Each year, approximately one million new cases of gastric cancer, diseases of malignant glandular cells, are diagnosed worldwide. And despite recent advances in treatment options, relapse is inevitable and patients become refractory to treatment.
According to recent data, the five-year survival for patients diagnosed with advanced gastric cancer is about 5–20% and the median overall survival is about 10 months 
The poor prognosis of these two cancer types highlights the need for additional treatment approaches.
Incidence in China
In 2020, there were 480,000 new cases of gastric cancer in China, accounting for 43.9% of the total incidence globally. Moreover, there is a rising trend in the incidence of gastric cancer among young people.
Major treatments for advanced gastric cancer are chemotherapy and HER2-targeted therapy, but the percentage of HER2-positive patients in gastric cancer is only 7-20%. Despite several products such as PD-1 monoclonal antibodies that have been approved for advanced gastric cancer in recent years, there are still significant needs for innovative therapies.
Results from an investigator-initiated trial (IIT) of CT041 a Claudin18.2 (CLDN18.2) CAR T-cell therapy being developed by CARsgen Therapeutics for the treatment of digestive system tumors were presented during the European Society of Medical Oncology Congress 2021 (ESMO 2021).
Claudin-18 isoform 2
The tight junction molecule claudin-18 isoform 2 or CLDN18.2 is a highly selective member of the claudin family of proteins, which includes tight junction proteins that establish paracellular barriers to control the flow of molecules between cells. 
CLDN18.2 is normally found in the cellular tight junctions of gastric mucosa and intestinal epithelium.  In the healthy stomach, it is strictly confined to differentiated epithelial cells of the gastric mucosa, but it is absent from the gastric stem cell zone.  CLDN18.2 is expressed in at least 60% of gastric cancers, as well as other cancers of the gastrointestinal tract.
Because the expression of CLDN18.2 is highly restricted in normal tissues, but frequent ectopic activation is seen in a diversity of human cancers, combined with the ability to specifically target this molecule at the cell surface of tumor cells, makes it a compelling protein for targeted therapy of epithelial tumors. 
The Only CLDN18.2-targeted CAR-T cell therapy
CT041 is currently the only CLDN18.2-targeted CAR-T cell therapy that has obtained IND clearance and is under clinical trials in both China and the United States. The drug was granted an “Orphan Drug” designation by the U.S. Food and Drug Administration (FDA) in 2020 for the treatment of gastric cancer/gastroesophageal junction (GC/GEJ) cancer and was granted the “Orphan Medicinal Product” designation by the European Medicine Agency (EMA) for the treatment of gastric cancer in 2021.
Results from an ongoing multicenter open-label investigator-initiated phase 1/2 clinical trial in China for patients with CLDN18.2+ (≥+, ≥10%) digestive system tumors, show positive results. The study consists of a dose-escalation stage and a dose-expansion stage. The primary objective of this trial is to assess the safety and tolerability of CT041 and the secondary objective is to assess the efficacy and pharmacokinetics.
As of April 8, 2021, 37 patients received CT041 infusion and completed at least 12 weeks of evaluation, including 28 cases of gastric/ gastroesophageal junction cancer (GC/GEJ), 5 cases of pancreatic cancer (PC), and 4 cases of other types of digestive system tumors. The cell dose levels were 2.5×108, 3.75×108, and 5.0×108 CAR-T cells respectively. Approximately 84% of patients had received at least 2 prior lines of therapies and the median number of metastatic organs was 3. For the 28 patients with GC/GEJ, 67.9% of the subjects had peritoneal metastases. 42.9% and 35.7% of the subjects had been exposed to anti-PD-(L)1 antibody and polykinase inhibitors respectively.
The results of the study show that CT041 was generally well-tolerated. No treatment-related death or immune cell therapy-associated neurotoxicity syndrome (ICANS) were reported. Approximately 95% of patients experienced CRS, all being grade 1 or 2.
For the 36 patients with target tumor lesions (GC/GEJ, PC and other types of digestive system tumors), 31 subjects had different degrees of shrinkage of target lesions with an ORR of 48.6% and a disease control rate (DCR) of 73.0%.
18 GC/GEJ patients who failed at least 2 prior lines of therapy (including 8 (44% of) patients ever exposed to an anti-PD-(L)1 antibody) at the dose of 2.5×108 (recommended phase 2 dose (RP2D)) CAR-T cells achieved an ORR of 61.1%, DCR of 83.3%, median PFS of 5.6m, median DOR of 6.4m, median OS of 9.5m with a median follow up of 7.6m.
For the 28 GC/GEJ patients, subgroup analysis revealed that ORR could be maintained at 50% and above in patients with different baseline characteristics.
Historical data shows that for the GC/GEJ patients who failed at least 2 prior lines of therapy, the efficacy rate of chemotherapy is about 4% to 8%, and the efficacy rate of anti-PD-1 antibody is about 11%. Therefore, compared with other treatments for GC/GEJ patients who failed at least two prior lines of therapies, CT041 has a significant improvement of ORR. Since many patients in this phase of the trial had received anti-PD-(L)1 antibody treatment, the efficacy data disclosed indicate that CT041 may become a new treatment for advanced GC/GEJ patients.
“Gastric cancer is of high incidence globally and particularly in Asia,” Noted Professor Lin Shen, MD of Beijing Cancer Hospital.
“Gastric cancer incidence in China is approximately 50% of the overall global incidence. Research and treatment options for gastric cancer are still quite limited and there is a strong need for more innovative therapies to change the treatment paradigm. Data presented at ESMO showed significant efficacy and excellent tolerability of CT041 and we hope that it could benefit more cancer patients,” she added.
“I would like to express the sincere gratitude to all investigators and researchers involved in the development of this CLDN18.2 CAR-T, which offers new hope for gastric cancer patients. With the mission of ‘making cancer curable’, we will continue our endeavors in developing more innovative technology and products for cancer patients worldwide,” said Zonghai Li, MD, Co-founder, CEO, CSO, Chairman of the Board of CARsgen Therapeutics
Claudin18.2 CAR-T (CT041) in Patients With Gastric or Pancreatic Cancer – NCT04404595
Study to Evaluate the Efficacy, Safety and Pharmacokinetics of CT041 Autologous CAR T-cell Injection – NCT04581473
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Featured image: Before COVID-19 – General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2019. Photo Courtesy: European Society for Medical Oncology (ESMO). Used with Permission.