Global CAR-T Therapy R&D Guide

1 Introduction Adoptive immunotherapy with chimeric antigen receptor (CARs) T cells is a promising approach to improve the prognosis of cancer patients
.
Although CAR-T cells are very effective against hematological malignancies, overcoming solid tumors is still difficult, and the efficacy of this therapeutic approach needs to be improved
.
At present, methods to improve the anti-tumor activity of CAR-T cells include: 1.
Targeting multiple antigens; 2.
Improving T cell proliferation/persistence; 3.
Enhancing tumor homing and making CAR-T cells immune to immunity Suppress the tumor microenvironment (TME) to generate resistance
.
Enhancing signaling of T cell activation by transgenic expression of cytokines or engineered cytokine receptors has emerged as a promising strategy as it not only enhances CAR-T cell expansion and persistence, but also enhances Their function in the immunosuppressive TME
.
2 History of development CAR-T therapy is a type of adoptive immunotherapy (ACT), and its family also includes TIL (Daodu Corresponding Article Portal: Anti-Solid Tumor "Black Technology" - Global R&D Panorama of TIL Therapy), TCR -T, CAR-NK (Yaodu Corresponding Article Portal: Heavy! Global CAR-NK Cell Therapy Panorama) and other historical or promising methods in the future
.
Medical research is like the stock market.
It is impossible to say which method is good and which is not
.
Different methods, different indications, different applicable objects, the effect is not good today, and may become the dark horse of tomorrow with the development of related disciplines.
Just like mRNA technology, it was moved to Taiwan with the popularity of the new crown vaccine.
before
.
The earliest successful case of adoptive immunotherapy for cancer was the treatment of leukemia by Professor E.
Donnall Thomas through bone marrow transplantation between twins in 1956 to avoid graft-versus-host disease (GVHD).
Attacked by the recipient, causing multiple organ damage or even death
.
At the same time, the transplant failed
.
(This is like a battle between two armies.
Although they are both of the same kind, but because of their own masters, they must fight to the death and lose both
.
) Subsequently, Miller et al.
discovered the origin of T cells - derived from hematopoietic stem cells (fetal bone marrow and heart ), mature in the thymus
.
It was not until Steven Rosenberg reported a study on tumor-infiltrating lymphocytes (TILs) in 1986 that people's eyes were locked on the idea that "the patient's own immune cells can fight their own cancer"
.
In 1992, Sadelain et al.
successfully created the therapy of retrovirus-mediated gene transfer to T lymphocytes, making genetic modification a means of controlling immunity in experimental or therapeutic settings
.
All these have paved the way for the generation of CAR-T technology
.
3 About CAR-T therapy CAR-T therapy is to form CAR-T cells by modifying the patient's immune cells, introducing receptor genes that can encode tumor-specific antigens and various gene fragments that help T cells activate.
The cells not only carry the "navigation head" for recognizing tumors, but also enhance their own "munition depot" for killing tumors.
After the transformed T cells are expanded and cultured in vitro, they are returned to the patient.
will be activated and re-amplified, exerting its great specific lethality, causing tumor death
.
Figure 1.
Structure of Chimeric Antigen Receptor (CAR) Figure 2.
The CAR-T treatment process of the CAR-T treatment standard is mainly divided into the following seven steps: 1.
Assess whether the patient meets the indications for CAR-T treatment; 2.
Separation of T cells: Mononuclear cells are separated from the blood of tumor patients by a peripheral blood cell separator, and T cells are further purified by magnetic beads; The viral vector of the chimeric antigen receptor of T cells is transferred into T cells, that is, the T cells are transformed into CAR-T cells; 4.
Amplification of CAR-T cells: In vitro culture to expand CAR-T cells in large quantities
.
Generally, a patient needs tens of millions, or even hundreds of millions of CAR-T cells.
The larger the body weight, the more cells are required; 5.
CAR-T cells are returned to the human body: the expanded CAR-T cells are intravenously infused into the human body.
In the patient's body, tumor cell immunotherapy was started
.
6.
Monitor the reaction: closely monitor the patient's body reaction, especially severe adverse reactions may occur within one to two weeks after the cells are infused into the body
.
7.
Evaluation of the therapeutic effect: The therapeutic effect on the primary disease is usually evaluated on the 15th and 30th days after the CAR-T cell reinfusion
.
4 Challenges facing CAR-T cell therapy Understanding the challenges facing CAR-T cell therapy, identifying the mechanisms that lead to limitations and overcoming these obstacles can enable CAR-T cells to better realize their potential, optimize treatment strategies, and improve patient outcomes
.
Several key factors that have been found to affect the efficacy of CAR-T cell therapy include the manufacture of CAR-T cells, the management of toxic side effects, and the recurrence of drug resistance.

