Synergistic Antitumor Activity of Anti-CD25 Recombinant Immunotoxin LMB-2 with Chemotherapy

Purpose: Although anti-CD25 recombinant immunotoxin LMB-2 is effective against CD25(+) hairy cell leukemia, activity against more aggressive diseases such as adult T-cell leukemia (ATL) is limited by rapid disease progression between treatment cycles. Our goal was to determine in vivo whether rapid growth of CD25(+) tumor is associated with high levels of tumor interstitial soluble CD25 (sCD25) and whether chemotherapy can reduce tumor sCD25 and synergize with LMB-2. Experimental Design: Tumor xenografts expressing human CD25 were grown in mice, which were then treated with LMB-2 and chemotherapy either alone or in combination, and sCD25 level and antitumor activity were measured. Results: CD25(+) human xenografts growing rapidly in nude mice had intratumoral sCD25 at levels that were between 21- and 2,200 (median 118)-fold higher than in serum, indicating that interstitial sCD25 interacts with LMB-2 in tumors. Intratumoral sCD25 levels were in the range 21 to 157 (median 54) ng/mL without treatment and 0.95 to 6.1 (median 2.6) ng/mL (P < 0.0001) 1 day after gemcitabine administration. CD25(+) xenografts that were too large to regress with LMB-2 alone were minimally responsive to gemcitabine alone but completely regressed with the combination. Ex vivo, different ratios of gemcitabine and LMB-2 were cytotoxic to the CD25(+) tumor cells in an additive, but not synergistic, manner. Conclusions: Gemcitabine is synergistic with LMB-2 in vivo unrelated to improved cytotoxicity. Synergism, therefore, appears to be related to improved distribution of LMB-2 to CD25(+) tumors, and is preceded by decreased sCD25 within the tumor because of chemotherapy. To test the concept of combined treatment clinically, patients with relapsed/refractory ATL are being treated with fludarabine plus cyclophosphamide before LMB-2. Clin Cancer Res; 18(1); 152-60. (C) 2011 AACR.