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The core mechanism of CAR-T therapy is to specifically identify tumor-associated antigens, so that the targeting, killing activity, and persistence of effector T cells are greatly increased compared with conventionally applied immune cells, thereby breaking the host immune tolerance state, overcoming immune escape, and ultimately killing tumor cells.
CAR-T therapy has the following characteristics compared to the traditional R&D of new drugs:

First, the CAR-T therapy technology is extremely strong and highly replicable. At present, there are as many as 23 CAR-T clinical trials in China, second only to the United States. This is the first time that China has reached the international forefront in the field of new drug development.

Second, CAR-T is a very individualized therapy. The supply of products is fundamentally different from traditional medicines. Therefore, the standardization of CAR-T products and the controllability of their efficacy and risks are the top priorities. The future market must belong to a company that can standardize CAR-T cells and standardize the treatment process. Hospitals or companies that are currently undergoing extensive development are bound to be eliminated in the future.

Third, the development of CAR-T therapy takes a short time. Once the first therapy is approved for marketing, the follow-up company will follow up quickly. Since Emily Whitehead received a T-cell transfusion from the Carl June team in April 2012, Novartis has completed a number of clinical trials in less than four years, and CTL019 is expected to be approved in 2017. In other words, this epoch-making treatment of CAR-T can be officially launched in only 5 years. It can be speculated that the follow-up CAR-T therapy companies’ R & D progress will be relatively fast.

Today, we will carefully analyze the status of CAR-T therapy from multiple perspectives including regulatory policies, market forecasts, and R&D patterns.

Technology leadership lags behind regulatory supervision,

highlighting policy improvement

The United States divides medical intervention drugs into three categories: small-molecule drugs, macromolecular drugs, and cell drugs (cell-based therapeutic molecules, ie, cell therapy). That is, the United States treats cell therapy as small molecules. Drugs and macromolecular drugs are a means of treatment, but cellular drugs are a kind of “living” ingredient. Different regulatory models, popularization and traditional medicines are different, and supervision is more difficult, leading to the formation of a “leading technology and poor supervision”. situation. Regardless of whether it is Europe or the United States or China, on the one hand it is hoped that the study of immune cells can be conducted. On the other hand, it is relatively cautious about the clinical and market of cell therapy. This “encouraging and strict management” attitude is also evident in the policy of stem cell drug development.

Objectively, this kind of supervision lags behind the status quo of technology and gives small and medium-sized companies the opportunity to develop rapidly. Small bio-pharmaceutical companies have fewer R&D projects, high efficiency, and low policy costs, and can quickly promote cell therapy technology. This is why VC/PE companies in the United States have been involved in the business background of small and medium-sized biopharmaceutical companies.
In the absence of supervision, some domestic small biotechnology companies and hospitals cooperated on fees and applied CAR-T as a clinical application. They were applied to late-stage cancer patients through internal examination and approval of hospitals and signing of exemption agreements. Such a gray zone has enabled companies and hospitals to obtain benefits, and has also objectively benefited some patients, but there are enormous medical and moral risks.

China’s immune cell treatment related policies issued time

On June 29, 2015, the China Health and Family Planning Commission repealed the “First Catalogue of Category III Medical Technology Allowed for Clinical Applications” published on May 22, 2009. The principle of medical technology forbidding clinical application and limiting clinical application is clarified. The medical technology that restricts clinical application is regarded as the management priority. The medical institution carries out medical application for restricting clinical application (2015 version) to record management of clinical application of medical technology. .

It is worth noting that “autoimmune cell (T-cell, NK cell) treatment technology” and “cell transplantation therapy technology (other than stem cell)” still belong to the medical technology that allows clinical application. Analog Stem Cell Management Policy. Since the beginning of this year, the Health and Family Planning Commission has launched Guidelines for Stem Cell Clinical Research Management (Trial) and Guidelines for Quality Control and Preclinical Research of Stem Cell Agents (Trial). The clinical research on stem cells in China has been rigorously managed, and stem cell research must be sun-resistant. And standardization.
We believe that the future Health and Development Commission will also introduce a similar standardization policy to address the current blooming of immune cell therapy. In the long run, strict policies are beneficial, and drugs or medical technology can only become standardized therapy under strict supervision.

