Prior Chemotherapy for Leukemia May Hinder Effective CAR T-Cell Development
Younger patients who received certain chemotherapies for solid tumors or leukemia may not have T-cells capable of becoming effective chimeric antigen receptor (CAR) T-cells, according to a study to be presented at the American Association for Cancer Research Annual Meeting (April 14-18, 2018; Chicago, IL).
Prior research has found that pediatric patients with solid tumors or leukemia may have poor-quality T-cells due to previous chemotherapy administration.
David M Barrett, MD, PhD, assistant professor of pediatrics, Children’s Hospital of Philadelphia, and colleagues studied blood samples from 157 pediatric patients with acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, or Ewing sarcoma. Researchers collected samples at diagnosis as well as after each cycle of chemotherapy to determine why some patients had poor-quality T-cells.
“In several of the patients with leukemia we first attempted to treat, we noticed the T-cells looked exhausted when we first collected them, and they either did not survive the lab process to turn them into CAR T-cells or did not have enough energy left to work in the patient as a result,” Dr Barrett noted in a press release (March 16, 2018).
While studies have shown that chemotherapy may be harmful toward T-cells, Dr Barrett and colleagues were interested in the potential of T-cells at diagnosis to determine whether CAR-T therapy may be useful in solid tumors.
Results of their analysis showed that T-cells that used glutamine and fatty acid pathways as fuel sources had better CAR-T potential compared with T-cells that depend on glycolysis. Additionally, CAR-T potential was reportedly poor prior to chemotherapy in all tumor types except ALL and Wilms tumor.
Researchers also noted that chemotherapy regimens containing cyclophosphamide and doxorubicin significantly decreased spare respiratory capacity in T-cells, which may be associated with poorly-performing CAR T-cells. Contrarily, the use of fatty acids improved spare respiratory capacity after chemotherapy.
“Based on [these] data, we have altered our practice for T-cell collection for children with leukemia,” Dr. Barrett added in his press release. “For children with high-risk disease—including those with very poor cytogenetics or those who are end of induction and high-minimal residual disease positive—we will collect T-cells early…simply because we know that cumulative chemotherapy is going to progressively deteriorate the likelihood that those cells will make a functional CAR product.”—Zachary Bessette