Nearly 50 faculty, staff and trainees from the Division of Hematology and Division of Oncology at Children’s Hospital of Philadelphia (CHOP) recently attended the 64th Annual American Hematology Society (ASH) Meeting in New Orleans, Louisiana.
CHOP experts were presenting and contributing authors to more than 200 posters and talks at the national conference. Highlights include:
- Regina M. Myers, MD, and Stephan A. Grupp, MD, PhD, presented data from a phase 1 study analyzing a novel, anti-CD22 CAR T-cell product for B-cell acute lymphoblastic leukemia (B-ALL). The CAR, known as CART22-65s, was tested in children and young adults who experienced relapse with CD19-antigen loss following treatment with CD19-directed immunotherapy. The CAR construct features a short scFv linker, which in preclinical work had been shown to improve T cell effector function. The study showed the new construct induced remissions in 13 out of 17 (77%) patients with highly refractory, CD19-negative B-ALL, including in 4 out of 5 (80%) patients with disease that was refractory to prior treatment with the CD22-directed therapy, inotuzumab. The findings provide support for a combined CD19/22-targeted approach using the CART22-65s construct.
Dr. Myers also received the 2023 ASH Fellow Scholar Award, which is designed to support blood scientists who have chosen a career in research. The award provides financial support to help early-career researchers achieve the status of an independent investigator.
- David T. Teachey, MD, was senior author on an abstract highlighted during “Best of ASH” that provided a genomic characterization – and identified genomic predictors – of relapse or refractory disease in T-cell acute lymphoblastic leukemia (T-ALL). Through whole genome, exome, and transcriptome sequencing of more than 1,300 patients enrolled in a Children’s Oncology Group (COG) trial for ALL, the researchers identified 16 T-ALL subtypes, several of which were previously unrecognized, and linked those subtypes with prognosis. They also made the novel observation that in over 55% of patients the primary oncogenic driver resides in the non-coding or intergenic regions, demonstrating the importance of whole genome sequencing in T-ALL. The abstract was highlighted by ASH organizers as an example of how large-scale genetic studies can change practice and how team science is important to advance the field.
- Denise E. Sabatino, PhD, presented data on a novel factor VIII variant that produces higher levels of clotting factor and could potentially increase the efficacy of gene therapy for hemophilia A. One of the main challenges facing the development of AAV gene therapy for hemophilia A is that human factor VIII is not expressed efficiently in vitro or in vivo compared to other proteins of similar size. Interestingly, dogs and pigs both express higher levels of factor VIII. To help increase expression, researchers made minor modifications to make the factor VIII look more "canine-like" by deleting three amino acid residues and making two amino acid substitutions. This variant produced 2 to 5-fold higher dose-dependent levels of factor VIII expression than wild type human factor VIII, providing an opportunity to improve the efficacy of AAV gene therapy for hemophilia A.
- Sarah K. Tasian, MD, presented data from a phase 2 study of ruxolitinib with chemotherapy in children with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). The presentation described the genetic and biologic characteristics of patients with non-CRLF2-rearranged Ph-like ALL enrolled in the Cohort C of the Children’s Oncology Group AALL1521 phase 2 clinical trial and their early treatment responses, as assessed by minimal residual disease (MRD). Dr. Tasian and her team reported that ruxolitinib and consolidation chemotherapy led to a notable decline in MRD in many of these patients during the initial treatment phases. Ongoing comprehensive analyses of patients enrolled in other cohorts of the trial will help to clarify the potential benefit of ruxolitinib addition to chemotherapy for patients with CRLF2-rearranged and other JAK pathway-mutant Ph-like ALL.
- Rodney M. Camire, PhD, was senior author on an abstract that analyzed the use of an antibody targeting human clotting factor V as a way of treating hemophilia. The researchers identified a procoagulant antibody (GB5) that binds with high affinity to human factor V and investigated its mechanism of action, both in vitro and in vivo. They found that GB5 neutralizes an anticoagulant protein and, in hemophilic plasma, enhanced the production of thrombin, an enzyme in blood plasma that causes clotting. The antibody also led to reduced bleeding in a hemophilic mouse model, suggesting the use of an antibody targeting factor V may be a viable and safe therapeutic approach for hemophilia. Sean Quinn, PhD, the CHOP post-doc who presented the research, received the Mary Rodes Gibson Memorial Award in Hemostasis and Thrombosis for this work which is part of the ASH Abstract Achievement Award Program.
- Amaliris Guerra, PhD, shared the first pre-clinical data related to the combination of two drugs to treat beta thalassemia. Luspatercept, a Transforming Growth Factor (TGF)-β ligand-trap, gained FDA approval in 2019 to treat transfusion-dependent beta thalassemia patients. However, the treatment does not improve anemia in all patients, so the researchers investigated whether combining the treatment with another that promotes iron restriction could be more effective and potentially beneficial to a greater number of patients. Using antisense oligonucleotides for iron restriction, the researchers found that combining the two treatments improved anemia and iron metabolism in preclinical models. The results strongly suggest that combination is strongly effective, showing not only a significant and beneficial effect on improving the anemia, but also the splenomegaly and iron parameters.
- Stefano Rivella, PhD, and Laura Breda, PhD, each presented abstracts related to the use of lipid nanoparticles (LNPs) as vehicles to treat or better model hematologic disease. Dr. Breda presented data on LNPs encapsulating modified mRNA that targeted a stem cell factor receptor. The approach could avoid the risks of chemotherapy conditioning and acute and chronic systemic toxicities, including sterility and secondary malignancies, associated with hematopoietic stem cell transplants. Separately, Dr. Rivella presented data on a new mouse model for alpha-thalassemia with a lethal phenotype that was rescued by a novel gene therapy vector. In order to create this model of alpha-thalassemia, Dr. Rivella and his colleagues used LNPs to achieve complete deletion of the alpha-globin genes. LNP technology allowed for faster generation of this lethal alpha-thalassemia model. The researchers also showed that their new gene therapy vector, ALS20αI, rescued these animals with stable expression of the human alphia-globin gene, suggesting ALS20αI could be a cure for severe forms of alpha-thalassemia.
Visit our CHOP at ASH page to learn more about all of the presentations by CHOP researchers at the conference.
Contact: Jennifer Lee, The Children’s Hospital of Philadelphia, 267-426-6084 or email@example.com