Just over a year ago, the U.S. Food and Drug Administration approved the use of chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of relapsed or refractory pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL). The therapy, referred to as CTL019 (or tisagenlecleucel) but now marketed by Novartis as Kymriah, reprograms the patient’s own T cells to locate and kill B cells that have the protein CD19 on their surface. FDA approval was the result of five years of clinical trials supervised by lead investigator Stephan Grupp, MD, PhD, Chief of the Cellular Therapy and Transplant Section and Director of the Cancer Immunotherapy Program at Children’s Hospital of Philadelphia (CHOP).
CHOP is a world leader in CAR T-cell therapy, having treated more than 250 patients — the busiest pediatric center in the world. The CHOP team continually takes what it learns through its exceptional amount of clinical experience and translates it to innovative research approaches that could be alternatives to or combined with Kymriah. “We are working on broad access to this therapy, and are excited about recent approvals for Kymriah in the EU, UK, and Canada,” says Grupp. “We are committed to the safe and excellent care of the more than 80 CAR-T patients we are treating yearly at CHOP. But we are most excited by future innovations in CAR T and other engineered cell therapies at CHOP.”
Trials of more game-changing cell therapies are underway or on the horizon
Shannon Maude, MD, PhD, is evaluating an alternative, humanized CD19 CAR-T product, referred to as huCART19 or CTL119. This CAR is being studied for retreatment in patients with CD19+ leukemia or lymphoma that was previously treated with cell therapy, as well as first CAR therapy for relapsed ALL. Phase 1, almost complete, has revealed promising data. Phase 2 of the trial will open soon at CHOP.
When leukemia cells don’t have or stop expressing CD19, they remain hidden from CD19 CAR therapies like Kymriah and then may multiply, causing a relapse. A research goal is to identify second targets on ALL that can be targeted along with the CD19. One such target is CD22. A new modified vector has been developed for this target in collaboration with Penn and Novartis. CHOP is designing a trial that will test this new therapeutic option in children, leading quickly to a larger trial that combines CD19 and CD22.
CHOP’s Immunotherapy team has been leading the development of a trial testing Kymriah as part of first line therapy, with Shannon Maude, MD, PhD, and Stephen Hunger, MD, serving as principal investigators. This study will enroll in multiple centers through the Children’s Oncology Group. Here, the focus will be on patients with high-risk (MRD+) disease, with an event-free survival at half what is usually seen among children with standard-risk ALL. The trial will test whether cell therapy can prevent relapse and/or the subsequent need for bone marrow transplant in these children with treatment-resistant ALL.
In addition, CHOP is designing trials to define other ALL populations that may benefit from CD19 CAR therapy, such as CNS ALL and patients with Down syndrome. The latter experience an increased incidence of ALL, higher frequency of adverse effects to chemotherapy and inferior probability of survival.
Acute myeloid leukemia (AML) accounts for approximately 20 percent of pediatric leukemias. Current intensive cytotoxic chemotherapy regimens achieve long-term cure in only 60 percent of children. Phase 1 trials of CAR T-cell immunotherapies for children with AML are currently in development under the leadership of Richard Aplenc, MD, PhD, and Sarah Tasian, MD.
Researchers are also working on developing new therapies that reprogram a patient’s own immune system cells to kill other types of cancer besides blood cancers. So far, solid tumors have generally resisted CAR-T cells. For patients with unresectable, metastatic, or recurrent synovial sarcoma — a rare form of soft tissue cancer — CHOP has participated in trials testing a different kind of engineered T cell, referred to as a TCR engineered T cells. CAR-T cells are being developed for another pediatric cancer, neuroblastoma. In addition, the possibility is being explored that solid tumors will respond to CAR-T therapies when they are combined with another agent intended to boost T-cell function.
A truly innovative approach to the use of cell therapy involves partnerships with other programs to treat non-malignant diseases. The CHOP Cellular Therapy and Transplant Section is collaborating with the Division of Hematology to design and implement trials that employ gene-editing technology to test autologous gene therapy for patients with thalassemia or severe sickle cell disease.
An ultimate goal of the field would be to use T cells edited with CRISPR technology to produce universal T cells, thereby eliminating the need to collect cells from and manufacture a product for each individual child.