CAR-T Potential Market Forecast

Major US analysts predict that the market for cancer treatment based on CAR-T therapy may reach $35 billion to $100 billion. Since the unit price of CAR-T therapy (about $300,000 to 450,000 per person, and the course of treatment is 14 to 21 days) is much higher than conventional therapy, and there are many indications that may be covered in the future, CAR-T therapy has a huge market potential. U.S. agencies give $100 billion in market space.

According to the number of cancer patients

The 2015 US cancer incidence statistics released by CA CancerJ Clin show that in 2015, the number of new types of blood cancer patients in the United States reached 162,000. Based on mainstream estimates of CAR-T treatment costs ($300,000/person), the potential market for new blood tumors in the United States will reach $48 billion each year.

According to the latest statistics from Professor Chen Wanqing, director of the National Cancer Registry, China has 117,300 leukemia patients and 157,600 lymphoma patients diagnosed as cancer and still alive within five years. Considering the outstanding curative effect of CAR-T on blood tumors, the potential market size of CAR-T therapy in these two major hematologic neoplasms exceeds RMB 25 billion according to the domestic treatment cost of RMB 100,000.

According to indications

At present, the fastest clinical progress of CAR-T therapy is Novartis’s CTL019, mainly for children with acute lymphoblastic leukemia (ALL). About 3750 (60%) of 6,250 newly-increased ALL in the United States are teenage patients under 20 years of age. At $300,000/person, the potential market size is about $1 billion per year.

Novartis CTL019 may be approved for marketing in 2017 for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). DLBCL is the most common NHL, accounting for about 31%, FL about 22% of NHL. According to the “Clinical Journal of Cancer,” the annual increase in the number of these two types of hematological neoplasms in the United States is approximately 38,000, and the potential market size is approximately $11 billion. If you consider that some patients are not suitable for CAR-T therapy and permeability factors, market space is expected to be around $5 billion.

CAR-T Therapy R&D Pattern

In the development of CART-T therapy, the United States took the lead, followed by China, and Europe and Japan fell significantly behind. So far, there are 87 CAR-T clinical trials underway, 54 in the United States, 23 in China, 8 in Europe, and 1 each in Japan and Australia. The United States is the origin of CAR-T technology and the leader of global pharmaceutical technology. It is not surprising that major pharmaceutical giants are coveting the emerging field. China has also grasped the trend of the times and ranked second in the world with astonishing 23 clinical trials, leaving behind Europe and Japan with stronger pharmaceutical R&D capabilities.

Comparing the targets of CAR-T clinical trials in China and the United States, we can find that blood tumors are still the key breakthroughs in CAR-T clinical research, among which CD19 has the most extensive and deep research (31 items). In addition, there are many studies on solid tumor targets such as HER-2, GD2, and EGFR.

CAR-T therapy listed on the target and clinical progress

Novartis, Juno, and Kite are leaders in the development of CAR-T therapies. CAR-T technology has its own characteristics and has obtained a lot of data in many clinical trials, leading the trend of CAR-T. In addition, several small biomedical companies have also made breakthroughs in their respective fields, such as Cellectis (using allogeneic T cells) and CBMG.

Novartis CTL019 Leading the World

Novartis’s CAR-T drug is CTL019, which belongs to the second-generation CAR-T category. Co-stimulatory signals in the intracellular signaling domain are CD3-zeta and CD137.

Results from ASH 2015 will present the largest clinical data of CAR-T therapy in children with relapsed or refractory ALL. It is noteworthy that, when the number of patients has almost doubled, this data is almost identical to the data of Phase I released in 2014 (complete remission rate is 92%), which means that CTL019 is a high-probability event when it is approved by the FDA for listing.

