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What the mRNA giants want to tackle most is cancer

 Last Update: 2023-01-06
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The highly anticipated cancer vaccine actually refers more to a "immunotherapy", and after the new crown, the mRNA technology path is moving from behind the scenes to the front
.

In August last year, Moderna and BioNTech, which successively broke through the market value of hundreds of billions, once rushed into the top 15 of the global pharmaceutical company market value
rankings hand in hand.
But just a year later, Moderna was slashed, and BioNTech was even left to the knee
.
The two major mRNA vaccine manufacturers entered the dormancy period at the same time, concentrating on sharpening their knives, preparing to continue to cut
each other in the next outlet - cancer vaccines.

On October 15, Uğur, founder of BioNTech In an interview with the BBC, the Şahins mentioned that they have made some breakthroughs in the field of cancer vaccines, and the results will be available
by 2030.
It's hard to say that this move is not-for-tat, because just 3 days before the report was issued, Moderna had just announced the joint development of a cancer vaccine
with Merck.
And the effect was immediate in the secondary market, with Moderna's stock price jumping nearly 12%
at the opening of the next day.

Since the beginning of this year, the shares of Moderna and BioNTech have both fallen by more than 40%, and the two companies are like a pair of anti-purpose brothers, genetically and with the same experience, but with opposite
attitudes.

mRNA technology is the link of blood, but it has been distorted
by the pandemic.
The huge wealth brought by the mRNA new crown vaccine is like a family inheritance that appeared out of thin air, leading the brothers to go to court
.
Moderna sued BioNTech in late August, arguing that its Covid vaccine "Comirnaty" with Pfizer infringed its own technology patents, but stressed that it did not seek to remove Comirnaty from the market or ban it
.

In fact, the value of the Comirnaty vaccine has almost been squeezed dry, considering the huge potential of mRNA technology, the new crown vaccine is only a dessert
at best.
BioNTech and Moderna's cancer vaccine race could well create the next blockbuster
in mRNA technology.

It is worth noting that this type of cancer vaccine is not a preventive vaccine in the traditional sense, but a therapeutic vaccine
.
If such vaccines are successful, it is foreseeable that the boundaries between mRNA vaccine manufacturers and innovative pharmaceutical companies will no longer be clear in the future, and investors seem willing to pay for this "transformation
".

In fact, as early as two years before the outbreak of the epidemic, cancer vaccines had already accumulated a certain amount of technology, and the main technical path was not mRNA
at that time.
But the pandemic gave mRNA the best stage to complete the proof of concept, and also created two capital myths
, Moderna and BioNTech.

Now that the coronavirus dividend is starting to fade, the few manufacturers with mRNA technology will also be freed up to explore how to develop cancer vaccines and combine them with existing therapies to obtain better clinical data
.
Moderna and BioNTech, two companies that are fighting each other because of new crown vaccine patents, may also have to save the future cancer field to divide the victory
.

01 Cancer vaccines are difficult to prove themselves

The cancer vaccine that mRNA manufacturers have high hopes for actually refers more to an "immunotherapy"
.

CDE released the "Technical Guidelines for Clinical Trials of Tumor Therapeutics Vaccines (Draft for Comments)" on October 9 this year, which defines cancer vaccines as follows: a class of products
that can control, kill tumor cells, remove small residual lesions, and establish lasting anti-tumor memory by inducing or enhancing the body's specific active immune response to tumor antigens.

In short, the principle of cancer vaccine as a treatment is to identify and destroy cancer cells
by activating the immune system.
The specific mechanism is to find some random mutations "incidentally" in the process of cancer mutations, which have little effect on the growth and replication of cancer cells themselves, so they will not be disguised by cunning cancer cells to deceive the body's immune system
.

Scientists call the proteins expressed in these mutations that trigger immune regulation "tumor neoantigens.
"
This is nothing new, or even the discovery of
this century.

As early as the early 90s, people began to work in
this field.
The researchers counted dozens of tumor antigens that may stimulate patients' immune defenses, which are usually expressed when cancer cells grow or spread, and are excellent tumor markers
.

But the end result was not satisfactory
.
Despite promising data from animal experiments, most cancer vaccines fail to stop tumors from growing
in humans.
These antigens may also be present in small amounts in normal cells, and cancer patients receiving chemotherapy can weaken the immune response, with the result that the immune system often turns a blind eye to these "neoantigens
".

