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Claudin-specific CAR T cells safe, effective in advanced gastric, pancreatic adenocarcinoma

CHICAGO — One-third of a small cohort of patients with advanced gastric or pancreatic adenocarcinoma achieved objective responses to treatment with a novel claudin 18.2-specific chimeric antigen receptor T-cell therapy, according to results of a single-arm, phase 1 trial presented at ASCO Annual Meeting.

CAR-CLDN18.2 (CARsgen Therapeutics) targets claudin 18.2, a stomach-specific isoform of claudin-18 that is highly expressed in gastric and pancreatic adenocarcinomas.

“Previous studies have shown that claudin 18.2 is expressed in gastric cancer, pancreatic cancer and gastroesophageal adenocarcinoma. More specifically, it is strictly confined to differentiated epithelial cells of the gastric mucosa,” Jie Li, MD, of Changhai Hospital at the Second Military Medical University of China, and one of the study’s co-authors, said during the presentation.

“Our preclinical study has shown potent in vivo antitumor activity of CLDN18.2 CAR T cells in mice bearing gastric [cancer cell] lines,” she added. “Claudin 18.2 is a pan-cancer target that is expressed in a diverse variety of epithelial tumor types.”

Li and colleagues conducted a first-in-human, open-label, single-arm, phase 1 pilot study to evaluate autologous CAR-CLDN18.2 T cells among patients with advanced gastric or pancreatic adenocarcinoma whose tumors expressed claudin 18.2. Assessment of safety, tolerability and pharmacokinetics of CAR-CLD18.2 T cells served as the study’s primary objective. Secondary objectives to determine efficacy and included objective response rate, time to disease progression, disease control rate, PFS and OS.

Twelve patients (seven women, five men; age range, 43-67 years) have been treated in the trial as of Nov. 30, 2018. All patients have biopsy-confirmed claudin 18.2-positive disease and have received at least one previous line of treatment. Five patients in the study have advanced pancreatic cancer, whereas seven patients have advanced gastric cancer.

The median manufacturing time for CAR-CLD1N8.2 T cells was 8 to 11 days after undergoing apheresis to harvest the patient’s T cells. Patients underwent lymphodepletion with fludarabine, cyclophosphamide and/or nab-paclitaxel before CAR-CLDN18.2 T-cell infusion. The trial design calls for follow-up evaluations for 2 years after infusion.

Patients have been treated with one to five cycles of CAR-CLDN18.2 T cells (range, 0.5-55 × 108).

Eleven patients had evaluable results, which included one complete response and three partial responses. Five patients achieved stable disease, whereas two patients experienced disease progression. Eight of the 12 patients had tumor regression per RECIST 1.1 criteria.

The ORR was 33.3%, with a disease control rate of 75%. Median PFS was 136 days (95% CI, 44-237), and median OS was 242 days (95% CI, 55-349).

All 12 patients in the trial experienced treatment-related adverse events, including one patient who had to withdraw from the study. There were no treatment-related deaths or dose-limiting toxicities.

Four patients (33.3%) experienced grade 3 fever. All 11 patients who remained in the trial had either grade 1 (n = 8) or grade 2 (n = 3) cytokine release syndrome.

“The peak of cell expansion is related to the occurrence of CAR [cytokine release syndrome],” Li said during the presentation.

There were no cases of grade 3 or higher neurotoxicity.

“Claudin 18.2 CAR T cells combined with preconditioning chemotherapy was well-tolerated in patients treated at the active dose for at least two cycles,” Li said.

The trial design calls for follow-up evaluations for 2 years after infusion.

“This first-in-human Claudin18.2 CAR T-cell therapy trial demonstrated that claudin 18.2 CAR T cells combined with preconditioning chemotherapy may have therapeutic efficacy in patients with advanced gastric and pancreatic adenocarcinoma,” Li said. – by Drew Amorosi

Reference:

Zhan X, et al. Abstract 2509. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosures: Li reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.

