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Chen Shuqing interview 8,000 words, take you to understand "tumor therapeutic vaccine"

 Last Update: 2022-10-25
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Interview summary

1.
The biggest difference between the development process of neoantigen tumor vaccines and other therapeutic tumor vaccines is the need to identify and obtain tumor neoantigens
individualized for patients.

2.
At present, Chinese scientists are leading in neoantigen analysis and vaccine design using artificial intelligence, while European and American scientists are leading
in clinical trials.

3.
CDE's release of the "Technical Guidelines for Clinical Trials of Tumor Therapeutic Vaccines (Draft for Comments)" proves that it has reached a critical period for the development of tumor therapeutic vaccines, and the intervention and vigorous promotion of the national regulatory system are needed to keep China ahead in this technology field and benefit more tumor patients
as soon as possible.

4.
It is expected that there will be a number of tumor therapeutic vaccines at home and abroad that will be applied for marketing
in the next 5 years.

Tumor therapeutic vaccines refer to a class of therapies
that induce or enhance the body's specific active immune response to tumor antigens, so as to control and kill tumor cells, remove small residual lesions, and establish long-lasting anti-tumor memory.

Therapeutic vaccines for tumors

With the sharp drop in the cost of gene sequencing, the development of artificial intelligence (AI) and mRNA technologies, tumor therapeutic vaccines have entered a new period of development, and a large number of pharmaceutical giants and biotech have joined the research and development of tumor therapeutic vaccines, for example, on October 12, Merck just paid $250 million
to license a cancer mRNA vaccine from Moderna.
According to the different antigen expression and presentation methods, tumor therapeutic vaccines include cell vector vaccines, viral vector vaccines, protein/peptide vaccines, nucleic acid (DNA or RNA) vaccines
, etc.
Due to the processing and presentation of antigens in vivo, lymphocyte activation and the killing process of tumor cells take a long time
.
Therefore, clinical trials of therapeutic oncology vaccines have many different considerations
compared to traditional cytotoxic drugs, targeted therapies or other immuno-oncology drugs.

Technical Guidelines for Clinical Trials of Therapeutic Oncology Vaccines (Draft for Comments), 21-page PDF (Source: CDE)

On October 9, in order to guide the development of clinical trials of domestic tumor therapeutic vaccines, the Center for Drug Evaluation (CDE) of the National Medical Products Administration recently issued the "Technical Guidelines for Clinical Trials of Tumor Therapeutic Vaccines (Draft for Comments)", a 21-page document that has aroused widespread attention
in the industry.

Why exactly did CDE issue the Draft at such a point in time? What are the important information provided by the Consultation Draft? Compared with other types of therapeutic tumor vaccines, what is unique about the development of "neoantigen vaccines" mentioned separately in the Draft for Comments? At present, what is the competition in the development of therapeutic tumor vaccines at home and abroad?

Why exactly did CDE issue the Draft at such a point in time? Compared with other types of therapeutic tumor vaccines, what is unique about the development of "neoantigen vaccines" mentioned separately in the Draft for Comments?

Professor Chen Shuqing, founder and chairman of Nuanjin

Recently, in response to these problems, PharmaCube Pro interviewed Professor
Chen Shuqing, the founder and chairman of Neoantigen, a pioneer company in the development of neoantigen vaccines for domestic tumors.
Professor Chen Shuqing proposed the concept of neoantigen-based therapy in China in 2005 and is one of the global leaders in the research and development of
neoantigen-related therapies.
In 2016, Professor Chen Shuqing founded Nuanjin, dedicated to the research and development
of personalized tumor vaccines.
Up to now, the company's fastest progress project, iNeo-Vac-P01 (an individualized peptide vaccine for tumor neoantigens), has completed a number of IIT studies in many hospitals and is about to apply for IND
.

I interviewed Professor
Chen Shuqing, founder and chairman of Neoantigen, a pioneer company in the development of neoantigen vaccines for oncology in China.
Professor Chen Shuqing proposed the concept
of neoantigen-based therapy in China in 2005.

