Acute lymphoblastic leukemia (ALL) is the most common cancer in children and adolescents, killing more pediatric patients every year than any other malignancy. When children with ALL relapse the survival rate is less than 50%, and this has not improved for more than 30 years. Although ALL is less common in adults, it is more deadly, reaching 5-year survival rates of less than 12% in people over 65, an age when tolerance for toxic therapies is poor. The majority of ALL cases in children and adults are the B-cell type (B-ALL) and those with the poorest outcome are characterized by overexpression of the CRLF2 gene (CRLF2 B-ALL). This type of leukemia is particularly devastating in Hispanic children where it occurs 5 times more often than in other children. In adults, CRLF2 B-ALL makes up 1/3 of all B-ALL cases. A safe and effective treatment capable of targeting CRLF2 B-ALL would have a significant health impact in the United States and in Central and South America where rates of CRLF2 B-ALL are even higher. We have discovered a novel biologic that selectively targets the signaling pathway that produces CRLF2 B-ALL while sparing normal immune cells. The proposed studies will establish the therapeutic efficacy of this novel biologic in patient-derived xenograft (PDX) models of high-risk ALL. Scientific premise: Our preliminary studies show that high physiological levels of the biologic exert an anti-leukemia effect against CRLF2 B-ALL and establish a likely mechanism for these effects. To advance the use of the biologic in clinical trial for the treatment of CRLF2 B-ALL, it is essential to establish the dose and efficacy of the biologic as a single agent and as a part of combination therapy in preclinical studies. The overall objective of the current proposal is to establish proof-of-principle for the use of the biologic and its efficacy in the treatment of high-risk CRLF2 B-ALL. The achieve this objective we will: Aim 1. Establish the dose of biologic required to achieve normal and therapeutic blood plasma levels in PDX mice and Aim 2. Evaluate the in vivo therapeutic efficacy of the biologic as a single agent and in combination therapy using PDX models of high-risk B-ALL. At the end of the proposed work we will have: 1) Determined the dosing required to generate PDX with normal and therapeutic levels of recombinant human biologic, 2) Assessed in vivo functional effects and toxicity of the biologic, 3) Evaluated the efficacy of the biologic as a single agent in the treatment of CRLF2 B-ALL using PDX models; 4) Evaluated the efficacy of the biologic to prevent relapse and restore normal B cell precursors in combination with standard of care therapy in PDX models of CRLF2 B-ALL. This work has the potential to produce a more effective and less toxic treatment strategy to improve survival in patients with high-risk CRLF2 B-ALL.
Public Health Relevance Statement: Our work is focused on the subtype of B cell acute lymphoblastic leukemia that has the worst prognosis. We have discovered a novel biologic that can selectively target the signaling pathway that produces this leukemia while sparing normal immune cells. The proposed studies will establish the therapeutic efficacy of this novel biologic in preclinical models of high-risk leukemia.
Project Terms: Acute Lymphocytic Leukemia; Adolescent; Adult; Age; B-Cell Acute Leukemia; B-Lymphocytes; Biological Response Modifier Therapy; cell type; Cells; cellular transduction; Central America; chemotherapy; Child; clinical efficacy; Clinical Treatment; Clinical Trials; Combined Modality Therapy; cytokine; Cytokine Receptors; Data; Dose; effective therapy; Gene Expression; Genes; Harvest; Health; high risk; Hispanics; Human; Immune; improved; in vivo; Injectable; Injection of therapeutic agent; Intravenous; Killings; leukemia; Malignant Childhood Neoplasm; Malignant Neoplasms; Modeling; Molecular; Mus; Neoadjuvant Therapy; novel; Outcome; outcome forecast; overexpression; Patients; pediatric patients; Physiological; Plasma; Pre-Clinical Model; preclinical study; prevent; Production; Recombinants; Relapse; restoration; Sampling; Signal Pathway; South America; standard of care; Stromal Cells; Survival Rate; targeted treatment; Therapeutic; Therapeutic Uses; Time; Toxic effect; Treatment Efficacy; treatment strategy; TSLP gene; United States; Work; Xenograft Model; Xenograft procedure
