University of Colorado Department of Pediatrics

Happy New Year and welcome to the first 2020 edition of the Department of Pediatrics Newsletter. Here you will find a sampling of all the amazing activity happening within the Department of Pediatrics and at Children’s Hospital Colorado. Thanks to all our talented faculty, trainees, and staff who make this the best Pediatrics Department in the country!

New Gates Grubstake Fund Awardees

The Gates Center for Regenerative Medicine announced four recipients of funding through its Gates Grubstake Fund, which provides translational research funding for projects and teams affiliated with the center. Two of the four awardees are from the Department of Pediatrics with each receiving up to $350,000 each to support their work.

Terry Fry, MD (Professor, Section of Hematology, Oncology and Bone Marrow Transplantation and Co-Director, Human Immunology and Immunotherapy Initiative), was awarded funding for his project titled, “Optimized manufacturing of CD19xCD22 CAR expressing T Cells for the clinic.”

The goal of this project is to perform the necessary pre-clinical studies to prepare for novel, early phase clinical trials that will use multi-targeted chimeric antigen receptors. Genetically modified T-cells expressing chimeric antigen receptors (CAR) targeting CD19 are approved by FDA for the treatment of chemotherapy refractory childhood B cell acute lymphoblastic leukemia and adult lymphoma based on a remarkable complete remission rate. Unfortunately, most patients achieving remission will relapse, the majority due to emergence of leukemia that loses expression of CD19.

Dr. Fry’s research team has developed an alternative CAR targeting CD22, which has demonstrated to ability to induce remission in 75% of patients refractory to CD19 CAR T-cells. As with CD19, remissions are not durable in most patients. To improve upon the clinical activity of CD19 and CD22 CAR T cells, the team has developed an approach to generate T-cells expressing both CARs using a single construct in which the two CAR genes are separated by a ribosomal skip site resulting in a T-cells that targets both CD19 and CD22. Using this bicistronic construct, it is hoped that multi-targeted T-cells will improve the response rate in lymphoma and increase the likelihood of durable remission in leukemia.

Holger Russ, PhD (Assistant Professor, Barbara Davis Center) was awarded funding for his project titled, “Generation of functional, patient-specific thymi for cell therapy.” The goal of this project is to perform studies that form the basis for patient specific cell replacement therapy to reconstitute thymus function in patients lacking a competent thymus. The thymus gland is an organ that is essential for adaptive immunity and establishing self-tolerance by providing positive and negative selection of developing T-cells. T-cells are crucial by providing protection from infections and cancer. Unfortunately, the thymus degenerates at the time of adolescence and with it the output of naïve T-cells decreases significantly. This thymus atrophy is further exacerbated by additional stresses, including conditioning regimes before transplantation, irradiation and chemotherapy. Autogenic and allogenic recipients of hematopoietic stem cell (HSC) transplants after cancer treatment suffer from high incidence of post transplantation complications, including bacterial pneumonia and graft versus host disease. While reconstitution of blood forming cell-types is fast upon HSC transplantation, T-cell reconstitution is very slow and incomplete due to the absence of a functional thymus of the patient. An attractive and practical approach to remedy these complications would be co-transplantation of HSCs and a functional thymus generated from patient cells.

Dr. Russ’ research team aims to establish an effective approach to generate a functional human thymus in a patient specific manner while demonstrating the efficient and reproducible generation of functional thymic cells from induced pluripotent stem cells.

Sokol Named to National CTSA Program Steering Committee

Ronald Sokol, MD (Professor and Head, Section of Gastroenterology, Hepatology and Nutrition, and Director of the Colorado Clinical and Translational Sciences Institute) has been appointed to the National Center for Advancing Translational Sciences (NCATS) Clinical and Translational Science Awards (CTSA) Program Steering Committee.

The Steering committee provides leadership for sharing of policies, practices and resources, and identifying and recommending best practices to advance clinical and translational research nationally.

Congratulations to Dr. Sokol on this well-deserved recognition.

Brooks-Kayal Honored by American Epilepsy Society

Each year, the American Epilepsy Society (AES) recognizes the outstanding research and clinical work of its members who have dedicated their life to bettering epilepsy care. At the AES 73rd annual meeting in December, Amy Brooks-Kayal, MD (Professor and Head, Section of Neurology) received the Founders’ Award. This award is one of the society’s most prestigious, recognizing a member who has a record of lifetime contributions and accomplishments related to epilepsy.

Dr. Brooks-Kayal was previously president of AES and director of the National Institute of Neurological Disorders and Stroke (NINDS) Advisory Council and CURE Scientific Advisory Board. Currently, she is co-director of the Child Neurology Career Development K12 program and a leader on many national initiatives related to the care and research of epilepsy.

Congratulations, Dr. Brooks-Kayal!

Enterovirus A71 Outbreak Revisited

Between March 10 and Nov. 10, 2018, 74 children presenting to Children’s Hospital Colorado were found to have enterovirus A71 (EV-A71) neurological disease. This is believed to be the largest reported outbreak to date of EV-A71 in the Americas. A retrospective observational cohort study recently published in The Lancet highlights the importance of enterovirus surveillance. Were it not for Children’s Hospital Colorado’s ongoing interest and commitment to the study of enterovirus, this outbreak likely would not have been detected.

Surveillance included enteroviral screening and recognition by team members that patients were presenting with an increased amount of myoclonus and ataxia with weakness and MRIs that looked suspicious. While the United States has not yet experienced largescale epidemics of enteroviruses, as have been seen in Asia and other countries, the study suggests that the U.S. should take proactive steps to become better prepared.

Kudos to the infectious disease and neurohospitalist multidisciplinary team members, including Kevin Messacar, MD and Christina Osborne, MD from the  Section of Infectious Diseases and Jan Martin, MD, Teri Schreiner, MD, Ricka Messer, MD, PhD, and Craig Press, MD, PhD from the Section of Neurology for their national leadership in this important area.