In the 8-question interview, Professor Chen Shuqing gave a nearly 8,000-word answer, which not only popularized the development history of tumor therapeutic vaccines, analyzed the current status of research and development at home and abroad, and predicted the breakthroughs expected in the next few years; It also provides detailed answers to the unique challenges and irreplaceable advantages
faced by the research and development of neoantigen vaccines for tumors.
Here's a share of this exclusive conversation:

What signal does the latest CDE file release?

MedCube Pro: Why did CDE release the Technical Guidelines for Clinical Trials of Oncology Therapeutic Vaccines (Draft for Comments) at such a point in time? What kind of signal does this Draft send?

Professor Chen Shuqing: Human beings have long known that the natural enemy of tumors is human immunity
.
Once tumor cells are produced, immune cells clear them, which is a dynamic balance
that continues to occur in the body.
As long as the immune system is normal, the average person will not develop tumors
.
One hundred years ago, William Coley, a famous doctor known as the father of immunotherapy, used a mixture of inactivated Streptococcus pus and Serratia marcescensis filtration to treat tumor patients, and achieved efficacy in hundreds of patients, which is to use the properties of bacterial antigens to activate the immune system in
the body.
However, due to the large toxic effects caused by non-specific activation of the immune system, Coley toxin has not been promoted in the long term in clinical practice
.
In recent decades, scientists have invented antibody drugs, such as HER2 antibodies, CD20 antibodies, etc.
, which belong to passive immunotherapy, the principle of which is to use antibody drugs to target tumor-associated antigens on the surface of tumor cells, and then attract immune cells to kill tumor cells
.
This class of drugs has shown good clinical results and has been widely used
.
In recent years, scientists have also invented CAR-T technology, which uses transgenic technology to express the recognition region of antibodies on the patient's own T cells, so that the modified T cells become specific T cells that can target tumor cells
.
Its treatment effect is extremely significant, and some patients have been cured, but the treatment effect of CAR-T technology for patients with solid tumors is still not ideal
.
Another class of immune checkpoint inhibitor drugs, such as PD-1 antibodies, PD-L1 antibodies and CTLA-4 antibodies, can relieve the inhibitory effect of T cells, so that T cells can continue to kill tumors
.
However, such drugs only show good results for patients who have T cell infiltration in their own tumor tissues but whose killing ability is suppressed by immune checkpoints, bringing them hope
for long-term survival.
However, the proportion of such patients is only about 20% to 30%.

Professor Chen Shuqing:

It is a long-term dream
of scientists to use vaccines to educate immune cells to more effectively recognize and kill tumor cells, so as to prevent tumor recurrence and treat tumors.
However, long-term efforts have not been successful, mainly due to the lack of understanding of tumor antigens, making a lot of research work futile
.
After entering the new century, with the significant reduction in the cost of gene sequencing, scientists have the opportunity to conduct comprehensive genetic mutation analysis of tumor cells, so as to realize that the natural target of T cells to recognize tumors is neoantigens
.
The so-called neoantigen is a protein fragment produced by gene mutation and presented to the surface of the cell membrane by the MHC molecule of the cell, and its essence is an endogenous foreign body, so it can be effectively recognized
by its own T cells.
If such antigens are used as vaccines, isn't it possible to activate specific immunity? In the past 5 years, European and American scientists and Chinese scientists have launched fierce competition in this field, and at present, Chinese scientists are leading in neoantigen analysis and vaccine design using artificial intelligence, while European and American scientists are leading
in clinical trials 。 The US FDA and the European EMA have respectively established the Oncology Center of Excellence (OCE) and the Innovation Task Force (ITF), which are mainly responsible for the registration and application of highly innovative new drug products such as tumor neoantigen individualized vaccines, which can promote clinical trials
of such vaccines in a timely manner.

It is a long-term dream
of scientists to use vaccines to educate immune cells to more effectively recognize and kill tumor cells, so as to prevent tumor recurrence and treat tumors.
At present, Chinese scientists are leading in neoantigen analysis and vaccine design using artificial intelligence, while European and American scientists are leading
in clinical trials.