This problem was not well overcome, so much so that it was only in 2008 that Russia first approved the world's first cancer vaccine, Oncophage, to personalize the treatment of early-stage kidney cancer, and this did not attract much attention
that year.
Even from today's perspective, Oncophage's approval may not be as important as BioNTech's founding
in the same year.

In fact, Russia's ratification does seem somewhat unconvincing in the West
.
In 2009, Oncophage, hoping to win the chase, was unexpectedly rejected by the European Council for Medicinal Products for Human Use, and the original manufacturer Agenus was forced to voluntarily withdraw its marketing application the following year, and instead slammed the FDA to seek a higher price in the US market
.
And after more than 10 years of unremitting efforts, this "first "in class" has now been listed as an orphan drug by the FDA and entered the fast track, but it has not been approved for marketing
.

In contrast, Sipuleucel-T's experience shows the dilemma
of cancer vaccines from a more "successful" perspective.
Sipuleucel-T became the first FDA-approved oncology vaccine in 2010 for asymptomatic or mild prostate cancer
.
Its original manufacturer is Dendreon in the United States Pharmaceuticals
。

It's not hard to imagine Sipuleucel-T and Dendreon Pharmaceuticals enjoyed a lot of praise and applause at the time, and labels like "epoch-making" and "milestone" were all over the place, but in fact, Sipuleucel-T impressed the FDA only because it extended the median survival of patients by 4 months in clinical trials, and correspondingly, patients had to pay a huge expenditure
of $93,000 per course of treatment.

Even more regrettable, Dendreon Even in 2015, when it declared bankruptcy, its Sipuleucel-T was bought by Valeant in Canada, and the price of $400 million cannot be said to be cheap, but it should obviously not be the price
of an epoch-making cancer treatment.

02 mRNA technology may be the best answer

For Moderna and BioNTech, mRNA-enabled cancer vaccines should have a higher ceiling and are expected to be the cornerstone
of their long-term support for hundreds of billions of dollars in the future.

Moderna and BioNTech currently have market capitalizations of about $55 billion and $33 billion, respectively, far from the $100 billion they were at their peak
.
The new crown is easy to fall, and the 100 billion market value experience card brought by the vaccine has a short shelf life, but mRNA technology still reaps huge benefits from it: an important proof of concept has been completed during the epidemic, and unprecedented capital support
has been obtained in the direction of cancer vaccines.
As a result
, mRNA technology has the opportunity to overtake in the new round of cancer vaccine competition.

At first, mRNA technology was not considered the mainstream technology
for cancer vaccines.
Back in 2017 Nature has actually reported two positive clinical results based on independent trials of neoantigen cancer vaccines: personalized vaccines tailored to tumor mutations have achieved significant success in the treatment of melanoma patients, but relying on tumor antigen peptide technology
.

In 2018 and 2019, according to the source and construction vector of tumor vaccines, tumor antigen peptides, viral vectors, dendritic cells, and nucleic acid vaccines including mRNA and other technical paths are secretly competing, each with its own advantages and disadvantages - until the new crown breaks the balance and mRNA technology stands out
.

In addition to the three high barriers of sequence design, delivery system, and scale-up production, mRNA was actually separated from tumor vaccines in the past by a thin veil
that was difficult to break.

The mechanism of action of mRNA vaccines begins with instructions to direct cells to make specific proteins (antigens), which then stimulate the immune system to recognize and produce antibodies
.
Once the protein is made, it means that the mRNA has fulfilled its mission, and scientists hope that it will break (degrade) on its own, but many times mRNA is not as well-behaved
as people hope.

If degradation does not occur, the cell will continuously produce specific proteins
.
For a long time, this "instability" became a major reason why
mRNA was difficult to use.
But in the new crown vaccine, this problem seems to be effectively solved, and this proof of concept is in mRNA is crucial
in the cancer vaccine story.

After all, in addition to the instability of degradation, mRNA technology does have many technical advantages
in cancer vaccines.
For example, mRNA comes with adjuvant function, and as an endogenous antigen, it can effectively stimulate the human body to produce killer T cells, which is a pain point that tumor peptide vaccines have been difficult to face; Or mRNA does not have the risk of genome integration and is safer, making next-door viruses and bacterial vector vaccines envious
.

More importantly, the new crown epidemic has made people see the incredible speed of research and development of mRNA technology, and the Moderna new crown vaccine took only 42 days from project approval to clinical phase I trial, which means that both the commercialization process and the cost can be greatly compressed
.

