3042 Background: Expressed by cancer stem cells of various epithelial cell origins, CD133 is an attractive therapeutic target for cancers. Autologous chimeric antigen receptor-modified T cells directed CD133 (CART-133) were firstly tested in this clinical trial. We aimed to determine the safety dosage, toxicity and biological activity of CART-133 in epithelium-derived solid tumors. Methods: The initially enrolled 8 patients with sorafenib-refractory hepatocellular carcinoma (HCC), treated by CART-133 monotherapy, were assigned into 3 dose cohorts (1, 0.5-1.5×105/kg; 2, 5-10×105/kg; 3, 1-2×106/kg). For the additional 16 patients (6 HCCs, 7 pancreatic carcinomas, 2 colorectal carcinomas, and 1 cholangiocarcinoma), all non-HCCs were conditioned by regimen (Nab-pacitaxel/cyclophosphamide or anti-PD1 antibody) before cell infusions. Results: For the initial 8 HCCs, 1 from cohort 2 occurred hemoglobin/platelet decline and direct hyperbilirubinemia (Grade 3), 4 from cohort 2/3 reported delayed low fever, nausea accompanied with elevation of CRP and serum cytokines. The 4-6 week persistence of relatively higher CAR copy numbers and its reverse relationship with the count of CD133+ cells harboring pro-metastatic epithelial progenitor cells in peripheral blood led to the determination of acceptable cell infusion dose from 0.5 to 2×106/kg and reinfusion cycle in 24 patients. Similar toxicities ( ≤ Grade 3) were observed in 15 cases. The cholangiocarcinoma patient who uniquely received 1 cycle of CART-133 infusion after anti-PD1, developed Grade 3 skin/mucosal vasculature damage, blood three-lineage decline and cytokine release syndrome, whereas, obtained a 4.5 month-lasting partial remission. Although no marked reduction of tumor volume was observed in most patients, 21 out of 23 patients had an 8-22 week progression-free survival, 2 patients without bulky tumor burden attained 8/10-month ongoing stable disease by the cut-off data (Jan 1, 2017). Conclusions: This trial showed the feasibility, controllable toxicities and effective biological activity of CART-133 transfer for the treatment of late-stage tumor patients. Clinical trial information: NCT02541370.
