Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers

Abstract

This phase I clinical trial (NCT01935843) is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell (CART) immunotherapy targeting human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancers (BTCs) and pancreatic cancers (PCs). Eligible patients with HER2-positive (>50%) BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nab-paclitaxel (100-200 mg/m²) and cyclophosphamide (15-35 mg/kg). CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CART-HER2 cell infusion (median CAR⁺ T cell 2.1 × 10⁶/kg). The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgia/arthralgia, and lymphopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase (>9 ULN), adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post-infusion toxicities included one case of reversible severe upper gastrointestinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1-2 delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months (range, 1.5-8.3 months). Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encouraging signals of clinical activity.

Keywords: CART; HER2; biliary tract cancers; clinical trial; pancreatic cancers.

Figure 1

Phenotype of the cultured CART-HER2 cells

Figure 2

Release of CRP and cytokines at scheduled time points and occasional time points from patients’ peripheral blood since the enrollment of CART-HER2 cell therapy. (A) Change of CRP during the CART-HER2 cell therapy. (B) The level of IL-6 release monitored according to the study flowchart. (C) Release of interleukin-2 (IL-2). (D) Fluctuation of interleukin-8 (IL-8) following the treatment of CART-HER2 cell infusion. (E) Interleukin-10 (IL-10) detected after the CART-HER2 cell treatment. (F) Release of tumor necrosis factor-α (TNF-α)

Figure 3

Clinical response. (A) Best overall response from baseline in the sum of the longest diameters of target lesions as assessed per RECIST 1.1 in patients who had at least one post-baseline tumor assessment. (B) Patient No. 1, a 62-year-old male with poorly differentiated perihilar CCA accompanied by Her2 protein overexpressed in >90% tumor cells, whose PET-CT showed 2 metastatic lesions in his hepatic hilum (yellow arrows) obtained a PR 4 weeks after one cycle of CART-HER2 therapy, assessed by PET-CT showing the disappearance of lesion 2

Figure 4

Change of CAR transgene copy number level in the peripheral blood following the infusion of CART-HER2 cells. Rapid elevation of CAR transgene copy numbers (>2.5-fold of the baseline value) was observed in 9/11 patients, meanwhile, 9/11 patients’ serum CAR transgene copy numbers were still above 2-fold of the baseline level. The CAR transgene copy number after the second cycle infusion of CART-HER2 cells could reach to a similar peak of the first cycle

Figure 5

Study flowchart of CART-HER2 therapy. PBMC: peripheral blood mononuclear cell. CTX: cyclophosphamide