CDE chose to release the "Technical Guidelines for Clinical Trials of Tumor Therapeutic Vaccines (Draft for Comments)" at such a point in time, reflecting its emphasis on the development of innovative drug technologies with obvious clinical value, such as tumor therapeutic vaccines, and keeping a close eye on the development of international cutting-edge technologies, aiming to solve the "stuck neck" problem of industrial innovation and development, improve the overall level of the industry, and keep it in sync
with the international level 。 This move of CDE also proves that it has reached a critical period for the development of tumor therapeutic vaccines, and the intervention and vigorous promotion of the national regulatory system are needed to keep China ahead in this technology field and benefit more tumor patients
as soon as possible.

At present, it has reached a critical period for the development of tumor therapeutic vaccines, and the intervention and vigorous promotion of the national regulatory system are needed to keep China ahead in this technical field

Mofang Pro: What important information did you read from the Consultation Draft?

Professor Chen Shuqing: The Draft for Comments has important guiding significance for the development of tumor therapeutic vaccine products, and is worthy of detailed interpretation and study
by relevant personnel in this field.

Professor Chen Shuqing:

First, the Draft clarifies the scope of application of the guidelines, pointing out that according to the different antigen expression and presentation methods, tumor therapeutic vaccines include but are not limited to cell vector vaccines, viral vector vaccines, protein/peptide vaccines, nucleic acid (DNA or RNA) vaccines, etc.
It is not suitable for vaccines for the prevention and treatment of infectious diseases, products that induce or enhance nonspecific immune responses, products that prevent or reduce tumor incidence in patients with no prior history of the same tumor, and adoptive immunotherapy products that directly target the killing of tumor cells (such as T cell or NK cell products).

It clarifies the scope of application of the guidelines and their inapplicable

Secondly, the Draft clearly points out that with the development, in-depth understanding and accumulation of experience in tumor immunotherapy, the recommendations or recommendations involved in its guiding principles will be continuously improved and updated
.
The applicant should always adhere to the principle of specific analysis of specific problems in the research, and it is recommended to communicate
with CDE in a timely manner on the specific design and details of the clinical trial of tumor therapeutic vaccines.
The note reflects that CDE encourages reform and innovation, seeks truth from facts, and maintains a positive and open attitude
to promote the development of tumor therapeutic vaccine technology.

It reflects that CDE encourages reform and innovation, seeks truth from facts, and maintains a positive and open attitude
to promote the development of tumor therapeutic vaccine technology.

Among the general considerations of clinical trial design, the Draft points out that for the subject population, multiple tumor populations can be included in early exploratory clinical trials to obtain more data; For personalized vaccines based on bioinformatics analysis, or therapeutic vaccines made from a patient's own tissue or cells, each patient's genetic background and tumor histology are different, resulting in different vaccine formulations, and analyzing clinical trial results in heterogeneous patient populations can be particularly difficult
.
Therefore, the impact
of heterogeneity of patient populations on trial design and evaluation should be carefully considered when selecting patient populations in clinical trials for therapeutic oncology vaccines.
This note reflects CDE's full understanding of the high heterogeneity of tumor existence, and also proves that tumor individualized treatment is the future development direction, so that tumor patients can receive more suitable treatment drugs
by continuously improving the accuracy of anti-tumor treatment.

It reflects the high heterogeneity of CDE fully understanding the existence of tumors, and also proves that personalized tumor treatment is the future development direction

Due to the relatively long time required for induction of tumor-specific immune responses, it is possible that the patient will progress to disease earlier than the time of onset of action of the vaccine
.
Sponsors should pre-specify in the protocol the conditions for
patients to continue receiving vaccine therapy after progression.
If the comprehensive assessment concludes that it is still necessary to continue vaccine treatment, the informed consent form should fully inform the subject of the expected possible risks and other alternative treatment options
.
This statement reflects that CDE requires pharmaceutical companies to always implement the concept of clinical demand-oriented, and provide patients with more effective, safer or more convenient treatment options as the highest goal, so as to maximize
patient benefits.

This statement reflects that CDE requires pharmaceutical companies to always implement the concept of clinical demand-oriented, and provide patients with more effective, safer or more convenient treatment options as the highest goal, so as to maximize
patient benefits.

