Our Science – Kreitman Website

Robert J. Kreitman, M.D.

Laboratory of Molecular Biology Head, Clinical Immunotherapy Section Senior Investigator NIH Building 37, Room 5124b 9000 Rockville Pike Bethesda, MD 20892-4255 Phone:   301-496-6947 Fax:   301-576-3920 E-Mail:   kreitmar@mail.nih.gov Link: Other Homepage

Biography

Dr. Kreitman received his M.D. from Ohio State University in 1985 and obtained his internal medicine residency training at Duke University from 1985 to 1988. He received his medical oncology fellowship training at the NIH from 1988 to 1991, has been working in the immunotoxin field since 1989, and has been directing clinical trials with immunotoxins since 1996.

Research

View Dr. Kreitman's Current Clinical Trials

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. A high CR rate has been observed and patients with low tumor burden have significantly better response earlier. BL22 has an excellent risk-benefit ratio in HCL since no patients died and all toxicity resolved. BL22 is also being tested in patients with pediatric acute lymphoblastic leukemia and in chronic lymphocytic leukemia and indolent lymphoma.

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 has been produced for clinical testing in patients with CLL, indolent lymphoma, pediatric ALL, and HCL, and these multicenter trials are expected to begin in early 2007.

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.

It is known that purine analogs cannot eliminate HCL cells, even in patients with CR. By cloning the cDNA for surface IgG displayed on the hairy cells, we have developed a new sequence-specific PCR test for HCL. While flow cytometry, currently the most sensitive test of minimal residual disease (MRD) in HCL, is able to detect 1 HCL cell in 104 normal, clone-specific quantitative PCR is able to detect 1 HCL cell in 106 normal. Thus this is by far the most sensitive test yet developed for MRD in HCL. We are prospectively cloning surface IgG in patients treated with BL22 to determine if BL22 can eradicate malignant cells with repeated cycle, and to molecularly characterize HCL.

LMB-2 is an anti-CD25 recombinant immunotoxin which we previously showed in phase I testing was active in HCL, CLL, cutaneous T-cell lymphoma (CTCL), adult T-cell leukemia (ATL), and Hodgkin's disease (HD). We have recently opened phase II trials of LMB-2 in patients with CD25+ CLL and CTCL. We have observed meaningful clinical responses in these trials. To determine if chemotherapy can prevent immunogenicity of immunotoxins, a trial has opened in which patients with Hodgkin's disease will be treated with fludarabine and cyclophosphamide, followed by LMB-2.

We have recently completed a phase I trial of the anti-mesothelin recombinant immunotoxin SS1P in patients with mesotheliomas, ovarian carcinoma, and pancreatic carcinoma. SS1P was administered by continuous infusion. Targeting solid tumors was much more challenging than targeting hematologic tumors, since patients were more likely to develop neutralizing antibodies, and tumors were less likely to be penetrated by immunotoxin. Nevertheless, evidence of antitumor activity was observed in several patients. Lessons learned in these studies should be useful in improving the treatment of patients with both solid and hematologic tumors lacking effective alternative therapies.

This page was last updated on 6/11/2008.