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Nobel Prizes are not awarded to the dead, with the obvious exception
of Ralph Steinman.
As one of the discoverers of dendritic cells (DCs), Steinman was also "fed back" by his research, extending his life expectancy after cancer by more than 4 years
.
Although Steinman missed the 2011 Nobel Prize in Physiology or Medicine, he did not miss the launch
of Sipuleucel-T.
This autologous DC vaccine, which reduces the risk of death in patients with advanced prostate cancer by 45%, is the first therapeutic tumor vaccine
approved by the FDA.
Before 2010, there was another blockbuster vaccine, which is now a hard-to-find HPV vaccine, which belongs to preventive tumor vaccines
.
The above progress seems to lay the groundwork
for the future of tumor vaccines.
However, in the next decade, standing at the center of the stage of cancer immunity, it is antibodies
that will first usher in an outbreak.
Also dormant is mRNA technology
.
mRNA was discovered in the 60s, but it was not until the last decade that related trials
began to be launched.
Until a sudden epidemic, mRNA vaccines successfully broke through many technical bottlenecks and became
famous.
The Pfizer vaccine Comirnaty was able to squeeze out Humira and smoothly sit in the position
of "medicine king" in 2021.
The window period of new crown drugs is short, this tens of billions of revenue is destined to be short-lived, mRNA technology should have a wider range of applications, and vaccine manufacturers also urgently need new revenue growth drivers
.
Poor is changing, tumor vaccines have returned to people's sights again
.
Recently, Merck made the option to cooperate in the development of Moderna's personalized tumor vaccine mRNA-4157, and another vaccine giant, BioNTech, also said that mRNA tumor vaccines have made a breakthrough and are expected to be launched
in 2030.
We want cancer to be overcome, and we want people to have access to affordable cancer drugs
.
Perhaps mRNA oncology vaccines still have a long way to go before cancer can be cured, but the combination with existing therapies has given this hope some light.
1 Find the perfect antigen
1 Find the perfect antigen Oncology vaccines, in short, are immunotherapies
that strengthen the immune system so that it can prevent, recognize and destroy cancer cells.
As a spontaneous disease, cancer is only a few caused by foreign viruses, so the development scope of preventive tumor vaccines is limited, but on the other hand, the inherent mutation of cancer cells also creates its unique antigen targets and future generations, and therapeutic tumor vaccines are to treat cancer
by targeting tumor antigens and amplifying tumor immune responses.
Theoretically, therapeutic tumor vaccines have a wider range of applications and are expected to achieve breakthroughs in the treatment of solid tumors, but compared with the great success of HBV vaccine to prevent hepatitis B virus and HPV vaccine to prevent human papillomavirus in the prevention of liver cancer and cervical cancer, the former is still in its infancy and has only shown limited efficacy
in clinical tests.
Approved cancer vaccine (Source: Reference 2)
In tumor immunity, antigens have always been the focus of
research.
There are two types of antigens secreted by tumors: tumor-associated antigens (TAAs), which are highly expressed in tumors and low in healthy tissues; Tumor-specific antigen (TSA), a neoantigen produced by tumor cell mutations, is only expressed in tumors and is highly immunogenic
.
Most trials have focused on TAA, such as MUC-1, HER2/neu, p53 and hTERT
.
This is one of the reasons why the development of therapeutic tumor vaccines has been repeatedly frustrated, because most of them have been naturally tolerated, causing only a weak anti-tumor response, in addition to the risk
of autoimmune toxicity.
Of course, it must be admitted that TAA also has highlight moments
.
At the 2020 San Antonio Breast Cancer Conference, Greenwich announced the phase II clinical data of the GP2 vaccine, and the five-year disease-free survival rate of HER2/neu3-positive breast cancer patients after surgery reached an astonishing 100%, and the recurrence rate was 0%.
The GP2 vaccine is amazing, but it is clear that the properties of neoantigens such as escape tolerance, stronger immunogenicity and MHC affinity are more attractive
to scientists.
Animal tests and clinical studies have shown that if neoantigens can be successfully presented to the cell surface by antigen-presenting cells, and recognized and bound by the TCR of T cells, they can successfully cause an immune response to tumors and produce memory effects, partially or completely eliminate tumors, and effectively prevent recurrence
.
.
In addition, mutations have characteristics, and neoantigens differ in type and quantity even in the same individual, showing strong individual differences, so personalization is a trend
.
Two independent studies released by Nature at the same time in 2017 are milestone breakthroughs in personalized treatment, and the results show that after receiving tumor vaccines, more than 50% of patients' tumors completely disappear, and after relapsing patients combined with immune checkpoint inhibitors, tumors also completely disappear, and the efficacy can last for more than
4 years.