CHICAGO — One-third of a small cohort of patients with advanced gastric or pancreatic adenocarcinoma achieved objective responses to treatment with a novel claudin 18.2-specific chimeric antigen receptor T-cell therapy, according to results of a single-arm, phase 1 trial presented at ASCO Annual Meeting.

CAR-CLDN18.2 (CARsgen Therapeutics) targets claudin 18.2, a stomach-specific isoform of claudin-18 that is highly expressed in gastric and pancreatic adenocarcinomas.

“Previous studies have shown that claudin 18.2 is expressed in gastric cancer, pancreatic cancer and gastroesophageal adenocarcinoma. More specifically, it is strictly confined to differentiated epithelial cells of the gastric mucosa,” Jie Li, MD, of Changhai Hospital at the Second Military Medical University of China, and one of the study’s co-authors, said during the presentation.

“Our preclinical study has shown potent in vivo antitumor activity of CLDN18.2 CAR T cells in mice bearing gastric [cancer cell] lines,” she added. “Claudin 18.2 is a pan-cancer target that is expressed in a diverse variety of epithelial tumor types.”

Li and colleagues conducted a first-in-human, open-label, single-arm, phase 1 pilot study to evaluate autologous CAR-CLDN18.2 T cells among patients with advanced gastric or pancreatic adenocarcinoma whose tumors expressed claudin 18.2. Assessment of safety, tolerability and pharmacokinetics of CAR-CLD18.2 T cells served as the study’s primary objective. Secondary objectives to determine efficacy and included objective response rate, time to disease progression, disease control rate, PFS and OS.

Twelve patients (seven women, five men; age range, 43-67 years) have been treated in the trial as of Nov. 30, 2018. All patients have biopsy-confirmed claudin 18.2-positive disease and have received at least one previous line of treatment. Five patients in the study have advanced pancreatic cancer, whereas seven patients have advanced gastric cancer.

The median manufacturing time for CAR-CLD1N8.2 T cells was 8 to 11 days after undergoing apheresis to harvest the patient’s T cells. Patients underwent lymphodepletion with fludarabine, cyclophosphamide and/or nab-paclitaxel before CAR-CLDN18.2 T-cell infusion. The trial design calls for follow-up evaluations for 2 years after infusion.

Patients have been treated with one to five cycles of CAR-CLDN18.2 T cells (range, 0.5-55 × 108).

Eleven patients had evaluable results, which included one complete response and three partial responses. Five patients achieved stable disease, whereas two patients experienced disease progression. Eight of the 12 patients had tumor regression per RECIST 1.1 criteria.

The ORR was 33.3%, with a disease control rate of 75%. Median PFS was 136 days (95% CI, 44-237), and median OS was 242 days (95% CI, 55-349).

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All 12 patients in the trial experienced treatment-related adverse events, including one patient who had to withdraw from the study. There were no treatment-related deaths or dose-limiting toxicities.

Four patients (33.3%) experienced grade 3 fever. All 11 patients who remained in the trial had either grade 1 (n = 8) or grade 2 (n = 3) cytokine release syndrome.

“The peak of cell expansion is related to the occurrence of CAR [cytokine release syndrome],” Li said during the presentation.

There were no cases of grade 3 or higher neurotoxicity.

“Claudin 18.2 CAR T cells combined with preconditioning chemotherapy was well-tolerated in patients treated at the active dose for at least two cycles,” Li said.

The trial design calls for follow-up evaluations for 2 years after infusion.

“This first-in-human Claudin18.2 CAR T-cell therapy trial demonstrated that claudin 18.2 CAR T cells combined with preconditioning chemotherapy may have therapeutic efficacy in patients with advanced gastric and pancreatic adenocarcinoma,” Li said. – by Drew Amorosi

Reference:

Zhan X, et al. Abstract 2509. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosures: Li reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.

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