JUNO and KITE follow

On June 1, 2015, JUNO announced its clinical phase 1 data for CAR-T drug JCAR015. The results showed that JCAR015 has a good effect on ALL patients. Of the 38 evaluable patients, 33 achieved complete remission and the complete remission rate was as high as 87%. The PFS is 8.5 months and the half-year survival rate is 59%. At the ASH 2015 annual meeting, JUNO also released data on JCAR015 targeting relapsed or refractory B-cell ALL. The complete response rate reached 82% (n=37/45).

KITE’s R&D progress slightly lags behind Novartis and JUNO. In February 2015, KITE announced its phase I clinical data for the treatment of advanced malignant lymphoma with its anti-CD19 CAR-T drug. Of the 15 patients, 8 had complete remission, 4 had partial remission, and 1 had stable disease. Of the 7 evaluable patients with DLBCL, 4 had complete remission and 1 died after 16 days of T cell transfusion. The cause was unknown.

At the ASH2015 on December 7, 2015, KITE announced its Phase I clinical data for the CAR-T therapy KTE-C19-101 (ZUMA-1) for refractory malignant NHL. Of the 7 patients with DLBCL, 4 had complete remission and 1 had partial remission. The overall response rate was 71% (5/7). At the same time, KITE’s KTE-C19 treatment for NHL was granted by the FDA as a breakthrough therapeutic drug during the Phase II clinical trial. This study began in May of this year and is expected to release relevant data next year. The qualification for breakthrough therapeutic drugs will undoubtedly accelerate the pace of KITE’s catch-up.

Cellectis: The Transformer in the CAR-T Field

On November 6, 2015, Cellectis’ allogeneic CAR-T therapy was an important step forward. A 11-month-old female patient with refractory leukemia achieved complete remission after 2 months of treatment with the company’s UCART19 therapy, and Cellectis’ share price rose by more than 20% on that day. At the ASH2015 annual meeting on December 7, 2015, Cellectis demonstrated the treatment process in detail. The baby received a single UCART19 reinfusion after chemotherapy. The dose was 4.5*106/kg. No significant toxicity or cytokine storm occurred during the procedure, and she had completed three months of complete remission.

If the allogeneic CAR-T is finally feasible, the single treatment price may be reduced to 5-10 million US dollars, the production efficiency will be greatly increased, and the field of CAR-T therapy will also usher in changes.

Sieberman Biotech: From China, Looking Across the World!

Siebelmann Biotech (Shanghai) Co., Ltd. was formally listed on the Nasdaq on the US (Stock Code: CBMG) on June 18th, 2014 and became the only Chinese cell biomedical technology company listed on the Nasdaq in the United States. Sieberman’s CAR-T clinical research mainly cooperates with Prof. Han Weidong from the People’s Liberation Army 301 Hospital.

On March 25, 2015, Syberia announced two clinical data of Phase I clinical trials of CAR-T, all of which were approved by the General Hospital of the People’s Liberation Army and reviewed and approved by the Hospital Ethics Committee. All patients signed informed consent. The results of a phase I clinical trial of seven advanced chemotherapy-neutral advanced DLBCLs with CART-CD20-targeted immune cells (NCT01735604) showed that up to 75% of patients (3/4) achieved a large lymphatic tumor burden. This is the first report of CART-CD20 combined with tumor reduction treatment. A phase I clinical study (NCT01864889) of nine cases of CART-CD19 targeted immunotherapy for relapsed adult acute B lymphoblastic leukemia with chemotherapy-ineffective relapse showed a total response rate (ORR) of 67.7%. For the first time, 6 patients with extramedullary lesions were reported to achieve significant remission of the bone marrow hematopoietic system and extramedullary lesions without the use of targeted pretreatment. Compared with the research results of international counterparts, it has significant advantages. For the first time, the Chinese R&D team has been ranked among the top in the field of translational medical research in the global CAR-T cell technology.

In September 2015, Sippman published Phase I clinical data of its CAR-T therapy “CBM-EGFR.1” targeting solid tumor EGFR targets. Responses were obtained on various types of solid tumors, and the progress of research and development was international. Leading.