Although the effect of private customization is good, it is necessary to carry out tumor tissue biopsy, sequencing and analysis of tumor cells, and screen out the neoantigens that are most likely to "win", and then carry out the design and production
of tumor vaccines.
This will undoubtedly lead to an increase
in production and treatment costs.
One of the reasons for the failure of Sipuleucel-T is that the efficacy is not long-lasting and the price is expensive
.
But from another aspect, there are also some neoantigens expressed at high frequencies
.
When there is enough sequencing analysis, it may be possible to build a shared library of neoantigens - mutant antigens that are common in different cancers
and do not exist in the normal genome.
and do not exist in the normal genome.
Sharing means fast, mass production, both in terms of indications and accessibility, to reach more patients
.
But as Dr.
Shen Dong, founder and president of Crown Biologics, said: "There are too few such antigens to meet
.
" ”
Shen Dong, founder and president of Crown Biologics, said: "This antigen is too few to be sought
.
”
Opportunities for 2 mRNA oncology vaccines
Opportunities for 2 mRNA oncology vaccines mRNA is located upstream of the central law and can encode almost any protein, directly directing the expression
of downstream proteins.
Compared with other types of vaccines, mRNA vaccines are more immunogenic, and entering the body can cause humoral immunity and cellular immunity at the same time, and self-adjuvants can also induce innate immune responses; In addition, the manufacturing process is simple and the production is fast
.
Less than a year after the outbreak, Moderna and Pfizer/BioNTech have launched a vaccine at an incredible pace, as the fastest vaccine took about 4 years to hit the market
.
Pfizer's CEO even wrote a biography to document the speed of life and death; In the landing of the product, the mRNA vaccine has also successfully verified its safety - no need to enter the nucleus, no risk of integrating the host genome, and can be degraded
by normal cells.
The mRNA vaccine has opened a path
for the development and regulation of mRNA vaccines.
However, the wind is not good, and the new crown track is already crowded with competitors
.
To see far in order to go far, the rudder must be turned
.
In September 2021, the Boston Consulting Group published a study that analyzed 180 research pipelines from 31 mRNA companies and showed that the development of therapeutic mRNA vaccines is mostly focused on tumor immunotherapy
.
In the next 2035, it is predicted that mRNA drugs will reach a market size of $23 billion, and mRNA tumor therapeutic vaccines will be divided into more than 30%.
.
In the next 2035, it is predicted that mRNA drugs will reach a market size of $23 billion, and mRNA tumor therapeutic vaccines will be divided into more than 30%.
mRNA Drug Market Forecast (Source: Nature Reviews Drug Delivery)
Based on antigen, mRNA oncology vaccines can be divided into universal and personalized mRNA oncology vaccines
.
The mRNA oncology vaccine that has entered the clinic is both
.
.
Incomplete statistics on clinical progress of tumor vaccines (Source: CITIC Securities)
The mRNA-5671 developed by Moderna, based on LNP delivery, encodes four mutant antigens, G12D, G12V, G13D, and G12C, basically covering 80% of the mutation types
of KRAS mutations.
It is used for the treatment of non-small cell lung cancer (NSCLC), colorectal cancer, pancreatic cancer with KRAS mutations, and is currently in clinical phase
I.
In 2018, Merck acquired its interest in a $125 million preferred equity investment, but two years later, Merck terminated the drug's partnership
.
BNT113, developed by BioNTech for the treatment of HPV16-positive head and neck squamous cell carcinoma, and BNT111 for the treatment of melanoma, have both entered phase II clinical trials
.
In the case of BNT111, it encodes 4 melanoma-associated antigens, covering more than 90% of the mutation range
of melanoma.
According to phase I data, the ORR of monotherapy reached 16%, and the ORR of combined PD-1 monoclonal antibody reached 35%, which has been fast-track designation
by the FDA.
In clinical phase I, BNT112 for prostate cancer and BNT115
for ovarian cancer are in clinical stage.
There are two representatives of personalized mRNA oncology vaccines under investigation, namely Moderna/Merck's mRNA-4157 and BioNTech/Genentech's BNT122, both of which have entered clinical phase
II.
mRNA-4157 contains up to 34 tumor antigens and has a wide range of indications, including melanoma, bladder cancer, HPV, NSCLC, SCLC, etc
.
In a phase II trial, mRNA-4157 is used as an adjuvant therapy in combination with Merck's K-drug for the treatment of high-risk melanoma patients, and data
are expected in the fourth quarter of this year.
