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Analysis of the three major innovation directions of CAR-T therapy enterprises

 Last Update: 2022-10-20
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October 10, 2022/eMedClub News/--At present, a total of 8 CAR-T products have been approved for marketing worldwide, of which 6 target CD19 and 2 target BCMA, all of which are indicated for hematological tumors
.
According to the financial reports disclosed by various companies, except for Kymriah, the sales of CAR-T cell products have increased
to varying degrees compared with the same period last year.

▲ Overview of 8 listed CAR-T products

At the same time, the global CAR-T market is also expanding
rapidly.
According to Frost & Sullivan's analysis, the global CAR-T market soared from about $100 million in 2017 to about $1.
08 billion in 2020, and is expected to accelerate at a compound annual growth rate of 53.
0% in the next five years
.
Among them, China's CAR-T market is expected to grow to $1.
15 billion
in 2025.

$1.
15 billion

▲Global R&D of cellular immunotherapy (Image source: Reference 2)

The growth of the market is also driving R&D enthusiasm
.
In June 2022, an article titled "Landscape of cancer cell therapies: trends and real-world data" was published in Nature analyzing the global research and development of
cellular immunotherapy.
As of April 15, 2022, there are 2,756 active cell therapy candidates in the global immuno-oncology research pipeline, of which the number of CAR-T therapies increased by 24%
compared to last year.

The number of CAR-T therapies increased by 24% compared to last year

Under this growth rate, competition is already a tired word in the CAR-T track, basically as long as the CAR-T layout is talked about, it will talk about involution and innovation
.
Previously, the author had seen Dr.
Wang Liqun's views on the involution of cell immunotherapy and thought deeply: taking CD19 as an example, there are 2 domestic companies on the market, and the market will be saturated with another 1-2, and then the subsequent homogeneous products have no commercial significance
.
Many companies have also realized this, and speed and differentiated innovation must be one
of them to occupy a place in the market.
At present, the innovation methods of CAR-T therapy tend to be diversified, and we roughly summarize them into three directions: targets, indications, and technologies
.

Taking CD19 as an example, there are already 2 listed in China, and the market is saturated with another 1-2, and then the subsequent homogeneous products have no commercialization significance targets, indications, and technologies

1.
Target innovation

In the field of hematological tumors, CD19, BCMA, CD22 and other proven targets are still hot spots in research and development, but some new target research and development such as GPRC5D, CLEC12A, CD7, etc.
have increased
significantly.
In the field of solid tumors, the targets of CAR-T's pipeline are concentrated in HER2, MSLN, GPC3, etc.
, and the research and development of targets such as Claudin18.
2 is gradually increasing
.

▲Overview of cellular immunotherapy targets (Image source: Reference 2)

There are also many domestic enterprises that have made differentiated layouts
in targets.
In April 2022, the GCC19CART independently developed by Stansail targeting the antigen guanylate cyclase 2C (GUCY2C) was granted fast-track designation by the US FDA for the treatment of relapsed and refractory metastatic colorectal cancer (R/R mCRC).

One clinical study showed an ORR of 50% (4/8)
in the Grade 2 dose group treated with GCC19CART.

Stansay GUCY2C

In September 2022, the IND application for targeted GPC3 (Glypican-3) Ori-C101 injection independently developed by Yuanqi Biotech has been officially approved for the treatment of advanced liver cancer
.
In addition, companies such as Keji Pharmaceutical and Legend Biotechnology are also carrying out innovative research and development
in the field of solid tumors.

GPC3

In addition, multiple new targets have been reported
.
For example, in May this year, researchers at Moffitt Cancer Center announced the discovery of a new potential target for CAR-T cells called OR2H1, and preliminarily demonstrated the role
of this target in lung cancer and ovarian tumors.
OR2H1 is expressed in multiple histological subsets of solid tumors and is hardly present in
normal cells.
At the same time, the center will also promote the research
of CAR-T therapy for this target.

OR2H1

2.
Indications expand

Hematological tumors account for about 10% of malignant tumors, while solid tumors account for nearly 90%.

CAR-T therapy has shown breakthrough efficacy in hematological tumors, but it has problems such as
ineffective homing, immunosuppressive microenvironmental influence, and poor persistence in the treatment of solid tumors.

