Chinese researchers have reported success in a phase II clinical trial of anti-CLDN18.2 chimeric antigen receptor T cells in refractory gastric and gastroesophageal junction cancer. The therapy significantly extended the lives of patients, according to a report on the trial published in The Lancet.
The technology of T-lymphocytes with chimeric antigen receptors (we talked about CAR-T-lymphocytes in detail in the article “Chimera against cancer”) allows achieving long-term remission and even complete cure in many patients who have not been helped by other types of therapy. Due to certain limitations of its first generations, only six drugs for the treatment of B-cell oncohematological diseases and one for the treatment of a solid tumor — one of the varieties of synovial sarcoma — have reached clinical use. The development of CAR-T therapy for other neoplasms is at various stages of preclinical and clinical trials.
Gastric cancer and gastroesophageal junction cancer are the fifth most common cancers in terms of incidence and mortality. About 40 percent of patients with these tumors intensely express claudin-18 isoform 2 (CLDN18.2). This is a protein that is part of the tight junctions of epithelial cells and is specific to the gastric epithelium. The tight junctions of healthy epithelium are inaccessible to biological drugs due to their location, but CLDN18.2 in tumors can serve as a target for therapy. A monoclonal antibody to this protein, zolbetuximab, is already used in CLDN18.2-positive gastric cancer in addition to chemotherapy; it must be administered regularly. The same target is targeted by the autologous CAR-T cell drug satricabtagene autoleucel (satri-cel, CT041), which showed satisfactory tolerability and possible efficacy in phase I trials.
Changsong Qi from Peking University, colleagues and CARsgen Therapeutics conducted the open-label, randomized phase 2 T041-ST-01 trial at 24 Chinese clinical centers. They enrolled 156 adult patients with HER2-negative, CLDN18.2-positive refractory unresectable gastric or gastroesophageal junction adenocarcinoma. After lymphodepletion, 104 of them were infused with 250 million cells of satricel up to three times, while the remaining 52 were prescribed standard therapy with nivolumab, paclitaxel, docetaxel, irinotecan, or rivoceranib at the physician’s discretion.
In the main group, 27 percent of participants had previously received three or more courses of chemotherapy, 69 percent had metastases to the peritoneum. In the control group, these figures were 19 and 60 percent. The median overall survival with satri-cel was 7.92 months versus 5.49 months with standard treatment (p = 0.0416), and the survival without tumor progression was 3.25 versus 1.77 months (p < 0.0001). Serious adverse events were reported in 99 percent of participants in the main group (most often a decrease in the level of leukocytes in general, lymphocytes, or neutrophils) and 63 percent in the control group. Cytokine release syndrome developed in 95 percent of patients after the introduction of satri-cel. The obtained results allow us to consider the use of satri-cel as a third-line therapy for advanced refractory HER2-negative, CLDN18.2-positive gastric and gastroesophageal junction cancer. Its use at earlier stages of such tumors deserves further study, the authors of the work conclude. Earlier, American researchers presented the results of pilot trials of new-generation CAR-T lymphocytes for recurrent glioblastoma, which involved three patients. The tumors quickly shrank in all participants, but subsequently relapsed in two.