For individualized tumor therapeutic vaccines, since antigen screening mainly relies on computer software algorithms, antigen screening software should comprehensively evaluate the ability of tumor neoantigens to induce specific anti-tumor immune responses, including but not limited to tumor genome mutations, gene expression, HLA genotype, HLA heterozygous loss, antigen affinity prediction, mutation antigen and normal proteome sequence comparison
, etc 。 This note reflects that CDE has conducted sufficient research on individualized tumor therapeutic vaccines, and the evaluation factors that need to be considered by the antigen screening software proposed by it are important key points
that need to be solved and analyzed by R&D companies of personalized tumor therapeutic vaccines.
CDE also proposes to target personalized or autologous vaccines that take longer to prepare and subjects may experience disease recurrence or progression
while waiting for treatment.
For autologous therapeutic vaccine products, a small number of participants may also be unable to receive vaccine treatment
due to manufacturing failures due to various source materials and/or manufacturing reasons.
Therefore, the guidelines recommend that sponsors should optimize the vaccine manufacturing process as much as possible before the start of confirmatory clinical trials, and increase the proportion of
subjects receiving vaccine treatment as scheduled.

This note reflects that CDE has conducted sufficient research on individualized tumor therapeutic vaccines, and the evaluation factors that need to be considered by the antigen screening software proposed by it are important key points
that need to be solved and analyzed by R&D companies of personalized tumor therapeutic vaccines.
The guidelines recommend that sponsors should optimize the vaccine manufacturing process before confirmatory clinical trials begin

In general, starting from the uniqueness of tumor therapeutic vaccine products, the Draft comprehensively considers the factors involved in clinical trials and the needs of different trial stages, and provides clinical trial guidelines
for developers of tumor therapeutic vaccines.
It repeatedly mentioned individualized vaccines and emphasized the special considerations of such vaccines, indicating the important strategic development position of personalized vaccines in the field of tumor therapeutic vaccine technology, and it is believed that in the near future, guidelines for pharmacy and non-clinical research related to personalized tumor therapeutic vaccines will be released
one after another.

What are the unique challenges of tumor "neoantigen vaccines"?

PharmaCube Pro: In the latest Draft for Comments, "neoantigen vaccine"
is mentioned separately many times.
What is unique about the development of "neoantigen vaccines" compared to other types of therapeutic tumor vaccines? What are the obstacles? And what are the advantages?

Professor Chen Shuqing: According to the specificity of antigens, tumor antigens are mainly divided into tumor-specific antigens (TSA) and tumor-associated antigens (TAA).

TSA is only present on the surface of cancer cells and is not expressed in normal tissues; TAA is generally highly expressed in tumor cells and low in
normal tissues.

Professor Chen Shuqing: Tumor-specific antigen TSA tumor-associated antigen TAA

Melacine, the world's first therapeutic oncology vaccine, was originally developed by Corixa and marketed in Canada in 1999 for the treatment
of advanced melanoma.
Oncophage, a kidney cell cancer vaccine developed by Antigenics in the United States, approved in Russia in 2008, is a tumor cell inactivated by radiation for the treatment of early-stage kidney cancer
.
In 2010, Provenge, a dendritic cell vaccine for the treatment of prostate cancer, developed by Dendreon, a biopharmaceutical company based in Seattle, USA, was approved by
the FDA.
Since then, pharmaceutical giants including GSK, Merck, and Sanofi have invested heavily in the development of cancer vaccines
.
Around 2011, the research and development of tumor vaccine products reached a golden period
.
However, since the second half of 2013, the Phase III clinical trials of several blockbuster vaccines have suffered from Waterloo, including star products
such as Stimuvax (targeting MUC1, Merck) and GSK1572932A (targeting MAGE-A3, GSK).
Even Provenge, the first oncology vaccine approved by the FDA, was acquired
because of problems of effectiveness and cost.
From the perspective of research and development strategy, these vaccines are selected by TAA
.
Because TAA is a protein that the body has itself (only expressed in large quantities on cancer cells), patients have long had "central immune tolerance" to these antigens, so no matter how stimulated, the target effect
cannot be achieved.
Therefore, TAA is not an ideal "antigen"
.

From the perspective of research and development strategy, these vaccines are selected by TAA
.

