Improving CAR T-cell Therapy Efficacy in Acute Lymphoblastic Leukemia by Optimizing Design and Placement
Shannon Maude
MD PhDThe Children's Hospital of Philadelphia
Project Term: July 1, 2023 - June 30, 2028
Pediatric acute lymphoblastic leukemia (ALL) that is resistant to standard therapy is a challenge that has been partially overcome by T-cell therapy, yet relapse still occurs in up to 50%. We are conducting two clinical trials that test a next-generation T-cell therapy and the first incorporation of T-cell therapy into initial therapy. These trials will inform future development and the optimal place for this therapy with the goal of improving cure rates for children with very high risk ALL.
Children and young adults with acute lymphoblastic leukemia (ALL) that is resistant to standard therapy historically have suffered from extremely poor outcomes. Recent development of approaches using the immune system to target ALL have revolutionized treatment for these high-risk patients. One such therapy uses T cells, a potent part of the immune system, which target and kill cancer cells through a chimeric antigen receptor (CAR). This approach, termed CAR T-cell therapy, has yielded dramatic and durable responses in highly resistant B-cell ALL. Unfortunately, up to 50% of patients will relapse after this therapy. Through study of our completed CAR T-cell clinical trials, we have identified risk factors for relapse. My research program focuses on developing innovative clinical trials of CAR T-cell therapy to address and overcome those risk factors in order to improve outcomes for children and young adults with high-risk disease. A principle behind CAR T-cell efficacy in ALL is durability of the modified T cells; however, on early clinical trials, between 25% and 80% of patients experienced early loss of CAR T cells, depending on the design. To address this risk factor for relapse, we developed a next-generation CAR, humanized (hu)CART19, in an attempt to reduce the chance of rejection of the CAR T cells by the patient’s immune system and improve durability. After conducting a phase 1 trial of huCART19, which demonstrated encouraging durable remission rates both in patients with poor response to prior CAR-T (retreatment) and those without prior CAR-T treatment, we developed a phase 2 trial of huCART19 for retreatment and relapsed/resistant B-cell ALL. This trial and accompanying studies will inform future development of next-generation CAR T-cell products to improve durability of response. Another risk factor for relapse after CAR T-cell therapy is high disease burden at the time of treatment. We posit that moving CAR T-cell therapy earlier in the treatment course for patients with low-level disease who are at very high risk of relapse with standard therapy will improve their chance of cure. Through the Children’s Oncology Group, we developed a clinical trial incorporating CAR T-cell therapy into first-line therapy for these high-risk patients, a first test of this approach. If successful, this trial could transform dramatically the treatment for children and young adults with newly diagnosed B-cell ALL and inform the optimal place for this therapy.