Biomedical Graduate Studies

Description of Research Expertise

1. ALL Basic Science (Acute Lymphoblastic Leukemia Genomics): My laboratory uses multiomic profiling to study disease biology and mechanisms of leukemogenesis in ALL. A major focus has been the comprehensive genomic profiling of ALL, integrating multimodal methodologies including bulk sequencing (whole genome, whole transcriptome), single cell genomics, epigenetic profiling and proteomics. We sequenced over 2000 cases of T cell lymphoblastic leukemia and lymphoma treated on two consecutive phase 3 trials, AALL0434 and AALL1231. Through this work, we identified novel subtypes of T-ALL, proposed a new classification system, and developed risk prediction outcome models. A key finding was the majority (59%) of genetic alterations driving leukemogenesis were non-coding or intragenic alterations in T-ALL, largely from enhancer hijacking or the formation of neoenhancers. We also found that the prognostic significance of genomic alterations such as mutations in NOTCH1 differed based on genetic ancestry. Through single cell genomic profiling of multiple leukemia types, including B-ALL and T-ALL we discovered treatment-resistant early lineage/stem cell-like populations driving resistance to therapy and identified novel mechanisms to overcome resistance. On-going work includes integration of genome and transcriptome sequencing with epigenetic profiling, mass spec proteomics, and ex vivo drug profiling to understand mechanisms of leukemogenesis, mechanisms underlying the differential impact of different genomic alterations based on ancestry and identify new targets for precision medicine and immunotherapies.

2. ALL Translational Science (Novel Targeted Therapies for Acute Lymphoblastic Leukemia): My laboratory has a long-standing history of investigating novel precision medicine therapies for children with high-risk subtypes of B-ALL and T-ALL. We demonstrated that both ETP-like and Ph-like ALL have dysregulated signaling in common pathways including MAPK, JAK/STAT, and PI3K/AKT/mTOR. Our preclinical data demonstrates that targeting JAK/STAT signaling with the JAK inhibitor ruxolitinib is highly active in both high-risk ALL subtypes and targeting BCL2 and other apoptotic pathways is highly active in immature T-ALL subtypes, including ETP-like. My lab has developed over genetically characterized patient derived xenograft models from over 500 children and adults with B-ALL and T-ALL to test novel therapeutics. We have a strong track record of testing novel agents in the laboratory and developing early phase trials to test those novel therapies. On-going projects include integration of bulk and single cell genomic profiling from samples collected from patients with B-ALL and T-LL at diagnosis and relapse with ex vivo drug profiling data to understand mechanisms of clonal evolution and to identify novel targets for therapy and then testing novel therapies directed at those targets in preclinical models.

3. ALL Translational Science (Immunotherapy for Acute Lymphoblastic Leukemia): My laboratory is also dedicated to developing and translating novel immunotherapies for patients with ALL and understanding the toxicity of those therapies, including cytokine release syndrome. I made the initial observation that patients treated with CAR T cells and blinatumomab develop a clinical, laboratory, and cytokine profile similar to HLH. It was this observation that directly led to the use of IL6 directed therapy with tocilizumab post-CAR T cells. Currently, patients treated with CAR T cells are followed for HLH and on-going research is dedicated to understanding the genotype-phenotype relationship of CRS and secondary HLH after these therapies. My laboratory has developed multiple novel immunotherapies for B and T-ALL. We used PDX models to establish tisagenlecleucel was effective in preclinical models and recently have been testing and developing novel immunotherapies for T-ALL, including the anti-CD38 monoclonal antibody daratumumab and novel CAR-T cell therapies targeting CD38 and CD7. On-going projects include the identification of new immunotherapy targets through surfaceome profiling of T-ALL patient samples and non-malignant healthy tissues to identify antigens on the surface of T-ALL but not healthy cells, the preclinical development and translation of novel CAR-T for T-ALL, and correlative studies focused on understanding mechanisms of response and resistance to immunotherapies. My laboratory is also investigating mechanisms underlying the response and resistance to immunotherapy in B-ALL, through correlative studies on patient samples collected on the international COG-initiated AALL1331 and AALL1821 clinical trials.

4. ALL Clinical Science (The Diagnosis and Management of Acute Lymphoblastic Leukemia): I am a recognized expert in the diagnosis and management of ALL in children and adults, designing and leading numerous local, national and international clinical trials and studying correlative samples from those trials in the lab. This work has improved understanding of corticosteroid resistance in T-ALL, led to the elimination of cranial radiation in most children with T-ALL and established that bortezomib improves overall survival in children with T-cell lymphoblastic lymphoma (T-LL). During my tenure as the chair of the ALL Disease Committee in the Children’s Oncology Group, we demonstrated blinatumomab improved outcomes for newly diagnosed children with standard-risk B-ALL. Based on these results, we have redesigned and opened multiple international clinical trials that include blinatumomab, including high-risk B-ALL (AALL1732), BCR::ABL1 and Ph-like ALL (AALL2131), infant ALL (AALL2321) and B-ALL in first relapse (AALL1821). We continue to develop new international immunotherapy and precision medicine trials for newly diagnosed and relapsed ALL, as well as trials focused on deintensification of cytotoxic chemotherapy in patients with exceptional outcomes.

5. LBL Basic and Translational Science (Understanding the biological differences between Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LBL) and how those differences impact response to novel therapies): T-cell acute lymphoblastic leukemia (T-ALL) and T-cell acute lymphoblastic lymphoma (T-LBL) were historically considered to be identical diseases. Pivotal clinical trials led in part by investigators in my research group made multiple seminal observations that overturned this dogma: on the NCTN-sponsored Phase 3 trials AALL0434 and AALL1231, nelarabine was effective in patients with T-ALL but not T-LBL and bortezomib was effective in patients with T-LBL but not T-ALL. Further, on multiple recent early phase trials response rates to cytotoxic chemotherapies, monoclonal antibodies and cellular immunotherapies were far inferior in patients with relapsed or refractory (r/r) T-LBL as compared with r/r T-ALL. Critically, little is known about the tumor microenvironment (TME) of T-ALL or T-LBL and little is also known about the differences in tumor biology and the TME in T-ALL vs T-LBL. Further, mechanisms of treatment resistance in T-ALL and T-LBL are poorly defined, especially those mechanisms driving the differential and inferior responses to novel therapies, including cellular immunotherapies in T-LBL. Ongoing projects include bulk and single cell genomic profiling of a large cohort of samples from T-LBL patients collected on AALL0434 and AALL1231 to define the genomic landscape of T-LBL and also comparing the biology of T-LBL with T-ALL in order to understand differences in tumorigenesis, define interactions between lymphoblasts and the tumor microenvironment in T-ALL vs T-LBL, and elucidate mechanisms driving response and resistance to novel therapies in T-LBL and T-ALL.

Description of Clinical Expertise

My clinical interests include pediatric leukemia and immune dysregulation with emphasis on acute lymphoblastic leukemia, lymphoproliferative disorders, cytokine storm syndromes, and hematopoietic stem cell transplant.