Neoantigen (neoantigen is a transliteration of the word) is found only in tumor cells and is a class of TSAs that can occur through a variety of mechanisms, such as mutant peptides, abnormal gene expression, viral infection, and abnormal posttranscriptional modifications
。 Compared with TAA, neoantigens not only have high tumor specificity, but also usually have stronger immunogenicity and better major histocompatibility complex (MHC) affinity, and are not affected by central immune tolerance, so they have great potential
in tumor clinical treatment 。 Since 2013, Rosenberg's team pioneered the use of exome technology to discover tumor neoantigens on tumor cell lines and verified that they can stimulate the body's immune response, and personalized tumor vaccines based on neoantigens have been greatly developed
。 The results of animal tests and clinical studies have shown that if tumor neoantigens can be successfully presented to the cell surface by antigen-presenting cells in the form of antigen-MHC complexes, and then recognized and bound by the TCR of T cells, these T cells may be activated to specifically kill tumor cells and produce immune memory effects, thereby partially or completely regressing tumors and effectively preventing tumor recurrence
.

Neoantigen (neoantigen is a transliteration of the word) is found only in tumor cells and is a class of TSA

The biggest difference between neoantigen tumor vaccines and other therapeutic tumor vaccines is the need to identify tumor neoantigens
that are individualized to patients.
Other therapeutic tumor vaccines can prepare off-the-shelf products
that can be stored for a long time according to the optimized production process according to the tumor antigen targets that have been confirmed in advance 。 The first step in the preparation of individualized neoantigen tumor vaccine is to use artificial intelligence analysis model to compare and analyze the DNA and RNA sequencing information of the patient's tumor tissue and normal tissue, and identify and select the tumor neoantigen from the obtained tumor mutation information through multi-dimensional modeling and prediction such as MHC affinity, antigen immunogenicity, potential toxicity, T cell activation ability, tumor cell killing ability, etc.
, for the design and preparation of
subsequent individualized vaccines.
It can be seen that how to identify neoantigens efficiently, accurately and quickly is the first problem
that needs to be solved in the development of individualized neoantigen tumor vaccines.
In addition, because tumor patients usually have rapid disease progression, and personalized vaccines take a long time to prepare compared with off-the-shelf products, how to develop a production process that is universal, capable of producing different sequences of vaccine products in a short period of time and with a high success rate is the second problem
that needs to be solved.
Finally, due to the heterogeneity of tumor patients, how to select appropriate bioactive markers and clinical efficacy indicators after treatment of patients, evaluate the correlation between bioactive markers and clinical efficacy, and explore the correlation of efficacy prediction or prognostic value of markers are also problems that need to be
solved.

The biggest difference between neoantigen tumor vaccines and other therapeutic tumor vaccines is the need to identify tumor neoantigens
that are individualized to patients.
How to identify neoantigens efficiently, accurately and quickly is the first problem
that needs to be solved in the development of individualized neoantigen tumor vaccines.
How to develop a production process that is universal, capable of producing different sequences of vaccine products in a short time and with a high success rate is the second problem
that needs to be solved.

PharmaCube Pro: How did Nuanzin overcome the challenges of developing "neoantigen vaccines"?

Professor Chen Shuqing: The core team of Nuanjin Company has carried out tumor neoantigen research since 2009, and is one of the earliest companies in the world to develop individualized immunotherapy new drugs based on neoantigens, and the company is committed to developing personalized tumor immunotherapy products through leading artificial intelligence analysis technology, and has also built three independent research and development core technology platforms
of bioinformatics artificial intelligence analysis, personalized vaccine preparations, and precision immunotherapy monitoring 。 At present, nearly 800,000 submitted antigen sequences and more than 1,500 neoantigen immunogenicity data
have been obtained through more than 140 immunopeptide group mass spectrometry experiments and clinical trials initiated by researchers.
At the same time, using artificial intelligence algorithms, an iNeo intelligent analysis software has been developed, which can realize one-stop automatic analysis from raw sequencing data analysis
, somatic mutation identification, HLA typing identification, neoantigen peptide prediction and optimization, to the final vaccine peptide sequence design.
The results of ELISpot experiments with patient follow-up in real clinical trials have strongly proved that the efficacy rate of iNeo intelligent analysis software in neoantigen prediction and optimization is as high as 82%.

It can be said that Nuanzin has reached the international leading level
in the identification and optimization of neoantigens.

