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Targeted Therapies Against Lymphocyte Signaling Pathways in Childhood Leukemia Stuart S. Winter, MD Pediatric Hematology/Oncology The T. John Gribble Endowed.

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Presentation on theme: "Targeted Therapies Against Lymphocyte Signaling Pathways in Childhood Leukemia Stuart S. Winter, MD Pediatric Hematology/Oncology The T. John Gribble Endowed."— Presentation transcript:

1 Targeted Therapies Against Lymphocyte Signaling Pathways in Childhood Leukemia Stuart S. Winter, MD Pediatric Hematology/Oncology The T. John Gribble Endowed Chair

2 Background- Acute Lymphoblastic Leukemia in Children & Young Adults Risk Classification Strategy Through improved approaches to risk classification, therapy intensification, and supportive care, children and young adults with acute lymphoblastic leukemia (ALL) have an overall survival rate that currently exceeds 80%. However: – salvage therapies often do not achieve long-term remissions – the late effects of intensified therapy are becoming more evident in cancer survivors – therapies that are tolerated by younger patients may be too toxic for older patients Kaplan-Meier Survival Curve

3 Monoclonal Antibodies Against pre-B ALL  Anti-CD20 (Rituximab®) has been developed to treat mature B-cell malignancies in patients, with early evidence of enhanced efficacy in Burkitt’s lymphoma when used in a conventional chemotherapy backbone.  Anti-CD22 (Epratuzumab®) is in the midst of completing its first clinical trial for children with relapsed pre-B ALL with results showing both safety and efficacy when utilized within the BFM therapeutic format.  Anti-CD19 has not yet entered into clinical trials. The manufacturer has developed a collaborative relationship with Drs. Winter and Wilson to be tested in a human pre-B ALL xenograft model in mice. A map of B-cell signaling pathways, and potential sites of interaction with targeted therapies.

4 IKK inhibition causes rapid cell death in pre-B ALL cell lines and blasts. (A) Effect of Bay 11-7082 on viability of four pre-B ALL cell lines after 20hr treatment. (B) Comparison of IKK inhibitors Bay 11- 7082, PS1145, BMS-345541 and Parthenolide (PTL) on the viability of 697 cells. (C) Effect of the cell-permeable NEMO (NFkB essential modifier) binding domain (NBD) peptide and control cell- permeable peptide on the viability of 697 cells was detected. Cell viability was tested by flow cytometry after PE- Annexin V (FL2H) and 7-AAD (FL3-H) double staining. (D) Time course of cell death in 697 cells after treatment with 2.5 µM Bay 11-7082. (E) Effect of Bay 11- 7082 on the viability of CD19+ blasts from six children and young adults compared to B cells isolated from buffy coat of a healthy donor. Staining with anti-CD19 antibodies identifies leukemic infiltrates in murine liver tissue. Red-stained cells show normal vascular structures. In this case, the leukemic infiltrates approach 95%. A Gamma secretase inhibitor can prevent ALL infiltration in NOD/SCID mice, but likely needs to be used in combination with other cytotoxic drugs. Small Molecules Against pre-B ALL

5 Future Clinical Trials Novel agent study design: incorporating new drugs with cytotoxic chemotherapy protocols. AALL1032 incorporates epratuzumab into a BFM format for higher-risk ALL. The randomizations questions will be to either receive or not to receive epratuzumab (orange and clear boxes) in pre-maintenance therapy, and to receive VCR/DEX every 4 weeks versus every 12 weeks (green and yellow boxes) in the maintenance phase of therapy. Our goal is to determine the relative importance of three important mechanisms that potentially permit humanized monoclonal antibodies to CD19 and CD22 to kill leukemia cells (Figure 7), by performing studies in cultured leukemia cells and in the animal model. *Winter’s clinical group is comprised of pediatric research nurses, clinical research associates and other clinical staff; this dedicated group meets personally with the parents of newly diagnosed acute leukemia patients for consent to participate in UNM ALL Cell Bank study 05-435. *Freshly acquired bone marrow is immediately taken to the laboratory of Dr. Wilson, where bone marrow blasts are isolated and tested using a variety of analytic assays.


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