mRNA vaccine second half: Moderna has switched to cancer treatment, clinically reducing the risk of recurrence and death by 44%.

At the top of the 2021 MIT Technology Review list of the "Top 10 Global Breakthrough Technologies" list is mRNA vaccines
.
Ugur Sahin, co-founders of BioNTech, once said: "The launch of an mRNA cancer vaccine may not be available until around
2030.
"The mRNA vaccine has been shown to activate the body's immune response
by delivering the genetic code to the body, allowing cells to produce antibodies.
Then, the same principle should be able to be tested in the fight against tumors, and by vaccinating against cancer, the body will be able to activate the immune system to attack tumor cells
.

The most powerful weapon against malignant tumors is the human immune system
.
However, cancer often "tricks" our immune system, but proper treatment can "arm/awaken" our immune system to fight the tumor
.
The purpose of cancer vaccination is to activate the host immune system and induce the immune system to target cancer cells, thereby destroying tumor cells
.
In the field of mRNA oncology vaccines, BioNTech is developing mRNA therapies
for rectal, melanoma and other cancers.
Moderna has teamed up with Merck to develop and market a personalized precision treatment cancer vaccine
.
The vaccine is based on Moderna's mRNA technology and is used in combination with Merck's star oncology therapy, Keytruda (K Drug), to treat high-risk melanoma patients
.

Together with Merck, Moderna applies mRNA technology to cancer treatment

Merck and Moderna have been working together on cancer treatment trials
since they formed a "strategic partnership" in 2016.
On October 12, 2022, Merck and Moderna signed a $250 million partnership agreement for the joint development and commercialization
of the Personalized Cancer Vaccine (PCV) mRNA-4157/V940 。 On December 13, Moderna's official website announced that the combination of personalized cancer vaccine mRNA-4157/V940 and PD-1 inhibitor Keytruda showed that compared with Keytruda monotherapy, it can significantly reduce the risk of recurrence or death in stage III and IV melanoma patients after complete tumor resection by 44%!

Figure 1 Moderna official website announcement (Source: Moderna official website)

The mRNA-4157/V940 cancer vaccine contains a single synthetic mRNA molecule encoding 34 neoantigens that are algorithmically designed based on the unique DNA sequence mutation characteristics of each
patient's tumor.
When this cancer vaccine is injected into the body, the neoantigen sequences carried by these RNAs are translated into proteins and through antigen presentation in the body, stimulating the production of T cell anti-tumor responses
.
It takes about 45 days from the time the tumor sample is obtained to the time the patient is treated
.
In this therapy, nine doses of mRNA-4157/V940 vaccine are injected every three weeks, and a course of Keytruda
is injected every three weeks.

Figure 2 The action process of cancer vaccine (Source: BioExploration Editorial Team&[1])

The published KEYNOTE-942/mRNA-4157-P201 trial is an open-label Phase 2b trial with 157 patients enrolled
.
Data analysis showed that compared with Keytruda monotherapy, cancer vaccine and Keytruda improved the primary endpoint of the trial, recurrence-free survival
, after complete tumor resection in patients with stage III and IV melanoma.
This combination reduced the risk of recurrence or death by 44% (HR: 0.
56, 95% CI: 0.
31 to 1.
08, unilateral P = 0.
0266).

The safety profile was also consistent with previous trials, with serious treatment-related adverse effects seen in the combination therapy versus Keytruda monotherapy groups of 14.
4% and 10%,
respectively.

If the therapy is approved, it can be very expensive
.
A similar cancer vaccine being tested costs about $100,000 (696,000 yuan)
per shot.
Moderna said: "This vaccine uses the same technology as the new crown mRNA vaccine, so its safety has been verified
to a certain extent.
This clinical result is a huge advance in the application of mRNA vaccines, which will open a new paradigm for the treatment of
cancer with mRNA vaccines.
We plan to initiate Phase 3 clinical trials in melanoma patients next year and expand this therapy to other tumor types
.
”

Who else is deploying neoantigen cancer vaccines outside of Moderna?