Professor Chen Shuqing: It is one of the first companies in the world to develop new drugs for individualized immunotherapy based on neoantigens, and has obtained nearly 800,000 submitted antigen sequences and more than 1,500 neoantigen immunogenicity data
through more than 140 immunopeptide mass spectrometry experiments and clinical trials initiated by researchers.
The effectiveness rate of iNeo intelligent analysis software for neoantigen prediction and optimization is as high as 82%.

We have laid out a pipeline of tumor personalized peptide vaccines, specific T cell products, personalized mRNA vaccines, peptide self-assembly vaccines and a series of universal vaccines
based on neoantigens 。 For our first product, iNeo-Vac-P01 (tumor neoantigen individualized peptide vaccine), the company's R&D personnel analyzed and designed samples from real clinical patients, obtained neoantigen peptide vaccine sequences, and then explored and optimized the peptide synthesis and preparation process of different sequences and vaccine preparation production processes based on these vaccine sequences, and finally obtained a neoantigen peptide tumor vaccine production process with strong universality, which can complete product preparation within 4-6 weeks and meet the clinical needs of patients
。

The first product, iNeo-Vac-P01 (Tumor Neoantigen Individualized Peptide Vaccine), can be prepared in 4-6 weeks

For vaccine effect evaluation and testing, on the basis of non-clinical research results, we take immunogenicity, bioactive markers and clinical efficacy as the main factors, select a number of closely related indicators, and use no less than two detection methods for multiple verifications
when the clinical sample size allows.
In contrast, our research basically meets the relevant requirements
of the Draft for Comments issued by CDE.

The "clinical data" of the first neoantigen peptide vaccine is gratifying

PharmaCube Pro: According to the company's official website, Nyuanzin's individualized tumor neoantigen peptide vaccine iNeo-Vac-P01 has completed clinical trials
initiated by investigators in a number of well-known tertiary hospitals.
As a new treatment, what challenges did neoantigen vaccines encounter in the process of conducting scientific clinical trials? What is the guiding significance of the newly released Draft for the next clinical trial design?

Professor Chen Shuqing: The first individualized tumor therapeutic vaccine developed by our team, iNeo-Vac-P01 (tumor neoantigen individualized peptide vaccine), has carried out 7 scientific research clinical studies since January 2018 in cooperation with the Affiliated Hospital of Zhejiang University, treating 70+ patients, and the relevant clinical research results have been published in the international top clinical journal Clinical Cancer Research and the Frontiers in Immunology Frontiers in Immunology, since 2018, has reported clinical research results
at the annual meeting of the American Society of Clinical Oncology (ASCO), the American Association for Cancer Research (AACR), the American Society for Immunotherapy for Cancer (SITC), and the Chinese Congress of Clinical Oncology (CSCO).
Based on the above clinical research, Nuanjin Biologics has collected the actual clinical feedback of 1500+ peptide vaccines, established the largest clinical research follow-up database of individualized immunotherapy of neoantigens in China, and provided rich data reference
for the design and algorithm development of neoantigen vaccines.

Professor Chen Shuqing: Since January 2018, we have cooperated with the Affiliated Hospital of Zhejiang University to carry out 7 scientific research and clinical studies, and have collected actual clinical feedback of 1500+ peptide vaccines for 70+ cases of Nuanjin Biologics

In May 2020, the team officially published the results of the world's first clinical trial of neoantigen peptide vaccine monotherapy for patients with advanced pan-cancer solid tumors who have failed standard treatment
.
More than 70% of the enrolled participants reported in the paper were advanced patients
who had failed 3 or more lines of treatment.
All patients had no serious adverse reactions during the regular course of treatment, and the overall disease control rate (DCR) was 71.
4%; 38.
1% of the subjects had a decrease in the treatment of neoantigen peptide vaccine, and the maximum reduction ratio was 16.
7%, which was significantly better than the historical data.
Through the ELISpot experiment of peripheral T cells of patients after treatment, up to 80% of vaccine peptides can be recognized by antigen-specific T cells; The safety and efficacy
of individualized tumor vaccines based on neoantigens have been demonstrated.