In a previous KEYNOTE-603 trial, mRNA-4157 in combination with K increased mPFS to 9.
8 months in patients with head and neck squamous cell carcinoma, a 100%
improvement over first-line standard treatment.
BNT122 contains 20 neoantigens and is based on BioNTech's proprietary RNA-lipoplex intravenous delivery
.
At the 2022 ASCO meeting, BioNTech announced positive Phase I results for BNT122B in combination with the PD-L1 inhibitor atezolizumab and chemotherapy, with 50% of patients relapse
free after 18 months.
Freehand Yijun once asked, which is the mainstream of personalized or universal tumor vaccines? Dr.
Shen Dong, the founder of Crown Biologics, replied that both are indispensable and complementary to
a certain extent.
Shen Dong, the founder of Crown Biologics, replied that both are indispensable and complementary to
a certain extent.
"Personalized tumor vaccines can effectively give full play to the advantages of multi-antigen combination of mRNA technology, attack multiple targets, and have good
therapeutic effects.
" However, there is huge genetic diversity between tumors, and it is not easy to predict neoantigens expressed only in tumors, and private customization will bring a lot of burden to patients; Although the cost of universal tumor vaccines is low, because it targets a single target, it is easy to have immune evasion and tolerance, which makes the efficacy lacking
.
"From the perspective of enterprises, priority is given to druggability and coverage of the patient population, and from the perspective of patients, we hope to use drugs with better efficacy, but it is true that price is an obstacle
.
" I think that the increase in shared neoantigens can balance the needs of the two
.
Dr.
Shen Dong said
.
.
3 On 1+1>2
3 On 1+1>2 In order to survive, the tumor staged "infernal affairs"
in the battle with the immune system.
Whether by expressing PD-L1 or recruiting immunosuppressive cells such as regulatory T cells and M2 macrophages, the ultimate goal is immune escape
.
The highly immunosuppressive microenvironment leads to the incompetence and depletion of T cells and the inability to kill tumors, so the tumor microenvironment is also known as another important battlefield
between tumors and the immune system.
Immune checkpoint inhibitors, represented by PD-(L)1 monoclonal antibodies, have been shown to affect the tumor microenvironment and have the potential to
reactivate and expand existing T cells or induce new anti-cancer immune responses.
However, clinical trials have shown that immune checkpoint inhibitors have low
response rates in many cases.
Therapeutic tumor vaccines can improve local immune cell composition and restore tumor immune surveillance
.
When the activated T cells enter the tumor tissue, they secrete IFN-γ and upregulate the expression of PD-L1 on the surface of tumor cells, thereby increasing the response rate
of PD-(L)1 monoclonal antibody.
In the above trials, it is not difficult to see that the treatment effect of tumor vaccine combined with PD-(L)1 monoclonal antibody is significantly better
.
.
The PD-(L)1 track is crowded and the battle for indications is becoming increasingly fierce, broadening the scope of indications and pushing to the front line has become the road
that has to be taken to break the "involution".
Therefore, behind the research and development of tumor vaccines, in addition to vaccine manufacturers, many PD-(L)1 monoclonal antibody owners can also be seen, such as Merck, Innovent Biologics, BeiGene and other companies have relevant cooperation
.
Top 20 enterprises with oncology vaccine pipeline layout
In addition to monoclonal antibodies, another major research direction in cancer immunity is adoptive cell therapy
.
This therapy requires the isolation of immunocompetent cells from the patient, inducing their differentiation in vitro, recombining, expanding, and then infusion into the patient's body to target antigen-specific tumor cells and exert their tumor suppression and tumor suppression effects
.
CAR-T therapy is one of
them.
However, although CAR-T therapy can alleviate the condition well, there are problems such as poor persistence, cytotoxicity, and may cause a storm
of inflammatory factors.
The addition of tumor vaccines enables CAR-T cells to be rapidly activated and expanded to improve the therapeutic effect
.
This brings room for the decline in the amount of CAR-T cell injection, after all, the larger the dose, the higher the
risk of toxicity.
In addition, when CAR-T cells fail rapidly, if the tumor is still growing, how to maintain the efficacy? Whether from the perspective of price or the patient's physical burden, another dose of
CAR-T cells is obviously impractical.
The tumor vaccine can act as a "booster shot" at this moment, and repeated vaccination can maintain immune cells in the body at a high therapeutic level
.
In terms of price, the cost of mRNA tumor vaccines is far less than that of CAR-T therapy, and can be reproduced in large quantities, which is one of the potential options for maintaining the efficacy of
CAR-T.
.
Of course, not limited to this, oncology vaccines can also be combined
with chemotherapy/radiotherapy and other methods.