Zoltan Kis, an expert in mRNA vaccine production at the University of Sheffield "Compared to vaccines in other pathways, mRNA does not require the manufacture of real antigens, and the process of making mRNA does not require living cells, only involves enzyme synthesis reactions
.
”

Zoltan Kis's words actually bring another advantage of mRNA technology: as long as the infrastructure is in place, humans can theoretically synthesize any type of mRNA, which in turn instructs human cells to produce any cancer protein and achieve all types of cancer treatment
.

03 Combination medication is the development trend

Treating all types of cancer is currently theoretical, but it doesn't seem out of reach
.
The wonderful thing about cancer vaccines using "neoantigens" as an entry point is that they can be used to treat patients with unknown cancer types, and the recognition of mutations is the only prerequisite
.

However, from past experience, the clinical data of cancer vaccines is usually not very good
.
The success and failure of Sipuleucel-T are based on "extending median survival by 4 months", after all, the vast majority of cancer vaccines at the same time as Sipuleucel-T are due to III Phase II trials failed with no improvement in overall survival
.

First came Bavarian Nordic's prostate cancer PROSTVAC-VF virus vector vaccine, Galena Biopharma's breast cancer Neuvax Peptide vaccines have failed
one after another.
Merck then voluntarily terminated the trial of two Tecemotide peptide vaccines; Cell Genesys failed two GVAX One of the allogeneic tumor vaccines was even discontinued
due to increased risk of death.

There are two main reasons for clinical failure: on the one hand, the human body is difficult to produce an immune response to many "neoantigens", and on the other hand, even if it successfully triggers an immune response, cancer cells may still escape
.

In response to the problem of finding the perfect antigen, we are trying to make up for this deficiency by taking the route of personalized cancer vaccines and using new technologies such as artificial intelligence
.
For the problem of immune escape, the new generation of cancer vaccine companies has also begun to learn the lessons of the martyrs and began to seek combinations with anti-tumor targeted drugs to prevent cancer cells from escaping
.

It has finally been discovered that vaccines and PD-1 drugs are not competing
or substituting in the immunotherapy pathway for cancer.
Stimulating the autoimmune system to recognize cancer cells and eliminate cancer cell escape should lead to cooperation, 1+1 will be greater than 2
.

In October, Moderna's collaboration with Merck was actually a combination of Moderna's mRNA-4157 and Merck's K drug for the treatment of melanoma
.
mRNA-4157 is likely to be a bombshell
of the future.
According to public information, this is a personalized neoantigen cancer vaccine encapsulated in lipid nanoparticles, which can encode 34 neoantigens and has been pushed into clinical phase
II.

The data show that the control rate (DCR) of mRNA-4157 for malignant tumors is more than 90%, which has exceeded many immunotherapy listed drugs
.
And Moderna claims that this cancer vaccine is the same as The results of the phase II study of K drug combination therapy will be announced
before the end of this year.

The pressure came to BioNTech
.

BioNTech's flagship product BNT122 is also an mRNA-based personalized neoantigen-specific cancer vaccine, which is also clinical phase II, and can encode 20 patient-specific neoantigens
.
BioNTech's first partner was Roche's atezolizumab (PD-L1).

In the data released in June this year, BNT122 in combination with atezolizumab and chemotherapy has achieved positive results in phase I clinical trials for the treatment of patients with pancreatic cancer who have undergone surgical resection, and BioNTech executives have said that BNT122 is also expected to be used in other cancer types such as melanoma and colorectal cancer, laying the seeds
for direct competition with Moderna.

It is worth mentioning that in addition to the little brothers of Moderna and BioNTech, there is also a big brother CureVac founded in 2000 who has also been quietly cultivating in the field of mRNA, and Moderna and BioNTech are collectively known as the mRNA Big Three
.
After being left behind, CureVac doesn't want to miss out on cancer vaccines
again.

In June, CureVac spent more than $34 million to acquire a company called Frame Cancer Therapeutics" of Dutch Biotech, a company that is developing personalized oncology vaccines
for neoantigens.
And there is also a neoantigen platform
that attracts CureVac.

CureVac's CEO said in a statement, "Frame's bioinformatics platform has the potential to identify a range of neoantigens beyond traditional neoantigens, greatly increasing the likelihood of
developing highly effective cancer vaccines.
" ” The clarity of intent is on paper
.

When the new crown vaccine is a thing of the past, new hatred and old hatred, wealth and dreams, all point to the land of
blood and honey of cancer vaccines.
As for whether there will really be a new therapeutic tumor vaccine before 2030? We are eagerly waiting
.

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