The world's first clinical trial of neoantigen peptide vaccine monotherapy for patients with advanced pan-cancer solid tumors who failed standard treatment showed an overall disease control rate (DCR) of 71.
4%; Up to 80% of vaccine peptides can be recognized by detectable antigen-specific T cells; The safety and efficacy
of individualized tumor vaccines based on neoantigens have been demonstrated.

In August 2021, the clinical trial results of the team's clinical trial "Feasibility and Preliminary Efficacy of Neoantigen-based Individualized Oncology Vaccine for Patients with Advanced Pancreatic Cancer Who Have Failed Standard Treatment" conducted by the team in Zhejiang Provincial People's Hospital were published in the journal
Frontiers in Immunology 。 None of the participants experienced serious vaccine-related side effects; The average values of OS, vaccine-associated OS and PFS were 24.
1, 8.
3 and 3.
1 months, respectively, which were significantly better than the historical data; the study found that patients with higher INF-γ titer and more CD4+ and CD8+ effector memory T cells detected in peripheral blood samples after vaccine treatment had relatively longer OS.
Moreover, ELISpot experiments on peripheral T cells of patients have proved that up to 80% of vaccine peptides can stimulate antigen-specific immune responses; It has been demonstrated that even patients with advanced pancreatic cancer with low TMB can benefit from
individualized neoantigen peptide vaccine treatment.

The average values of OS, vaccine-associated OS and PFS were 24.
1, 8.
3 and 3.
1 months, respectively, which were significantly better than historical data

Each patient's genetic background and tumor histology are different, resulting in different vaccine formulations, and analyzing clinical trial results in heterogeneous patient populations can be particularly difficult
。 Therefore, which patient groups to select as subjects in the clinical trials of tumor therapeutic vaccines, and how to design observation indicators in clinical research, are the challenges encountered in the clinical research of individualized tumor therapeutic vaccines, so we will carefully study the latest "consultation draft" released by CDE in the future, implement patient needs as the core, clinical value-oriented, design reasonable clinical research protocols, and allocate subjects to safe and effective dose groups as soon as possible to maximize the benefits of subjects
。

Which patient groups to select as subjects in clinical trials of oncology therapeutic vaccines, and how to design observation indicators in clinical studies, are challenges encountered in clinical research of individualized tumor therapeutic vaccines

PharmaCube Pro: Are there any recent developments to share about iNeo-Vac-P01?

Professor Chen Shuqing: On September 29, 2022, Nuanjin Biotech published a paper entitled "Combination Treatment of Radiofrequency Ablation and Peptide Neoantigen Vaccination: Promising Modality for Future Cancer" in the journal Frontiers in Immunology Immunotherapy"
.
The results showed that if advanced pan-cancer patients underwent local radiofrequency ablation (RFA) within 6 months before receiving iNeo-Vac-P01 treatment, the tumor microenvironment could be further improved and clinical efficacy
could be improved 。 The team also verified the anti-tumor synergy between RFA and iNeo-Vac-P01 through a mouse model; At the same time, it was further found that the combination of RFA, iNeo-Vac-P01 and immune checkpoint inhibitors can further enhance antigen-specific immune response, improve tumor suppression, and provide a feasible and effective new immune
combination therapy for patients with advanced solid tumors who have failed standard therapy.

Prof.
Shuqing Chen: Local radiofrequency ablation (RFA) within 6 months before iNeo-Vac-P01 treatment can further improve the tumor microenvironment and enhance clinical efficacy
.

In the next five years, multiple products will be submitted for marketing

PharmaCube Pro: Overall, what is the current stage of development of foreign and domestic cancer therapeutic vaccines? Are there any new achievements in this area that deserve attention this year?

Professor Chen Shuqing: Overall, although no new tumor therapeutic vaccines have been approved for marketing at home and abroad in the past ten years, the development of foreign tumor therapeutic vaccines is ahead of China
in terms of quantity and clinical trial progress.
A review article titled "Cancer vaccines: the next immunotherapy frontier," published in the journal Nature Cancer in August, summarizes the current state
of product development for oncology vaccines for different tumor antigen types.
The article shows that the current cancer vaccines developed for confirmed shared antigens are still ahead of the tumor vaccines
developed for individualized neoantigens in terms of the number and clinical trial progress.
The vast majority of tumor therapeutic vaccine products are still in the clinical phase I, II and III research stage, especially the individualized neoantigen tumor vaccines are almost all in clinical phase
I/II.

