の治療に応用できると確信しています。では、がん治療にmRNA療法が取り入れられる日は近いのでしょうか。

Coming full circle — mRNA vaccines and cancer

To many, it may seem like the COVID-19 mRNA vaccines were developed overnight. Yet, the rapid design, manufacturing, and testing of these vaccines would not have been possible without years of research forming the groundwork for flu, Cytomegalovirus, and Zika vaccines.

In 1995, pivotal research demonstrated that an intramuscular injection of naked RNA encoding carcinoembryonic antigens could elicit antigen-specific antibody responses in mice. The following year, a separate study showed that mRNA-transfected dendritic cells injected into tumor-bearing mice induced T-cell immune responses and inhibited the growth of those tumors. This work paved the way for numerous studies exploring the feasibility, efficacy, and safety of mRNA-based technologies. However, until recently, instability, innate immunogenicity, and inefficient in vivo delivery have limited mRNA vaccine and therapeutic applications. A key challenge faced by researchers was how to deliver mRNA to where it needed to go; an mRNA sequence injected into the body without some form of protection would be recognized as a foreign substance and destroyed.

The rapid development of mRNA vaccines to treat the novel coronavirus, SARS-CoV-2, has helped accelerate mRNA vaccine use from bench to bedside. For instance, the Pfizer-BioNTech and Moderna vaccines demonstrated the effectiveness of utilizing lipid nanoparticles (LNPs) for delivering mRNA to target cells. At the end of 2019, stimulated by the SARS-CoV-2 epidemic, both published literature and patent applications relating to mRNA therapeutics quickly rose worldwide. After 2020, the number of published papers showed a rapid growth trend, increasing to 3,361 in 2021 and nearly 5,000 in 2022. The number of patent applications continued its upward trend after 2020, reaching 382 in 2021, and is estimated to have increased to 510 in 2022 (Figure 1).

The success of the COVID-19 mRNA vaccine has revealed the potential of the mRNA platform not only for expansion to other infectious diseases but also for cancers. With insights from virus studies potentially informing work on cancer vaccines, it appears we’ve come full circle.

Recruiting the immune system — how mRNA cancer vaccines work

The applications of mRNA in cancer vaccines are broad, with researchers exploring several strategies for cancer immunotherapy:

• Antigen presentation: mRNA vaccines deliver cancer antigens to antigen-presenting cells (APCs) for the presentation of major histocompatibility complex class I and II.
• Adjuvant function: mRNA stimulates immune activation by binding to pattern recognition receptors expressed by APCs.
• Antigen receptors: mRNA introduces antigen receptors such as chimeric antigen receptors (CARs) and T-cell receptors into lymphocytes.
• Protein production: mRNA allows the expression of immunomodulatory proteins, including toll-like receptors, chemokine receptors, co-stimulatory ligands, cytokines, chemokines, and different monoclonal antibody formats into various cell subsets.

Is mRNA cancer therapy within reach?

Companies such as Genentech, CureVac, and Moderna are developing mRNA vaccines with encoding neoepitopes that can elicit immune responses against target tumors. Dozens of clinical trials are testing mRNA vaccines either as monotherapies or as part of a combination treatment in people with various types of cancer, including pancreatic cancer, colorectal cancer, and melanoma. Several candidates have entered Phase 2 trials, demonstrating favorable efficacy in melanoma, non-small cell lung cancer, and prostate cancer (Table 1).

Table 1. mRNA vaccines in cancer clinical trials (Phase 2 and beyond)

While mRNA cancer vaccines are garnering interest within the research community, most oncology research has historically focused on mRNA therapeutics, with a wide variety of candidates entering clinical development (Table 2), including:

• TriMix-MEL (eTheRNA Immunotherapies), a mixture of three mRNAs that activate key immune cells against cancer.
• An mRNA therapeutic (BioNTech) encoding a monoclonal antibody targeting claudin 18, a protein expressed in multiple cancers.
• An LNP-encapsulated mRNA (MedImmune LLC) administered by intratumoral injection designed to drive local interleukin-12 (IL-12) production and induce anti-tumor immunity.

Table 2. mRNA therapeutic products in cancer clinical trials

Making mRNA cancer vaccines a reality

We have made great strides in mRNA cancer technology in recent years, but some fundamental challenges remain. Firstly, mRNA cancer vaccines need specific packaging and delivery systems with an appropriate affinity for the target tissue/organ. Researchers are currently evaluating approaches to facilitate this, including the conjugation of organ-targeted moieties to oligonucleotides. Though LNPs are the most studied vehicles for mRNA delivery, their clinical application has been impeded by cytotoxicity concerns and their relatively short circulation time. Therefore, various alternative smart delivery systems (e.g., exosomes) are being evaluated to improve the bioavailability, loading, and release of the mRNA cargo.

Successful delivery of the mRNA cargo is not enough. To ensure maximal efficacy, researchers have been investigating approaches to enhance protein expression in vivo. All parts of the mRNA—the cap, 5′, and 3′ regions, open reading frame, and polyadenylated tail—can be optimized to augment protein expression. Chemically modified nucleosides have shown promise in this area.

In addition to the amount of protein expression, a crucial hurdle of mRNA vaccines is the relatively short period of protein production, which requires repetitive administrations. Self-amplifying and circular mRNAs are being explored as strategies to prolong the RNA lifespan and raise the total protein yield.

Though much work remains to be done, mRNA vaccines are a versatile clinical option for treating several cancer types when used alone or in combination with existing therapeutic options, such as checkpoint inhibitors. While we anticipate the arrival of the first mRNA therapeutics to market, it will be exciting to explore the outcomes from the multitude of innovative strategies seeking to tackle the global burden of cancer.

To learn more about mRNA vaccines and therapeutics, read our peer-reviewed journal publication in ACS Pharmacology and Translational Science.

Download the full Chinese report collaboration between the National Science Library of the Chinese Academy of Sciences and CAS.