Abstract 5606: Preclinical and clinical development of anti-CD25 recombinant immunotoxin LMB-2 in combination with chemotherapy for the treatment of adult T-cell leukemia

Abstract

Abstract LMB-2, previously called anti-Tac(Fv)-PE38, is a recombinant immunotoxin containing the variable domains of the anti-CD25 Mab and a truncated form of Pseudomonas exotoxin. LMB-2 binds and internalizes via CD25, and a processed toxin fragment translocates to the cytosol where catalytic ADP-ribosylation leads to cell death. LMB-2 induces complete and partial responses (CR + PR) in patients with CD25+ hairy cell leukemia, and partial responses were reported in other hematologic malignancies including adult T-cell leukemia (ATL). While nearly all ATL cells express CD25 at high levels, clinical efficacy was limited by rapid progression between cycles and immunogenicity. Recently, preclinical studies using the anti-mesothelin recombinant immunotoxin SS1P indicated that soluble receptor is ∼10-fold higher in the interstitial space of the tumor xenograft than in the serum (PNAS, 104:17099, 2007) and that gemcitabine was synergistic against the xenografts when used prior to SS1P to deplete interstitial soluble receptor (Clin Cancer Res, 13:7166, 2007). To determine if soluble CD25 (sCD25) in the interstitial space of tumors could be a limiting factor in the antitumor activity of LMB-2 in ATL, xenografts of CD25+ human ATAC-4 cells were grown subcutaneously in nude mice and harvested so that the serum and intratumoral sCD25 concentrations could be compared. Intratumoral sCD25 concentrations were 21-159 (median 43) ng/ml, compared to between undetectable and 0.33 (median 0.093) ng/ml in serum (p=0.0008, n=8). Thus, intratumoral sCD25 was 86-2200 (median 610)-fold higher than serum sCD25 in this model. To determine if chemotherapy would improve the efficacy of LMB-2 towards these tumors, groups of ATAC-4-bearing mice (tumor implantation day −3) were treated with gemcitabine on days 1 and 3, and then LMB-2 on days 3, 5 and 8. Mice treated on this schedule with gemcitabine 40 mg/Kg x2 and LMB-2 50 ug/Kg x3 had smaller tumors than mice treated with twice the dose of either agent alone, confirming in vivo synergy, with the mechanisms currently under study. A clinical trial in ATL is now underway with fludarabine and cyclophosphamide on days 1, 2, and 3 followed by LMB-2 on days 3, 5 and 7, to determine if chemotherapy can prevent immunogenicity, enhance the antitumor activity of the immunotoxin, and when possible, determine if intratumoral sCD25 is depleted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5606.