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

Lana E Kandalaft,Daniel J Powell,George Coukos

doi:10.1186/1479-5876-10-157

Lana E Kandalaft, Daniel J Powell + Show 1 more

Open Access

https://doi.org/10.1186/1479-5876-10-157

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Abstract

PurposeIn spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease.RationaleGenetically 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.DesignHere 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.InnovationThis 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.

Highlights

Background and rationaleAdoptive T cell therapy in ovarian cancer Ovarian cancer is the fifth most common cancer in women, affecting one of every 55 women
There has been a single study of adoptive transfer of chimeric antigen receptor (CAR)-T cells in ovarian cancer, with specificity directed against folate receptor-α (FRα) [26]; while this study demonstrated safety, the results were disappointing, with no clinical tumor responses, most likely due to low expression of the transgenic CAR, and poor persistence of the transferred T cells
To maintain a low frequency of CAR-T cells in the repopulated host, we introduced a design whereby after uncontrolled expansion of CAR-T cells is allowed for 48 hours, a bulk of untransduced autologous peripheral blood lymphocytes (PBL) is infused

Summary

Introduction

Background and rationaleAdoptive T cell therapy in ovarian cancer Ovarian cancer is the fifth most common cancer in women, affecting one of every 55 women. There are about 21,650 new cases annually in the United States, with 15,520 deaths estimated in 2008 [1] making ovarian cancer the most common cause of death from gynecologic malignancy. While there have been improvements in the treatment of epithelial ovarian cancer, most patients present with Stage III or IV disease, which has a 5-year survival rate of less than 25% [2,3,4]. Cell transfer trials in ovarian cancer have been promising: In one such trial, administration of autologous tumor-infiltrating lymphocytes (TILs) to ovarian cancer patients after surgical resection and cisplatin chemotherapy resulted in prolonged disease-free survival and increased the 3-year survival rate, supporting the notion that T cell transfer can actively inhibit ovarian tumor growth [7]. Adoptive immunotherapy has much promise, several problems remain to be solved (reviewed in [5,6,9])

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