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Chemotherapy may limit ability to develop effective CAR T cells
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Pediatric patients with solid tumors may have poor-quality T cells compared with patients with leukemia, and certain prior chemotherapies significantly affected the ability of T cells to become effective chimeric antigen receptor T cells, according to a study scheduled for presentation at American Association for Cancer Research Annual Meeting.
Tisagenlecleucel (Kymriah, Novartis), a CD19-targeting CAR T-cell therapy, is indicated to treat patients aged younger than 25 years with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.
“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,” David M. Barrett, MD, PhD, assistant professor of pediatrics at Children’s Hospital of Philadelphia, said in a press release.
Barrett and colleagues studied blood samples from 157 pediatric patients with ALL, chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor or Ewing sarcoma.
Samples were taken at diagnosis and after each cycle of chemotherapy to assess why some children had poor-quality T cells.
“I think that everyone knows that chemotherapy is really bad for your T cells, and the more chemotherapy you get, the less likely you are to have healthy T cells,” Barrett said during a press conference. “But I really wanted to know what is the potential at diagnosis, before these patients had ever seen therapy, because as we think about expanding CAR T cell therapy to other cancers besides leukemia and lymphoma, we really want to know what are our challenges.”
Researchers found T cells that use glutamine and fatty acid pathways as fuel sources had superior CAR T-cell potential compared with those that depend on glycolysis as a fuel source.
CAR T-cell potential was poor prior to chemotherapy in all tumor types except ALL and Wilms tumor. In all cancer types, chemotherapy decreased CAR T-cell potential.
Researchers also found chemotherapy regimens containing cyclophosphamide and doxorubicin significantly impacted spare respiratory capacity, a measure of the energy reserve of the cell.
In an oxygen consumption rate analysis, poor spare respiratory capacity in T cells appeared associated with poorly performing CAR T cells. However, use of fatty acids — such as palmitate — improved spare respiratory capacity after chemotherapy.
“We’re trying to understand what goes into making the best starting material so that we can alter our approaches to make sure that we can make a highly functional CAR T cell product, not only for kids with leukemia, but also for solid tumors as we try to develop those in the future” Barrett said.
“Based on [these] data, we have altered our practice for T cell collection for children with leukemia. 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, even if that patient is not currently eligible for a CAR T cell therapy trial, simply because we know that cumulative chemotherapy is going to progressively deteriorate the likelihood that those cells will make a functional CAR product. And we’ve been recommending that to other centers,” Barrett added. – by Cassie Homer
Reference:
Barrett DM, et al. Abstract 1631. Scheduled for presentation at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
Disclosure: Barrett reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.