On October 26, 2015, Siepirman announced the Phase IIa clinical progress of its CAR-T therapy for advanced B-cell NHL with a target of CD20, in collaboration with Prof. Han Dongdong. Of the 10 evaluable patients, 5 had complete remission, 3 had partial remission and 2 had stable disease. The overall response rate was 80% (8/10), the complete remission rate was 50% (5/10), and the duration of complete remission was 4 ~> 11 months.

Bo Shengji begins to exert force

Hengrui Pharmaceutical, a leading Chinese drug research and development company, cooperated with Shenzhen Yuanzheng Cell in this year to establish Hengruiyuan Biotechnology Co., Ltd. and began to use immunotherapy. Anke Biotech has also entered this field through cooperation with Boshengji.

In November 2015, Bo Shengji registered two CAR-T studies, respectively with the Armed Police Zhejiang Corps Hospital (recruiting 20 people) and the Armed Police Anhui Corps Hospital (recruiting 10 people). Targeting solid tumor MUC1 targets, indications include hepatocellular carcinoma, non-small cell lung cancer, pancreatic cancer, and triple negative breast cancer. If the study progresses smoothly, it is expected that the progress of Phase I clinical trials can be announced in June next year.

The Challenge of CAR-T Therapy

CAR-T therapy is faced with many problems at the technical level, such as: Cytokine storm, target/off target toxicity, neurotoxicity, and poor solid tumors. However, we believe that these problems may eventually be overcome through continuous technological improvements. For example, the initial cytokine storm, Novartis CTL019 clinically used the IL-6 receptor antagonist tocilizumab to relieve symptoms. Although cytokine storms are still a serious phenomenon in clinical trials, they have basically been controlled and no longer cause fatal danger. At present, the technical problems faced by CAR-T therapy are mainly how to reduce the recurrence rate and standardize the treatment process.

Reduce the recurrence rate

According to published data, 10 cases of Novartis CTL019 in stage I clinical patients experienced recurrence of the disease, of which 5 cases of CAR-T cells disappeared, 5 cases of CD19-positive cancer cells disappeared, and finally 5 cases died.

Phase I clinical data from JCAR 015 showed that 33 of 38 assessable patients had complete remission (87%), but the median survival was only 8.5 months. Assuming that 33 patients with complete remission are still alive, the median survival will not be only 8.5 months, which means that some patients with complete remission have relapsed.

Phase II clinical data of CTL019 for r/r children and adolescent ALL patients showed complete remission (93%) in 59 patients, but the 1-year survival rate was 79%, which means that 8 patients with complete remission died within 1 year. The half-year recurrence-free survival rate was 76%, and the one-year recurrence-free survival rate was 55%, meaning that 13 patients relapsed within half a year, 25 patients relapsed within one year, and only 18 patients continued to complete remission after 12 months. .

Of course, patients receiving CAR-T therapy are basically refractory, relapsed, or advanced. The high recurrence rate is not unacceptable.

Standardized treatment procedures

As a personalized treatment, CAR-T requires specific treatment for each patient, which also causes high treatment costs and uncertain therapeutic effects. In particular, the uncertainty of efficacy may be miraculous in some patients but not in others.

Due to different patients, the quality of each batch of T cells may be uneven, and other scientific and production variables (carriers used for foreign DNA insertion, cell culture techniques, timing of transport and reinfusion into patients, and selected chemotherapy regimens) are It will make the results unpredictable.

Carl June’s team encountered such problems early in its development. After curing 3 patients, they used a new carrier prepared CAR-T in January 2012 to treat 3 other patients without remission. The team in June didn’t know why this happened, and didn’t even know if there was a problem with the carrier material or because of random fluctuations in the success rate of the therapy. (Science’s article “The Dizzying Journey to a New Cancer Arsenal” records the uncontrollable factors that Carl June and his team faced during the development of CAR-T. “I was just stumped out to the max,” June says. He had No idea what had happened and still can’t saywhether something went awry with the vector material or whether the outcome wasdue to random fluctuations in the therapy’s success. “All we knew was, it workeded three times, and then it didn’t work three times .” Science. 2013. 340.1514-1518) Therefore, how to standardize the CAR-T treatment process is the top priority of whether this type of therapy can enter clinically beneficial patients in the future.

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