Original closed-loop immunotherapy: Merck acquires Moderna oncology vaccine

News events

Today, Merck announced that it will acquire the co-development rights of Moderna (MRNA) black tumor vaccine mRNA-4157 for $250 million, and the two companies will jointly undertake the development investment and share the commercial benefits
.
M&M has been working together since 2015, when Big M paid Little M (of course, MRNA was worth nearly $200 billion last year, surpassing Merck) $50 million
.
In 2018, the two expanded their collaboration, and now 4157 has a Phase II clinical trial of KN942 in maintenance therapy for evil black in combination with Merck Sharp & Dohme Dynasty Drug, which is about to release some data
.
Affected by this news, MRNA rose by 10%.

Drug source analysis

MRNA has made a lot of quick money in the past two years because of the new crown vaccine, and its market value once entered the world's top 10 pharmaceutical companies, but with the stability of the new crown epidemic and the global stock market entering the trough, MRNA has also shrunk by 70%.

Rebuilding brilliance can not be expected to be a new crown vaccine A product, other viral infection mRNA vaccines such as influenza vaccine and other technologies seem to have no advantages over other technologies, and the expansion to the field of therapeutic tumor vaccines has become an important growth point, which is also a core goal
in the early days of mRNA technology.
And Merck's K medicine is expensive as the medicine king (King Keytruda), but response rates are still relatively low in most tumors, and expanding response rates through combination therapy is an important strategy
to continue to grow.

Current immunotherapies mainly focus on T cell activation, such as PD-1 antibody to alleviate killer T cell failure, CTLA4 antibody to relieve Treg inhibition, and CAR-T artificially creating a kill scene
.
But T cells are only part of the immune response, and just like the team's forwards, no matter how hard they train to increase their speed, the effect is limited
if there is no improvement in the level of organization in the midfield.
The immune system has become highly complex after hundreds of millions of years of evolution, and it is therefore very complex
for drugs to comprehensively improve the level of tumor immune response.
But the simple fact is that the immune system is optimized primarily to deal with microbial infections, not to prevent tumorigenesis
.
Because tumors occur many years after childbearing age and have little impact on species survival, trauma and infection are the first threats
to animal survival.
Evolutionary optimization is related to species survival, so it is necessary to find the optimal solution under the existing diversity limitation, so a simple and practical strategy for tumor immunotherapy is to draw on the anti-infection immune response
.

Microbial infection begins with infected cells, first the natural immune response is simple and crude to control the spread of local infection, and then through training the acquired immune system to complete, long-term, system-wide control of invading microorganisms
.
Although there are some steps in this procedure that are not yet clear, I believe in the power of evolution and the best procedure
for removing damaged cells.
MRNA's tumor vaccines are mainly aimed at so-called neoantigens, that is, personalized antigens unique to each patient (as opposed to tumor-associated antigens, which are available to all).

The mRNA vaccine enters tumor cells, expresses proteins, and then presents them to the cell surface to attract the attention of the immune system, a process very similar
to microbial infection.
If we believe that the human immune system, however complex, is designed to fight every step of the way peer-to-peer against microbial infections, then mRNA tumor vaccines can be counted as an integral part of
closed-loop immune activation.
This activation strategy, which begins with tumor cells, may activate the tumor immune response more comprehensively and in a balanced manner than unilaterally activating downstream T cells, including regulatory details
that we don't yet understand.

A major feature of tumors that do not respond to PD-1 drugs is that there are not enough abnormalities (or other inhibitory mechanisms) in TME to attract T cell invasion, and the lack of training and coordination of innate immunity is also one of
the reasons for insufficient tumor-specific T cell activity.
On the one hand, mRNA vaccines can controllably allow tumors to express a large number of mutant proteins as neoantigens, and on the other hand, they can activate the natural immune system through the PRR system, so the combination of the two may make cold tumors hot and expand the response rate
of PD-1 drugs.
Another similar strategy is to use real infections such as oncolytic viruses and oncolytic bacteria to create incidents in tumor TME and enhance the immune response, and there are many clinical trials of these therapies in combination with PD-1 drugs
.
Although these technologies are fascinating in theory, they require a lot of painstaking exploration in operation, which is also an aspect
of defining druggability.
The strong cooperation of top companies such as M&M is a positive event
to accelerate progress in this field.

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