The long-term goal of the proposed research is the development of novel and highly effective immunochemotherapy protocols for more successful treatment of poor prognosis B-lineage acute lymphoblastic leukemia (ALL) patients. It is our central working hypothesis that combinative immunochemotherapy regimens employing B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin will improve event-free survival of poor prognosis B-lineage ALL patients. We propose as our first major goal to conduct a phase II study of B43 (anti-CD19)-PAP immunotoxin in relapsed B-lineage ALL patients. The main focus of this project will be the examination of the correlation between the clinical response of a relapsed B-lineage ALL patient to B43-PAP therapy and the efficacy of B43-PAP against primary blasts from the same patient. To this end, we will examine the anti-leukemic efficacy of B43-PAP against primary blasts from patients on this protocol using both the in vitro leukemic progenitor cell (LPC) assay system as well as the in vivo SCID mouse model system. We will also attempt to correlate the initial LPC burden as well as the residual LPC burden on day 14 with the duration of the achieved remission. We are further proposing to examine the effects of the interpatient differences in immunotoxin disposition on systemic toxicity, immunogenicity and anti-leukemic activity of B43 (anti-CD19)- PAP immunotoxin. We will examine the efficacy and toxicity of combinative immunochemotherapy regimens employing B43 (anti-CD19)-PAP immunotoxin in a preclinical SCID mouse model of human B-lineage ALL and subsequently implement regimens with the highest therapeutic index in phase I/II clinical trials. We will also examine the impact of B43 (anti-CD19)-PAP immunotoxin therapy on the pretransplant residual leukemia burden and outcome of high risk remission ALL patients undergoing BMT. The knowledge gained from the proposed research, as outlined under CLINICAL PROGRAMS I & II and LABORATORY PROGRAMS I & II, may lead to the design of more effective treatment protocols for ALL. Furthermore, we anticipate that a new generation of anti-CD19 immunotoxins such as homogeneous 210 kDa B43-PAP and single chain Fv B43- PAP, will become available for clinical studies during the projected grant period.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA061549-01
Application #
3550153
Study Section
Special Emphasis Panel (SRC (59))
Project Start
1993-09-30
Project End
1997-08-31
Budget Start
1993-09-30
Budget End
1994-08-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Ek, O; Reaman, G H; Crankshaw, D L et al. (1998) Combined therapeutic efficacy of the thymidylate synthase inhibitor ZD1694 (Tomudex) and the immunotoxin B43(anti-CD19)-PAP in a SCID mouse model of human B-lineage acute lymphoblastic leukemia. Leuk Lymphoma 28:509-14
Uckun, F M; Yanishevski, Y; Tumer, N et al. (1997) Pharmacokinetic features, immunogenicity, and toxicity of B43(anti-CD19)-pokeweed antiviral protein immunotoxin in cynomolgus monkeys. Clin Cancer Res 3:325-37
Waurzyniak, B; Schneider, E A; Tumer, N et al. (1997) In vivo toxicity, pharmacokinetics, and antileukemic activity of TXU (anti-CD7)-pokeweed antiviral protein immunotoxin. Clin Cancer Res 3:881-90
Messinger, Y; Yanishevski, Y; Avramis, V I et al. (1996) Treatment of human B-cell precursor leukemia in SCID mice using a combination of the investigational biotherapeutic agent B43-PAP with cytosine arabinoside. Clin Cancer Res 2:1533-42
Gunther, R; Chelstrom, L M; Wendorf, H R et al. (1996) Toxicity profile of the investigational new biotherapeutic agent, B43 (anti-CD19)-pokeweed antiviral protein immunotoxin. Leuk Lymphoma 22:61-70, follow.186, color plate
Uckun, F M; Reaman, G H (1995) Immunotoxins for treatment of leukemia and lymphoma. Leuk Lymphoma 18:195-201
Myers, D E; Yanishevski, Y; Masson, E et al. (1995) Favorable pharmacodynamic features and superior anti-leukemic activity of B43 (anti-CD19) immunotoxins containing two pokeweed antiviral protein molecules covalently linked to each monoclonal antibody molecule. Leuk Lymphoma 18:93-102
Uckun, F M; Myers, D E (1993) Allograft and autograft purging using immunotoxins in clinical bone marrow transplantation for hematologic malignancies. J Hematother 2:155-63