Anti-EGFR chimeric antigen receptor-modified T cells in metastatic pancreatic carcinoma: A phase I clinical trial.

The current clinical outcome for patients with metastatic pancreatic carcinoma (PC) remains poor. Epidermal growth factor receptor (EGFR) is detectable in PC, suggesting that EGFR is a rational target in PC. We conducted a phase I clinical trial to evaluate the safety and efficacy of autologous anti-EGFR chimeric antigen receptor-modified T (CAR T-EGFR) cells in patients with metastatic PC. The expression levels of EGFR on tumor cells detected by immunohistochemistry were required to be more than 50%. Sixteen patients were enrolled and received one to three cycles of the CAR T-EGFR cell infusion within 6 months (median dose of CAR T cells: 3.48 × 106/kg; range, 1.31 to 8.9 × 106/kg) after the conditioning regimen with 100 to 200 mg/m2 nab-paclitaxel and 15 to 35 mg/kg cyclophosphamide. Grade ≥3 adverse events included fever/fatigue, nausea/vomiting, mucosal/cutaneous toxicities, pleural effusion and pulmonary interstitial exudation and were reversible. Of 14 evaluable patients, four achieved partial response for 2-4 months, and eight had stable disease for 2-4 months. The median progression-free survival was 3 months (range, 4-months) from the first cycle of CAR T-EGFR cell treatment, and the median overall survival of all 14 evaluable patients was 4.9 months (range, 2.9-30 months). Decreased EGFR expression on tumor cells was observed in patients who achieved stable disease with shrinkage of metastatic lesions in the liver, and enrichment of central memory T cells in infused cells improved the clinical response. In conclusion, the treatment with CAR T-EGFR cells is safe and effective in patients with metastatic PC. This trial was registered at www.clinicaltrials.gov (identifier no: NCT01869166).

Liu Y ，Guo Y ，Wu Z ，Feng K ，Tong C ，Wang Y ，Dai H ，Shi F ，Yang Q ，Han W ... -  《-》

Phase I Study of Chimeric Antigen Receptor-Modified T Cells in Patients with EGFR-Positive Advanced Biliary Tract Cancers.

Purpose: This study is an expanded and parallel clinical trial of EGFR-specific chimeric antigen receptor-engineered autologous T (CART) cell immunotherapy (NCT01869166) to assess the safety and activity of CART-EGFR cell therapy in EGFR-positive advanced unresectable, relapsed/metastatic biliary tract cancers (BTC).Experimental Design: Patients with EGFR-positive (>50%) advanced unresectable, relapsed/metastatic BTCs were enrolled. Well-produced CART-EGFR cells were infused in a manner of dose escalation after the conditioning treatment with nab-paclitaxel (100-250 mg/m2) and cyclophosphamide (15-35 mg/kg).Results: A total of 19 patients (14 cholangiocarcinomas and 5 gallbladder carcinomas) received one to three cycles of CART-EGFR cell infusion (median CART cell dose, 2.65 × 106/kg; range, 0.8-4.1 × 106/kg) within 6 months. The CART-EGFR cell infusion was tolerated, but 3 patients suffered grade ≥3 acute fever/chill. Grade 1/2 target-mediated toxicities including mucosal/cutaneous toxicities and acute pulmonary edema and grade ≥3 lymphopenia and thrombocytopenia related to the conditioning treatment were observed. Of 17 evaluable patients, 1 achieved complete response and 10 achieved stable disease. The median progression-free survival was 4 months (range, 2.5-22 months) from the first cycle of treatment. Analysis of data indicated that the enrichment of central memory T cells (Tcm) in the infused CART-EGFR cells improved the clinical outcome.Conclusions: The CART-EGFR cell immunotherapy was a safe and active strategy for EGFR-positive advanced BTCs. The enrichment of Tcm in the infused CART-EGFR cells could predict clinical response. Clin Cancer Res; 24(6); 1277-86. ©2017 AACRSee related commentary by Kalos, p. 1246.

Guo Y ，Feng K ，Liu Y ，Wu Z ，Dai H ，Yang Q ，Wang Y ，Jia H ，Han W ... -  《-》

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

Feng K ，Liu Y ，Guo Y ，Qiu J ，Wu Z ，Dai H ，Yang Q ，Wang Y ，Han W ... -  《-》

Phase I clinical trial of EGFR-specific CAR-T cells generated by the piggyBac transposon system in advanced relapsed/refractory non-small cell lung cancer patients.

This phase I clinical trial is designed to assess the safety and feasibility of the epidermal growth factor receptor (EGFR) chimeric antigen receptor (CAR) T-cell generated by the piggyBac transposon system in advanced relapsed/refractory non-small cell lung cancer (NSCLC) patients. Compared to viral systems, the piggyBac transposon system is a simpler, more economical, and alternative way to introduce chimeric antigen receptor (CAR) transgenes into T cells. This study recruited nine patients with advanced relapsed/refractory EGFR-positive NSCLC for two cycles of the piggyBac-generated EGFR-CAR T cells at dose of 1 × 106 cells/kg or 3 × 106 cells/kg of body weight. The patients were monitored for adverse events, clinical response, and persistence of plasma GFR-CAR T cells. Infusions of piggyBac-generated EGFR-CAR T cells were well tolerated in all nine patients. The most common adverse events were grade 1 to 3 fever and there were no patients who experienced grade 4 adverse events or serious cytokine release syndrome. After treatment, eight of nine patients showed detectable EGFR-CAR T cells in their peripheral blood. One patient showed a partial response and lasted for more than 13 months, while six had stable disease, and two had progressed disease. The progression-free survival of these nine patients was 7.13 months (95% CI 2.71-17.10 months), while the median overall survival was 15.63 months (95% CI 8.82-22.03 months). This Phase I clinical trial revealed that the non-viral piggyBac transposon system-engineered EGFR-CAR T-cell therapy is feasible and safe in treatment of EGFR-positive advanced relapsed/refractory NSCLC patients. Future study will assess it in more patients or even possibly with a higher dose. Trial registration number NCT03182816.

Zhang Y ，Zhang Z ，Ding Y ，Fang Y ，Wang P ，Chu W ，Jin Z ，Yang X ，Wang J ，Lou J ，Qian Q ... -  《-》

Pilot Trial of Adoptive Transfer of Chimeric Antigen Receptor-transduced T Cells Targeting EGFRvIII in Patients With Glioblastoma.

Goff SL ，Morgan RA ，Yang JC ，Sherry RM ，Robbins PF ，Restifo NP ，Feldman SA ，Lu YC ，Lu L ，Zheng Z ，Xi L ，Epstein M ，McIntyre LS ，Malekzadeh P ，Raffeld M ，Fine HA ，Rosenberg SA ... -  《-》