.
1 Problems in CAR-T cell manufacturing The challenges faced by CAR-T cell manufacturing involve multiple links such as T cell acquisition, isolation and screening, transduction, culture expansion, and initial T cell phenotype selection.
Optimization can achieve higher clinical efficacy and less toxic side effects of CAR-T cell products
.
At present, the CAR-T cells approved by the FDA are all autologous, and there is no risk of allogeneic rejection and graft-versus-host disease (GVHD), but it is difficult to obtain, and the cell quality is often not available.
Guaranteed
.
Using cells from healthy donors to produce CAR-T products is one solution to the problem of low-quality CAR-T cell sources
.
2 Toxic and side effects of CAR-T cell therapy Almost all patients receiving targeted CAR-T cell therapy have experienced toxic side effects of varying degrees, including cytokine release syndrome (CRS) and immune effector cell-related neurotoxicity Syndrome (immune effector associated neurotoxicity syndrome, ICANS), etc.
, the latter is also called neurotoxicity
.
The American Society for Transplantation and Cellular Therapy (ASTCT) has developed and published standardized grading recommendations for CRS and ICANS, which have guiding significance for the management and treatment of CAR-T toxicity
.
The clinical symptoms of CRS often start with fever, which can lead to systemic inflammatory response, hypotension, hypoxia and organ failure in severe cases; ICANS mainly manifests as toxic encephalopathy, which can lead to seizures, cerebral edema and coma in severe cases
.
Most of the patients with ICANS have a history of CRS, suggesting that CRS may be the initiating factor or promoting factor of ICANS
.
Toxic side effects are currently an important factor limiting the efficacy of CAR-T, hindering the enhancement of the anti-tumor effect of CAR-T cells by increasing the dose of CAR-T cells or enhancing effector activity
.
High tumor burden, advanced age, and high-intensity lymphodepleting preconditioning are thought to be associated with the occurrence of immunotoxic side effects
.
With the increase of treatment cases and the extension of follow-up time, more toxic and side effects appeared, such as hemophagocytic lymphohistiocytosis/macrophage activation syndrome-like toxicity, B cell aplastic anemia-related immune dysfunction Damaged state complicated by fatal infection, fatal cerebral edema,
etc.
Existing studies have found that adding suicide genes, such as inducible caspase-9 or herpes simplex virus thymidine kinase, to CAR is a possible way to reduce the cytotoxic side effects of CAR-T, but it will cause irreversible clearance of CAR-T cells and reduce resistance.
Tumor efficacy
.
3 Recurrence of drug resistance after CAR-T cell therapy Despite the great breakthrough of CAR-T cell therapy for hematological malignancies, more than half of the patients who received BCMA CAR-T therapy in a relatively short follow-up Relapse within a year
.
The exact mechanism leading to disease relapse/resistance is still unclear, but several possibilities have been proposed: 1) survival of CAR-T cells; 2) antigen escape; 3) tumor immune microenvironment
.
5 Research and development progress According to the statistics in the figure above, as of the end of 21, 6 CAR-T cell therapies have been approved for the market globally, of which the FDA has approved 5 models, including four CAR-T cell therapies targeting CD19 and one targeting BCMA
.
In 2021, the FDA has approved the marketing applications of Breyanzi and Abecma, the former is a CD19 CAR-T and the latter is a BCMA CAR-T; NMPA approved 2 CAR-T cell therapies
.
(Legend Bio has received an email notification from the US FDA on February 11, suspending the Phase I clinical trial of its CAR-T product LB1901.
It is understood that the clinical trial was not stopped by the FDA, but the patients who were tested appeared.
the situation
.
) 1 International progress International leading companies are also constantly updating progress and competing with each other
.
Such as: Allogene, Atara, Precision, Poseida, Adicet Bio, Cellectis, Takeda Pharmaceutical,
etc.
2 Domestic progress Leading domestic companies such as Gracell Bio, Beiheng Bio, Maoxing Bio, Bangyao Bio, and Longyao Bio have maintained their development momentum, and have also added some new rising stars
.
Gracell On January 13, 2021, Gracell announced that GC007g injection has been approved by China's National Medical Products Administration (NMPA) to conduct Phase 1/2 clinical trials in December 2020, of which Phase II clinical trial data will be used as Pivotal clinical studies are used to support launch
.
GC007g is the first donor-derived allogeneic CAR-T cell therapy in China for the treatment of B-ALL patients who have previously undergone allogeneic transplantation (HSCT)
.
On April 2, 2021, Gracell announced that the first patient was enrolled in the Phase 1/2 registrational clinical study of GC007g
.
