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Grant Details

Grant Number: 1R03CA256550-01 Interpret this number
Primary Investigator: Teachey, David
Organization: Children'S Hosp Of Philadelphia
Project Title: Genomic Profiling of T-Cell Acute Lymphoblastic Leukemia in Children
Fiscal Year: 2021


Abstract

PROJECT SUMMARY/ABSTRACT The outcome for patients with relapsed T-ALL is dismal with 3-year event free survival of <15%. Thus, the primary goal in the treatment of T-ALL is to prevent relapse, which requires accurate risk stratification. Unfortunately, no genetic alterations have been identified to date that are reproducibly prognostic independent of minimal residual disease (MRD), making it difficult at diagnosis to identify which patients are more likely to relapse. AALL0434 was a Children's Oncology Group-initiated phase 3 randomized clinical trial comparing Capizzi-style escalating methotrexate plus pegaspargase (CMTX) vs. high dose methotrexate (HDMTX), with/without six 5-day courses of nelarabine. Survival on this study was superior to any prior trial for de novo T-ALL, changing the standard of care. Yet, a substantial minority (~15%) of patients had relapsed or refractory (r/r) disease. Our group recently received an X01/Gabriella Miller Kids First award to perform comprehensive genomic profiling on 1262 cases of T-ALL treated on the AALL0434 clinical trial (1X01HD100702-01). This includes whole genome sequencing (WGS), whole exome sequencing (WES), and transcriptome profiling (RNAseq) of tumor and WGS of germline. We have separately performed copy number analysis (SNP) on germline samples that will be integrated with this work. We hypothesize that comprehensive genomic profiling of the entire AALL0434 cohort will identify recurrent genetic alterations that can be segregated into biologically relevant deregulated pathways that can be combined with MRD to identify patients at risk for poor outcomes before they relapse and provide rationale for treatment with alternative therapies. In addition, a number of small recent studies demonstrated that many of the biologically relevant alterations in T-ALL occur in non-coding regions of the genome, but no large studies have performed whole genome sequencing in T-ALL. We further hypothesize that whole genome sequencing of a large cohort of patients with T-ALL will identify novel lesions in coding and non-coding regions that will be highly impactful in the understanding of T-ALL pathogenesis. We will test our hypotheses with the following specific aims: (1) identify recurrent genetic alterations that predict poor outcome in T-ALL; (2) identify novel alterations, including non-coding alterations in T-ALL; and (3) identify germline genetic variants that predispose to T-ALL. The goal of the Kids First Program is improve understanding of genetic mechanisms of disease, leading to improved diagnostic capabilities and ultimately more targeted therapies or interventions. This proposal will meet that important goal through identification of germline and somatic alterations in T-ALL that can be used to identify patients that are likely to relapse before they relapse and can be treated with new therapies.



Publications

Cytosine base editing enables quadruple-edited allogeneic CART cells for T-ALL.
Authors: Diorio C. , Murray R. , Naniong M. , Barrera L. , Camblin A. , Chukinas J. , Coholan L. , Edwards A. , Fuller T. , Gonzales C. , et al. .
Source: Blood, 2022-08-11; 140(6), p. 619-629.
PMID: 35560156
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Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma.
Authors: Teachey D.T. , Devidas M. , Wood B.L. , Chen Z. , Hayashi R.J. , Hermiston M.L. , Annett R.D. , Archer J.H. , Asselin B.L. , August K.J. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2022-07-01; 40(19), p. 2106-2118.
EPub date: 2022-03-10.
PMID: 35271306
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Comprehensive Serum Proteome Profiling of Cytokine Release Syndrome and Immune Effector Cell Associated Neurotoxicity Syndrome in B-Cell ALL Patients Receiving CART19.
Authors: Diorio C. , Shraim R. , Myers R. , Behrens E.M. , Canna S. , Bassiri H. , Aplenc R. , Burudpakdee C. , Chen F. , DiNofia A.M. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2022-06-15; , .
EPub date: 2022-06-15.
PMID: 35705524
Related Citations

Taking a BiTE Out of CAR-T Cell Efficacy.
Authors: Newman H.M. , Teachey D.T. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2022-03-20; 40(9), p. 921-923.
EPub date: 2021-11-12.
PMID: 34767437
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Potential Role of IFN╬│ Inhibition in Refractory Cytokine Release Syndrome Associated with CAR T-cell Therapy.
Authors: McNerney K.O. , DiNofia A.M. , Teachey D.T. , Grupp S.A. , Maude S.L. .
Source: Blood cancer discovery, 2022-03-01; 3(2), p. 90-94.
PMID: 35015687
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