In addition, tumor vaccines are more
effective in treating and preventing recurrence than when the tumor has reached a certain level or when metastasis has occurred, and when used in the early stages of the disease (such as during adjuvant therapy).
4 Challenges and prospects
4 Challenges and prospects Decades ago, American television did a survey asking people which was easier to achieve
by landing on the moon or conquering cancer.
Almost everyone thinks it's harder to get to the moon, but in fact, Apollo landed on the moon in 1969, but cancer has not yet been overcome
.
There are many bottlenecks waiting to be solved in mRNA oncology vaccines, but some problems have begun to be solved
.
Among them, as the basis for development, the prediction of neoantigens is still a pain point
.
Dr.
Shen Dong pointed out, "Neoantigens
should be deeply understood.
If we can broaden our horizons and include structural variants such as fusion proteins, we can expand the prediction range
of tumor neoantigens.
When there are more and more targets, more and more
neoantigens will be shared.
”
In addition, vaccine formulation is also related to the success
of a vaccine.
Especially for mRNA vaccines, the delivery system is not only related to targeting, but also closely related
to safety.
The side effects of the new crown vaccines of Moderna and Pfizer are likely to be vector-related, so the optimization and exploration of safer vectors will not stop
.
In terms of tumor vaccine design, the prediction of tumor neoantigens takes 3 months conservatively, and with the intervention of artificial intelligence and the accumulation of experience, the speed of this aspect can now be shortened to less
than 1 month.
In terms of production, the development
of vaccine printers has also begun.
As the name suggests, this is a kind of mini-factory, a container large enough to cover its size, to make mRNA vaccines
directly wherever needed.
It is reported that Tesla and Curevac launched relevant research and development cooperation
in 2020.
mRNA is an unstable molecule, so during transport, the temperature should reach at least -20 to -80 degrees Celsius
.
And there will be many problems
such as security checks during transportation.
The decentralized production of vaccine printers will bring solutions
.
In 2013, cancer immunotherapy was listed by Science as the top ten breakthroughs of the year, and under the new crown epidemic crisis, the application of mRNA vaccines has become an established fact, and this experience is bound to lay the foundation
for later oncology vaccines.
Whether a new therapeutic tumor vaccine will appear before 2030 cannot be determined for the time being, but I believe that under the grind of time, a new chapter of immunotherapy will open
sooner or later.
References:
References: References:
1.
Tumor vaccine: drunk to pick the lamp and look at the sword, who can be the first to break through?; Kelleying Pharma
Tumor vaccine: drunk to pick the lamp and look at the sword, who can be the first to break through?; Kelleying Pharma
2.
Grimmett E, Al-Share B, Alkassab MB, Zhou RW, Desai A, Rahim MMA, Woldie I.
Cancer vaccines: past, present and future; a review article.
Discov Oncol.
2022 May 16; 13(1):31.
doi: 10.
1007/s12672-022-00491-4.
PMID: 35576080; PMCID: PMC9108694.
Grimmett E, Al-Share B, Alkassab MB, Zhou RW, Desai A, Rahim MMA, Woldie I.
Cancer vaccines: past, present and future; a review article.
Discov Oncol.
2022 May 16; 13(1):31.
doi: 10.
1007/s12672-022-00491-4.
PMID: 35576080; PMCID: PMC9108694.
3.
Zhang Z, Lu M, Qin Y, Gao W, Tao L, Su W, Zhong J.
Neoantigen: A New Breakthrough in Tumor Immunotherapy.
Front Immunol.
2021 Apr 16; 12:672356.
doi: 10.
3389/fimmu.
2021.
672356.
PMID: 33936118; PMCID: PMC8085349.
Zhang Z, Lu M, Qin Y, Gao W, Tao L, Su W, Zhong J.
Neoantigen: A New Breakthrough in Tumor Immunotherapy.
Front Immunol.
2021 Apr 16; 12:672356.
doi: 10.
3389/fimmu.
2021.
672356.
PMID: 33936118; PMCID: PMC8085349.
4.
Cancer vaccines may be available before 2030! Founder of BioNTech: Breakthrough progress; Cailian
Cancer vaccines may be available before 2030! Founder of BioNTech: Breakthrough progress; Cailian
5.
Is the cancer vaccine unreliable? In fact, this is a history of repeated defeats
Is the cancer vaccine unreliable? In fact, this is a history of repeated defeats
6.
Exclusive Original | Challenges and prospects of mRNA oncology vaccine development; Advances in Pharmacy
Exclusive Original | Challenges and prospects of mRNA oncology vaccine development; Advances in Pharmacy