In April 2021, Gracell announced its general CD7 CAR-T product candidate GC027 based on the TruUCAR platform in the form of an electronic poster at the American Association for Cancer Research (AACR) annual meeting in the treatment of relapsed or refractory acute T lymphoblastic leukemia ( r/r T-ALL) latest long-term follow-up data in adult patients
.
In December 2020, Beiheng Bio announced the research data of its universal CD19/CD22 dual-target CAR-T product CTA101 in the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia at the ASH annual meeting
.
The results will be published as a paper in Clinical Cancer Research in April 2021
.
Perhaps based on the positive test results, in March 2021, Beiheng Bio announced the completion of a RMB 520 million Series B financing to accelerate the development and clinical transformation of universal immune cell therapy
.
In December 2021, according to the official website of the Center for Drug Evaluation (CDE) of the State Food and Drug Administration, the new drug clinical trial application for the CTA101 UCAR-T cell injection product independently developed by Beiheng Bio was accepted (acceptance number: CXSL2101509), which is a drug review The first "off-the-shelf" allogeneic CAR-T product accepted by the center
.
In June 2021, Beiheng Bio's anti-CD7 universal CAR-T (UCAR-T) cell therapy product CTD401 received FDA Orphan Drug Designation (ODD) for the treatment of T-cell acute lymphoblastic leukemia (T-cell acute lymphoblastic leukemia).
-cell Acute Lymphoblastic Leukemia (T-ALL))
.
In January 2022, the anti-claudin18.
2 autologous CAR-T cell therapy product CTB001 developed by Beiheng Bio received Orphan Drug Designation (ODD) from the U.
S.
Food and Drug Administration (FDA) for the treatment of Gastric cancer
.
In October 2021, Guangdong Ruishun Biotechnology Co.
, Ltd.
(referred to as "Ruishun Bio" or the "Company") announced the completion of RMB 137 million in Series A financing
.
This round of funds will be used for the registration clinical trial of the world's first universal DNT cell drug RC1012 injection; the preclinical research and IND application of CAR-DNT, Gene Editing CAR-DNT, iPSC-CAR-iDNT and other product pipelines ; and the construction of places such as R&D centers and preparation centers, and the expansion of subsequent project teams
.
Maoxing Technology In August 2021, Maoxing Technology Co.
, Ltd.
(hereinafter referred to as Maoxing Technology) announced the completion of an angel + round of financing of tens of millions of yuan.
This round of financing was led by Haibang Medical Fund, followed by Hongfeng Investment, and Haoyue Capital served as this round.
Exclusive financial advisor for financing
.
The company's product candidate has demonstrated a 100% objective response rate in three patients with relapsed advanced glioblastoma in an investigator-initiated clinical trial
.
Boshengji In May 2021, the clinical trial application (IND) of Boshengji for CD7-targeted allogeneic CD7-CAR-T cell injection was accepted by NMPA
.
The injection is a CD7-targeting CAR-T cell drug produced by using T lymphocytes of stem cell transplant donors from patients
.
6 Summary CAR-T cell immunotherapy has brought new hope to patients with hematological malignancies, making it possible to cure refractory and recurrent hematological malignancies
.
Although there are still many challenges in CAR-T cell therapy, such as immunogenicity, drug resistance, toxicity, etc.
, with the development of gene editing technology and the development of other immune target drugs, through continuous optimization of design and combination with With the combined use of other immunotherapies, it is believed that CAR-T cells are still one of the most promising cancer immunotherapy methods, and are expected to break through the limitations of solid tumors, expand indications, and cure more diseases in the future
.
*Disclaimer: The statistics in this article are as of December 31, 2021, and due to the limited level of the author, if there are any deficiencies in the content and statistics, please add and correct
.
References: [1] Batlevi Connie Lee, Matsuki Eri, Brentjens Renier J, Younes Anas.
Novel immunotherapies in lymphoid malignancies.
[J].
Nature reviews.
Clinical oncology, 2016, 13(1).
[2] Teresa R.
Abreu , Nuno A.
Fonseca, Nélio Gonçalves, João Nuno Moreira,Current challenges and emerging opportunities of CAR-T cell therapies,Journal of Controlled Release,Volume 319,2020,Pages 246-261.
[3] Larson RC, Maus MV.
Recent advances and discoveries in the mechanisms and functions of CAR T cells.
Nat Rev Cancer.
2021 Mar;21(3):145-161.
[4] Teresa R.
Abreu, Nuno A.
Fonseca, Nélio Gonçalves, João Nuno Moreira, Current challenges and emerging opportunities of CAR-T cell therapies,Journal of Controlled Release,Volume 319,2020,Pages 246-261.
[5] R&D guest "Universal cell therapy research and development company Usainuo completed 160 million yuan in Series A financing| Press release"
.
[6] Chinese Journal of Cancer Prevention, Volume 13, Issue 6, December 2021
.
[7] Official website of each company