Immunological targeting of CD133 in recurrent glioblastoma: A multi-center phase I translational and clinical study of autologous CD133 dendritic cell immunotherapy.

Abstract

2059 Background: A hallmark of glioblastoma is the high incidence of tumor recurrence, thought to be triggered by cancer stem cells. These tumorigenic cells are resistant to irradiation and chemotherapeutic agents. The target antigen, CD-133, was chosen because it has been reported as a cancer stem cell antigen overexpressed in glioblastoma tumors and associated with shorter survival. Recent clinical trials suggest that the mean overall survival for these patients is roughly 5-9 months, emphasizing the important unmet medical need in this disease requiring additional strategic approaches. Dendritic cell immunotherapies such as ICT-121 could provide benefit to patients by educating their immune systems to induce the formation of cytotoxic T cells that attack tumor cells bearing the target antigen. In addition to immediate attack on tumor cells present at dosing, a long-term memory response effective against tumor recurrence might be induced. Immunotherapy, such as ICT-121, that targets cancer stem cells could be an important treatment for this disease. Methods: This Phase I multi-center trial of ICT-121 targeting CD133 was designed to assess safety and tolerability (primary endpoint) and to monitor overall survival and progression-free survival (secondary endpoints). ICT-121 is comprised of autologous dendritic cells that are loaded with two HLA-A2 restricted epitopes of the CD133 antigen. CD133 is overexpressed on glioblastoma cancer stem cells. The HLA-A2 patients that had undergone resection for recurrence of glioblastoma were treated with ICT-121 once a week for 4 weeks during the induction phase and then once every 2 months during the maintenance phase until disease progression, death, ICT-121 depletion or discontinuation. Results: A total of 20 patients were treated and eight of these patients are still alive. Immune response data with cytokine mRNA expression demonstrated a response to the CD133 epitopes. A total of 20 patients were treated and eight of these patients are still alive. Conclusions: The results from this Phase I trial suggest that ICT-121 is both safe and well-tolerated with an immune response seen in a subset of patients. Clinical trial information: NCT02049489.

The role of CD133 in cancer: a concise review

“…Once mature, these cells were loaded purified peptides from the CD133 antigen [ 146 ]. An ongoing phase I clinical trial (NCT02049489) is still investigating the safety and effectiveness of ICT-121 administration to recurrent glioblastoma patients, however, preliminary results suggest that ICT-121 is safe and well tolerated and an effective immune response is currently being observed in a subset of patients [ 147 ].…”

Design, Characterization, and Evaluation of scFvCD133/rGelonin: A CD133-Targeting Recombinant Immunotoxin for Use in Combination with Photochemical Internalization

“…In spite of this, only modest cytotoxic effects on murine normal progenitor cells have been reported after systemic administration of CD133-targeting immunotoxins, which was related to lower CD133 expression levels in normal progenitor cells compared to CSCs [21]. Furthermore, immunological targeting of CD133 by a vaccine, ICT-121, containing autologous dendritic cells loaded with two HLA-A2 restricted epitopes of the CD133 antigen, in patient with recurrent gliomas was found both safe and well-tolerable [22]. However, as putative CSC-markers-including CD133are expressed on normal stem or progenitor cells, strategies that enhance the specificity and efficacy of CSC-targeting immunotoxins are warranted to avoid potential adverse effects.…”

An Fc-Optimized CD133 Antibody for Induction of Natural Killer Cell Reactivity Against Colorectal Cancer

“…However, in our previous in vitro studies with 293C3-SDIE, no toxicity against healthy hematopoietic progenitor cells was observed, likely due to their profoundly lower CD133 antigen levels [14]. In addition, the first two clinical phase I studies evaluating CD133 targeting therapeutics—anti-CD133 CAR-T cells and DC-based CD133 vaccination—did not reveal any unbearable toxicity against healthy CD133 expressing cells [36,37]. Nevertheless, this issue and the question whether and how it is effective to target the CD133 positive cell fraction—potentially representing CSCs as reported in previous studies for CRC [38,39,40]—requires further elucidation.…”