At first, the cancer vaccine was not successful, and after seeing high levels of adverse reactions and low efficacy, enthusiasm and interest in the technology declined
.
However, with the development of sequencing technology, innovative delivery systems, bioinformatics data processing technology, and vaccine adjuvants, cancer vaccines have an increasingly prominent opportunity to penetrate the market
.
In 2021, the market size of cancer vaccines was estimated at $10.
72 billion, and it has reached $16.
47 billion
in 2022.
Cancer vaccines have begun to form a separate branch of industry
.
At present, there are five main platforms for the research and development of cancer vaccines: neoantigen platform, oncolytic virus platform, tumor-associated antigen platform, antigen essence platform and whole cell platform
.

Figure 3 Five major cancer vaccine platforms (Source: BioDiscovery Editorial Team &[2])

Moderna uses the cancer vaccine neoantigen platform
.
Neoantigens are vaccines based on specific classes of antigens, including antigens produced by tumor viruses integrated into the genome and antigens
produced by mutant proteins.
These antigens are only abundantly expressed in cancer cells and have high immunogenicity and tumor heterogeneity
.
At present, a considerable number of neoantigens have been discovered, which are specific to tumor cells and are not affected by
immune tolerance mechanisms.

Figure 4 Introduction to neoantigens (Source: BioExploration Editorial Team&[2])

There is currently no approved neoantigen cancer vaccine
.
According to ClinicalTrials.
gov search results, there are 190 neoantigens in the pipeline, but none of them have entered phase III clinical trials (HPV-vaccine is not considered).

There were 30 more neoantigen studies in 2022 compared to the search results in the third quarter of 2021, indicating a huge increase
in market interest in cancer vaccine platforms.

Figure 5 Status of global neoantigen R&D companies (Source: BioExploration Editorial Team&[2])

Research into neoantigen therapies started relatively late and is still in the laboratory phase
.
The Genocea Biosciences GEN-009 vaccine trial (NCT03633110) is currently undergoing Phase I/IIa clinical trials
.
The purpose of NCT03633110 is to evaluate the safety, tolerability, immunogenicity, and antitumor activity
of the GEN-009 individualized vaccine for the treatment of patients with solid tumors.
So far, 40 doses of the vaccine have been administered with no dose-limiting toxicity, and vaccinated patients have not relapsed
.
With an estimated completion date of December 2022, GEN-009 is currently the most effective cancer vaccine
for personalized neoantigens.

BioNTech and Moderna are leaders
in developing neoantigen-based cancer vaccines.
BioNTech has six cancer vaccines in development, all sharing neoantigens (FixVac platform) and sharing two individualized approaches (iNeST platform) with Genentech; Achilles Therapeutics develops precision T cell therapy
against clonal neoantigens.
Currently, the company has two vaccines in phase I/IIa clinical trials: Chiron, for the treatment of advanced non-small cell lung cancer, and Thetis, for the treatment of melanoma, to evaluate the safety and clinical activity of neoantigen-responsive T cells; Transgene completed a Phase I clinical trial of the personalized neoantigen vaccine TG4050 in ovarian and head and neck
cancers.
This cancer vaccine is based on Transgene's myvac® platform and is powered by advanced artificial intelligence capabilities; Granite and Slate are two cancer vaccines
developed by Gritstone Oncology.
Both drugs are currently in Phase I/IIa clinical trials for the treatment of different types of solid tumors
.

Figure 6 Neoantigen cancer vaccine under development (Source: Deep-pharma)

The first phase of neoantigen vaccine development is complex and time-consuming
.
Even though genomic and transcriptome sequencing technologies are actively evolving, bioinformatics processing of data remains extremely challenging
.
As a result, it will face both the complexity of the neoantigen platform and the cost, speed, data storage, and analysis of
sequencing.
However, with the widespread introduction of digitalization, artificial intelligence, robotics and data storage technologies, these problems will be at least partially alleviated
, if not fully solved.

Figure 7 Step-by-step scheme for neoantigen cancer vaccine development (Source: BioDiscovery Editorial Team&[2])

Merck's combination therapy with Moderna's mRNA-4157/V940 and PD-1 inhibitor Keytruda has good development prospects
.
PD-1 inhibitors have been developed for immune evasion of tumor cells, which can activate T cell activity and induce the secretion
of immunogenic factors.
This solves the problem that
neoantigen vaccines are difficult to activate the T cell immune response.
Therefore, the combination of the two will become a new strategy
for the application of neoantigen vaccines.
Dendritic cell vaccines in combination with immune checkpoint inhibitors have shown significant clinical advantages
in the treatment of both solid tumors and hematological tumors.