Gastric Cancer CAR T-cell Target Antigen ID'd

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the care of patients with advanced hematologic malignancies, but to date it has not made significant inroads against solid tumors. The difference is likely due to the greater heterogeneity of solid tumor antigens, a stronger immunosuppressive tumor microenvironment, and a higher likelihood of off-target effects and toxicities, according to cellular therapy researchers.

For example, a clinical trial of a promising CAR T-cell construct directed at prostate-specific membrane antigen on prostate cancer cells was recently halted because two patients died from immune effector cell–associated neurotoxicity syndrome (ICANS), despite the lack of dose-limiting toxicities in the trial and only a single, treatable case of cytokine release syndrome (CRS; Lancet Oncol 2021;22:893).

Now, however, investigators from China have identified what they describe as a promising antigen target for treating patients with advanced gastric cancers and cancers of the gastroesophageal junction (GE/GEJ) and possibly other late-stage digestive system cancers.

“The acceptable safety profile with very promising results of this CAR T-cell therapy could be a breakthrough treatment for gastric or other GI cancers,” said investigator Changsong Qi, MD, from Peking University Cancer Hospital and Institute in Beijing, China, who presented data from a 37-patient phase I trial at the 2021 European Society for Medical Oncology Congress, held September 16–21.

Qi and colleagues conducted the dose-escalation and safety trial using a CAR T-cell construct (CT041; CARsgen Therapeutics) targeted to isoform 2 of the tight junction protein claudin 18—claudin 18.2—which is expressed at medium to high levels on the cell membranes of stomach mucosal cells in about 60% of patients with GE/GEJ cancers and becomes targetable in gastric malignancies when the tight junctions are disrupted.

An efficacy analysis from the trial showed that 31 of the 37 patients—all of whom had GE/GEJ cancer, pancreatic ductal adenocarcinoma, or other, unspecified digestive system malignancies that were previously treated—had some measurable degree of tumor shrinkage. Among all patients, the median overall survival (OS) and duration of response had not yet been reached at a median of 7.8 months of follow-up from the time of CAR T-cell infusion. At the time of data cutoff, the objective response rate (ORR) was 48.6%, and the disease control rate (DCR) was 73%.

Among 22 patients in the dose-expansion phase, the ORR and DCR for patients who had previously received two or more therapies were 61.1% and 83.3%, respectively. The median progression-free survival (PFS) was 5.4 months, and OS was 9.5 months.

Patients generally tolerated the drug well, with only one dose-limiting toxicity and no treatment-related deaths or cases of ICANS. However, nearly all patients (94.6%) had grade 1 or grade 2 CRS, and all 37 patients enrolled in the dose-finding and dose-escalation phases of the trial had grade 3 or grade 4 hematologic toxicities.

The trial results support further development of claudin 18.2 as a target for cellular therapies, with efficacy superior to that seen with other third-line therapies, commented Kohei Shitara, MD, from the National Cancer Center Hospital East in Kashiwa-shi, Chiba, Japan, the study's discussant.

He noted that the ORR for third-line therapies in gastric cancers in clinical trials of chemotherapy, immunotherapy, and targeted agents has ranged from about 10% to 30%, with median PFS lasting less than 6 months with generally short OS. The PFS with CT041 was comparable to that seen with trastuzumab deruxtecan (Enhertu; Daiichi-Sankyo, AstraZeneca), but the latter is effective only in patients with HER2-positive tumors, which account for roughly just 22% of gastric cancers.

Shitara did acknowledge the pitfalls of comparing outcomes from different trials, but he added that “the results from this study are really encouraging.”—Neil Osterweil