At present, CAR-T therapy for the treatment of solid tumors has become one of the directions of
differentiated layout.
In March 2022, Carl June, the "father of CAR-T", released new research progress in Nature, confirming that anti-TGF-β CAR-T is safe and feasible
for the treatment of metastatic castration-resistant prostate cancer (mCRPC), a solid tumor.
At the same time, this is also the first clinical study result of
CAR-T treatment of mCRPC.

CAR-T therapy for the treatment of solid tumors has become one of the first directions of differentiated layout

Domestic Keji Pharmaceutical has developed a Claudin18.
2 CAR-T candidate CT041, which is mainly used for the treatment of gastric cancer/esophageal gastric junction adenocarcinoma and pancreatic cancer, which is also a potential first of
its kind in the world.
In June 2022, CARsgen announced the results of CT041 at the 2022 ASCO Annual Meeting, indicating that CT041 has good efficacy and safety
.

Keji Pharmaceutical's CT041 is the first of its kind in the world

Data from a multicenter phase 1b trial conducted in the United States in patients with advanced gastric and pancreatic cancer showed an objective response rate (ORR) of 60% in the grouping of patients with gastric/oesophageal and gastric junction adenocarcinoma, with one patient achieving complete remission (CR).

60%

Data from the Phase 1b/2 trial in China in patients with advanced gastric cancer/oesophagegastric junction adenocarcinoma showed that 8 of the 14 patients (57.
1%) achieved a partial response in the first tumor assessment after the first infusion of CT041, based on investigator evaluations of 57.
1% ORR and DCR of 78.
6%.

57.
1% and 78.
6%

In addition, in September 2022, a research paper entitled "Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus" was published in Nature, which reported on 5 patients with refractory systemic lupus erythematosus (SLE) who improved after CAR-T cell therapy, and no patients experienced recurrence during up to 17 months of follow-up.
And all achieved drug-free remission
.
This also broadens the indications for CAR-T therapy, autoimmune diseases are the second largest market after tumors, if more results can be achieved in this indication, the prospects of CAR-T therapy will be broader
.

Autoimmune diseases

In this area of the disease, domestic companies have also stepped up
.
In August this year, Reindeer Biologics and Innovent Biologics jointly developed BCMA CAR-T product Iquilencera injection received implied approval from CDE for the treatment of AQP4-IgG-positive neuromyelitis optica spectrum disease
.
This is also the first clinical trial application submitted for CAR-T therapy for the treatment of autoimmune diseases in China, which is of milestone significance
.

Reindeer Bio Innovent Bio Iquilencer injection

3.
"Depth" and "width" of technological innovation

The innovation of CAR-T therapy technology can be mainly divided into two types, one is the change and innovation of CAR-T itself; The other is the combination
with innovative technologies.
Since the inception of CAR-T therapy, five generations of technology have passed
.
Among them, the second generation adds a co-stimulatory body on the basis of the first generation, which enhances the survival time and therapeutic effect of CAR-T cells, which is also the current mainstream structure
.
The later three generations of CAR structures can theoretically bring better results, but in practice more experiments are still needed to explore
.

Five generations of technology change

▲Five-generation CAR structure (Image source: Reference 1)

In addition, in addition to the iteration of CAR technology, 5 new CAR-T cell models have been reported in the literature:

5 novel CAR-T cell models

Tandem CAR: A single CAR structure enables targeted recognition of two tumor antigens through tandem scFv;

Tandem CAR

Bispecific CAR: Bispecific CAR can express two scFv at the same time to recognize two different tumor-specific antigens;

Bispecific CAR

Physiological CAR: Replace traditional scFv with a CAR structure containing ligand and receptor molecules to recognize tumor cells in pairs;

Physiological CAR

Universal CAR: replace scFv with a monoclonal antibody that can express avidin-biotin labeling, and then recognize the corresponding target antigen;

Universal CAR

I CAR: PD-1 and CTLA-4 can reversibly regulate TCR signal transduction and enhance the function of chimeric receptors;

I CAR

▲5 new CAR-T models (Image source: Reference 4)

At the 2021 AACR conference, Dr.
Sanaz Ghafouri, a researcher in hematology and oncology at UCLA Medical Center, announced the clinical research data of CD19×CD20 bispecific CAR-T therapy: 5 patients with B-cell malignancies who received treatment with positive expression of CD19 and CD20 tumor antigens achieved complete remission (4/5) after a median follow-up of 13 months, which also preliminarily proved the prospect of a new structure of CAR-T
。

CD19×CD20 bispecific CAR-T therapy

The domestic enterprise Huaxia Yintai has also innovatively developed a world's first dual-target CD19×CD20 STAR-T candidate HXYT-001 autologous cell injection, which is a synthetic T cell receptor and antigen receptor (STAR)-modified T cell using humanized antibodies targeting CD19 and CD20, mainly used for the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma
.
In September this year, the product candidate was approved for IND
.

