Camptothecin (CPT), a natural alkaloid isolated from Camptotheca acuminata, has potent broad spectrum antitumor activity by inhibiting type I DNA topoisomerase. It has not been used clinically because it is water-insoluble and highly toxic. As a result, irinotecan (CPT-11), a water-soluble analogue of CPT, has been developed and used as salvage chemotherapy in patients with refractory/relapsed lymphoma, but with only modest activity. For intravenous administration, we have developed IT-101, a ca. 40 nm diameter nanoparticle that is an assembly of cyclodextrin-based polymer conjugates of 20-(S)-CPT. The purpose of this study is to compare the preclinical efficacy of IT-101 with CPT-11 both in vitro and in vivo. Fluorescence microscopy studies demonstrated that incubation of a human lymphoma cell line with IT-101 resulted in the uptake and intracellular accumulation of CPT. Based on the demonstration of in vitro cytotoxity of IT-101 against multiple human lymphoma cell lines, we initiated experiments in xenograft models of lymphoma. In subcutaneous human xenograft models, a single cycle of three weekly doses of intravenous IT-101 at 10 mg/kg (CPT equivalents) showed significantly potent antitumor activity against Daudi, Karpas 299, and L540 cell lines compared to three weekly doses of intraperitoneal CPT-11 at its maximum tolerated dose in mouse of 100 mg/kg (P < 0.0001, P = 0.0072, and P < 0.0001, respectively). In the same animal models, IT-101 led to pathologically complete remissions in 78%, 44%, and 78% of animals inoculated with Daudi, Karpas 299, and L540 cell lines, respectively. In disseminated human xenograft models, IT-101, administered using the same dosing schedule, significantly prolonged the survival of animals intravenously injected with either Daudi or Karpas 299 cell lines when compared to CPT-11 (P < 0.0001 and P = 0.0049, respectively). The promising present results in a variety of lymphomas provide the basis for a phase I/II clinical trial in patients with refractory/relapsed lymphoma.
Disclosure:Employment: Thomas Schluep and Julienne Duringer are employed by Insert Therapeutics, Inc. Consultancy: Stephen J. Forman and Mark E. Davis are consultants of Insert Therapeutics, Inc. Ownership Interests: Stephen J. Forman, Mark E. Davis, Thomas Schluep, and Julienne Duringer. Membership Information: Mark E. Davis is a member of Board of Directors of Insert Therapeutics, Inc. Stephen J. Forman is a member of Scientific Advisory Board of Insert Therapeutics, Inc.