A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer

J Transl Med. 2012 Aug 3;10:157. doi: 10.1186/1479-5876-10-157.

Abstract

Purpose: In spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease.

Rationale: Genetically reprogrammed, patient-derived chimeric antigen receptor (CAR)-T lymphocytes with the ability to recognize predefined surface antigens with high specificity in a non-MHC restricted manner have shown increasing anti-tumor efficacy in preclinical and clinical studies. Folate receptor-α (FRα) is an ovarian cancer-specific tumor target; however, it is expressed at low levels in certain organs with risk for toxicity.

Design: Here we propose a phase I study testing the feasibility, safety and preliminary activity of FRα-redirected CAR-T cells bearing the CD137 (4-1BB) costimulatory domain, administered after lymphodepletion for the treatment of recurrent ovarian cancer. A novel trial design is proposed that maximizes safety features.

Innovation: This design involves an initial accelerated dose escalation phase of FR-α CAR-T cells followed by a standard 3 + 3 escalation phase. A split-dose approach is proposed to mitigate acute adverse events. Furthermore, infusion of bulk untransduced autologous peripheral blood lymphocytes (PBL) is proposed two days after CAR-T cell infusion at the lower dose levels of CAR-T cells, to suppress excessive expansion of CAR-T cells in vivo and mitigate toxicity.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer*
  • Feasibility Studies
  • Female
  • Folate Receptor 1 / immunology*
  • Humans
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / therapy*
  • Recurrence
  • T-Lymphocytes / immunology*

Substances

  • Folate Receptor 1