Huaxia Intech is the world's first HXYT-001 autologous cell injection

At the same time as the development of CAR-T technology, CRISPR gene editing technology, iPSC, mRNA and other technologies are also advancing
.
The developers combined it with CAR-T therapy to "learn from each other"
.
If combined with CRISPR gene editing technology, knocking out TRAC, B2M, PD-1 and other genes can greatly reduce autoimmunogenicity and improve CAR-T anti-tumor activity, which also provides a technical means
for general-purpose CAR-T cell therapy and CAR-T therapy to overcome solid tumors.

Combined with CRISPR gene editing technology

At present, one of the common characteristics of CAR-T therapies on the market is that they are high cost and high price, and iPSC technology provides new ideas
for solving this problem.
In August this year, a research team at Harvard Medical School and Boston Children's Hospital announced the results of a study that through epigenetic remodeling inhibited by histone methyltransferase (EZH1), iPSCs can efficiently differentiate into T cells, and then further combined with gene editing technology to transform into CAR-T cells to produce an enhanced CAR-T
.
In fact, iPSC-derived CAR-T therapy has long entered the clinical stage, such as Fate's FT819 is the first FDA-approved iPSC-derived allogeneic CAR-T cell therapy
.

iPSC technology provides new ideas for solving this problem

In the combination of mRNA technology and CAR-T technology, BioNTech, which is famous for mRNA vaccines, has developed a CAR-T + CARVac (code: BNT211) therapy
.
It consists of two parts, one is autologous CAR-T therapy targeting the carcinoembryonic antigen Claudin-6, and the other is a CAR-T cell amplification RNA vaccine encoding CLDN6, which can stimulate CAR-T cell expansion
in vivo.
At the AACR Annual Meeting in 2022, the preliminary data of the Phase 1/2 clinical trial of BNT211 in the treatment of solid tumors verified the safety and efficacy
of this candidate therapy.

In combination with mRNA technology and CAR-T technology

In fact, there are still many companies
worthy of attention in the innovation of T cell therapy in domestic companies.
For example, in September this year, Guangzhou Baiji Biologics' world's first BRG01 injection IND was accepted
by CDE.
BRG01 injection is an autologous T cell immunotherapy product prepared by expressing receptors targeting Epstein-Barr virus (EBV) antigen on the surface of T cells by gene modification technology for the treatment of recurrent/metastatic nasopharyngeal carcinoma
.
At the same time, it is also the first product candidate targeting EBV antigen for the treatment of virus-associated solid tumors, filling the gap
in cell therapy in this field.

Guangzhou Baiji Biotech BRG01 injection is the first

Also in September, the IND of CAR-201 targeting CD19 non-viral PD1 fixed-point integration CAR-T cell injection BRL-201 independently developed by Bangyao Biologics was also accepted by CDE, which is the world's first CAR-T product targeting CD19 non-viral PD1 fixed-point integration, which can obtain genome fixed-point integration CAR-T cell products
through one-step preparation without using viral vectors.

The first BRL-201 of BRL-201

Behind these achievements are the continuous burst of innovation ability and clinical transformation ability
of research results of China's pharmaceutical companies.

Innovation ability and clinical transformation ability of research results

summary

Overall, CAR-T therapy is quite "plastic", in addition to the above innovative directions, there are more directions to be explored, and this extends to the entire cell therapy
.
What is exciting is that although China's cell immunotherapy started late, it has great development potential, gradually transforming from license in to independent research and development, and has successfully developed a number of First in class products
.
In recent months, China has also made a number of progress in the field of cellular immunotherapy, with a total of 20 product candidates entering the IND
in the third quarter.
I believe that in the future, more innovation potential
will burst out.

▲Summary of clinical declaration of cell immunotherapy in July to September in China (if there is omission, welcome to add)

Resources:

1.
White paper on the development of China's cell therapy industry

2.
Landscape of cancer cell therapies: trends and real-world data

3.
Official website of each company

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