CD133-directed CAR T cells for advanced metastasis malignancies: A phase I trial

Abstract

Expressed by cancer stem cells of various epithelial cell origins, CD133 is an attractive therapeutic target for cancers. Autologous chimeric antigen receptor-modified T-cell directed CD133 (CART-133) was first tested in this trial. The anti-tumor specificity and the postulated toxicities of CART-133 were first assessed. Then, we conducted a phase I clinical study in which patients with advanced and CD133-positive tumors received CART-133 cell-infusion. We enrolled 23 patients (14 with hepatocellular carcinoma [HCC], 7 with pancreatic carcinomas, and 2 with colorectal carcinomas). The 8 initially enrolled patients with HCC were treated by a CART-133 cell dose escalation scheme (0.05–2 × 106/kg). The higher CAR-copy numbers and its reverse relationship with the count of CD133+ cells in peripheral blood led to the determination of an acceptable cell dose is 0.5–2 × 106/kg and reinfusion cycle in 23 patients. The primary toxicity is a decrease in hemoglobin/platelet (≤ grade 3) that is self-recovered within 1 week. Of 23 patients, three achieved partial remission, and 14 achieved stable disease. The 3-month disease control rate was 65.2%, and the median progression-free survival was 5 months. Repeated cell infusions seemed to provide a longer period of disease stability, especially in patients who achieved tumor reduction after the first cell-infusion. 21 out of 23 patients had not developed detectable de novo lesions during this term. Analysis of biopsied tissues by immunohistochemistry showed CD133+ cells were eliminated after CART-133 infusions. This trial showed the feasibility, controllable toxicities, and effective activity of CART-133 transfer for treating patients with CD133-postive and late-stage metastasis malignancies.

CD133 as a regulator of cancer metastasis through the cancer stem cells

“…In a case report from a clinical trial, a metastatic cholangiocarcinoma patient who received therapy of CART-EGFR followed by CART-CD133 responded to the CART cocktail treatment (Feng et al, 2017). In the most recently reported phase I clinical trial for CART-CD133 therapy, 23 patients with metastatic and CD133 + tumors of hepatocellular carcinoma, pancreatic cancer or colorectal cancer were repeatedly given CART-CD133 infusions (Wang et al, 2018). No severe cytotoxicity was observed among these patients, and 21 of them had no detectable de novo tumor cells after CART-CD133 treatments.…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…In sarcoma, anti-HER2 CAR T cells showed a reassuring safety profile (134) and led to CR in one case (135), while anti-GD2 constructs demonstrated significant clinical activity in 5 out of 11 patients with active neuroblastoma, including 3 CR (136). Signs of activity were also shown in recent studies involving epithelial tumors (137)(138)(139)(140). The concept of the central nervous system (CNS) as an immune privileged site has been overturned in recent years, since T cells can penetrate the blood-brain barrier and infiltrate the brain in a diffuse manner (141); as a matter of fact, one of the most promising field of CAR T cells development in solid malignancies are CNS tumors.…”

CAR T cells for brain tumors: Lessons learned and road ahead

“…On the other hand, CAR T cells have been developed against CD133 which is one of the surface markers of cancer stem cells including GSCs . CD133‐CAR T cells have shown preclinical cytotoxicity against patient‐derived GSCs, as well as anti‐tumor response in patients with tumors in liver, pancreas, and colon . However, CD133 is also expressed in neural stem cells, thus raising the safety concerns of applying CD133‐CARs to GBM patients.…”