Professor Chen Shuqing: Although no new tumor therapeutic vaccines have been approved for marketing at home and abroad in the past ten years, the development of foreign tumor therapeutic vaccines is ahead of China
in terms of quantity and clinical trial progress.
At present, the oncology vaccines developed for the confirmed shared antigens are still ahead of the oncology vaccines
developed for individualized neoantigens in terms of the number and clinical trial progress.

At the ASCO conference held in June this year, a number of companies and institutions (BioNTech, Gritstone oncology, Advaxis, Nouscom, Transgene, as well as the University of Washington and NIH, NCI) announced the clinical trial results of their tumor vaccines based on tumor neoantigens, which demonstrated the good safety, tolerability and anti-tumor activity
of neoantigen therapeutic tumor vaccines 。 In addition, many teams, including the above-mentioned companies and institutions, have successively published clinical research articles related to individualized neoantigen tumor vaccines in the past 5 years, detailing the research results and proving the safety and efficacy
of individualized neoantigen tumor vaccines.

This year, in the field of tumor therapeutic vaccines, especially individualized neoantigen tumor vaccines, in addition to Nuanjin and the above teams, many other teams have also published new results
worthy of attention 。 For example, Inge Marie Svane's team in Denmark published the results of a clinical study using the individualized neoantigen peptide vaccine EVX-01 combined with PD-1 monoclonal antibody with CD8+ T cell-inducing adjuvant CAF®09b (liposome-based cationic adjuvant product) in the treatment of patients with advanced metastatic melanoma, demonstrating the feasibility and safety of EVX-01 products.
A durable EVX-01-specific T cell response
was found in all five patients treated with the vaccine.
3 of the 5 patients were assessed as OR (2 PR, 1 CR); These results demonstrate the anti-tumor potential
of EVX-01 in combination with PD-1 monoclonal antibody.

In summary, the field of tumor therapeutic vaccines is currently in an important stage of development, and Nuanzin is also doing its best to promote the development and listing
of related products.

MedCube Pro: Looking forward to the next 3-5 years, what kind of breakthroughs do you think will be made in the research and development of cancer therapeutic vaccines? What are your development goals for Nuanjin?

Professor Chen Shuqing: Looking forward to the next 3-5 years, as tumor therapeutic vaccines, especially neoantigen tumor vaccines, are paid attention to by more and more companies and research institutions, more researchers will join the development of this technology, thereby promoting the rapid development of
this field.
According to the current speed of clinical research progress, it is expected that a number of tumor therapeutic vaccines at home and abroad will be applied for marketing in the next 5 years, so that more tumor patients will benefit
.

Professor Chen Shuqing: It is expected that there will be a number of tumor therapeutic vaccines at home and abroad that will be applied for marketing in the next five years

Globally, 25 individualized drugs for tumor neoantigens have been approved by the FDA or EMA to enter the clinical research stage, of which the same peptide as iNeo-Vac-P01 accounts for the highest proportion, with 6 (2 have entered phase II clinical trials).

And its clinical research results have been disclosed one after another, and it is expected that the fastest similar products will be submitted for marketing next
year.
Nyuanzin's first personalized tumor therapeutic vaccine, iNeo-Vac-P01, has completed a pre-IND communication meeting and is ready to submit an IND application
in the near future.

iNeo-Vac-P01 has completed a pre-IND communication meeting and is ready to submit an IND application
in the near future.

For Nuanjin, we must do solid research, use real experimental data to verify the accuracy of artificial intelligence analysis results, continuously improve the level of algorithms, develop different forms of neoantigen vaccines, and find the most suitable clinical indications so that patients' tumors can be cured
.
On the other hand, neoantigens are not only the therapeutic targets of tumors, but also the targets of other refractory diseases, such as diabetes, atherosclerosis, Alzheimer's disease, etc.
, we must optimize the prediction algorithm of neoantigens, gradually develop drugs for the treatment of these diseases, and become a company
with hard technology platform technology.

On the other hand, neoantigens are not only therapeutic targets for tumors, but also targets for other refractory diseases, such as diabetes, atherosclerosis, and Alzheimer's disease

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