Our section directs clinical trials of recombinant toxins at the NIH and in the lab studies the interaction of such toxins with the patient's malignant and normal tissues. Therapy of patients with chemotherapy resistant hematologic malignancies has been remarkably effective with Fv-toxins recombinant immunotoxins) targeting CD25 or CD22 in hairy cell leukemia and efficacy is observed in some other hematologic malignancies as well. The anti-CD22 recombinant immunotoxin BL22 produces complete remissions (CRs) in a high percentage of patients with hairy cell leukemia who have little chance for CR with conventional therapies. We are continuing to treat patients to optimize safety and efficacy. Patient samples are studied in the lab to better predict and understand recombinant toxin efficacy, to better understand the role of cytotoxic T-cells observed in hairy cell leukemia patients, to study novel and established tumor markers in patients to better quantitate overall tumor burden, and to develop new assays of minimal residual disease.Our goal is to help develop bacterial toxins which are engineered to kill cancer cells in patients who cannot be cured by standard therapy. The binding domain of the bacterial toxin, usually Pseudomonas exotoxin (PE), is replaced with a ligand, either a growth factor or an Fv fragment of an monoclonal antibody (MAb), which binds to a tumor associated antigen. Thus the recombinant toxin binds to and is internalized by malignant cells and causes cell death after the catalytic domain of the toxin enters the cytosol of the host cell. BL22 is a recombinant immunotoxin containing an anti-CD22 Fv fused to truncated PE. We had previously shown in the lab that BL22 was capable of inducing complete regressions of human CD22+ tumor xenografts in mice at plasma concentrations tolerated in monkeys and in killing malignant cells freshly obtained from patients with CD22+ B-cell leukemias. We completed accrual of 46 patients in a phase I trial of BL22 in patients with B-cell tumors, 31 of whom had hairy cell leukemia (HCL). Of these 31 HCL patients, 19 (61%) achieved CR and 6 (19%) had partial responses (PR). A phase II trial is currently underway to establish its safety and efficacy in HCL. Currently, out of 18 patients enrolled, 9 have been treated or followed for at least 24 weeks; 6 (67%) of these 9 achieved CR and 1 had a PR. BL22 has an excellent risk-benefit ratio in HCL since not patients died and all toxicity resolved. BL22 is also being tested in patients with pediatric acute lymphoblastic leukemia and a trial in chronic lymphocytic leukemia and indolent lymphoma has recently opened.HA22, a variant of BL22 with higher affinity for CD22, is also being developed. We have compared this molecule with BL22 against cells ex vivo from patients with CLL and have found significant improvements in efficacy. HA22 is currently being produced for clinical testing in patients with CLL, indolent lymphoma, pediatric ALL, and HCL, and these trials are expected to begin within a year.It was noted for the first time that soluble CD22 could be detected in the serum and its level correlates closely with overall disease burden. Another phenomenon studied is expansions of cytotoxic T-lymphocytes (CTLs), observed in most HCL patients treated with BL22. We found that increased percentages of CTLs correlated with T-cell oligoclonality, monoclonality and a more limited repertoire of polyclonal T-cells, suggesting that such patients had limited immunity. We found that limited T-cell repertoire was more frequent with more recent purine analog therapy, but BL22 treatment had no adverse effect on T-cells. Our study suggests that monitoring CTLs in patients with HCL after purine analogs may be very useful to gauge the T-cell repertoire and could be used to help decide whether relapsed patients should receive a repeated course of purine analog or instead try biologic T-cell-sparing therapy.
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| Pastan, Ira; Hassan, Raffit; Fitzgerald, David J et al. (2006) Immunotoxin therapy of cancer. Nat Rev Cancer 6:559-65 |
