Making Better CARs for Kids

The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah; Novartis)—approved last year for the treatment of children and young adults with acute lymphoblastic leukemia (ALL)—has led to complete remissions in many patients who had stopped responding to chemotherapy. Yet such personalized treatments aren't always effective, and researchers have been trying to tease apart the reasons why.

“We treated a number of children between 2012 and 2014 and one of the things that became very clear is that it was quite challenging to make an effective CAR T-cell product,” said David Barrett, MD, PhD, of Children's Hospital of Philadelphia, PA.

T cells extracted from a patient's blood must be healthy enough to be modified into CAR T cells and to expand at least five-fold to possibly be effective, explained Barrett. When subsequently infused into the patient, the CAR T cells need to be sufficiently active to attack the cancer. In several patients Barrett's team treated early on, T cells expressed markers of exhaustion when they were collected and either died in the lab or were too worn out for the therapy to work.

“What was the difference between the cells that were successful and those that weren't? It was the starting material,” Barrett said. “I think everybody knows that chemotherapy is really bad for your T cells, and the more chemo you get, the less likely you are to have healthy T cells. But I really wanted to know what is the potential [for success] at diagnosis, before these patients have ever seen therapy.”

The researchers collected blood from 157 children with ALL, chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, or Ewing sarcoma upon diagnosis and after each cycle of chemotherapy. In the prechemotherapy samples, Barrett reported, they found that the CAR T-cell potential was poor in all of the malignancies except ALL and Wilms tumor. RNA profiling of metabolic pathways revealed that the poorly performing T cells relied on glycolysis for fuel instead of fatty acids like normal cells.

Further, the researchers noted a decline in T-cell potential with successive chemotherapy cycles in all of the cancer types. In one patient with ALL, T cells examined prior to and after the first and second cycles looked relatively normal, but by the sixth cycle, the cells had little potential of success as CAR therapies.

“Cumulative chemotherapy is altering the metabolic profile of the T cells,” said Barrett, who outlined his team's findings at a press conference in advance of the American Association for Cancer Research Annual Meeting 2018, which was held April 14–18 in Chicago, IL.

In later preliminary experiments, Barrett said researchers demonstrated that “force-feeding” fatty acids to T cells could restore their spare respiratory capacity, a measure of their energy reserve.

The goal now, said Michael Caligiuri, MD, president and physician-in-chief at City of Hope National Medical Center in Duarte, CA, and moderator of the press conference, is to develop “alternate strategies—different chemotherapies, different preparatory regimens—that really decrease the injury to the T cells' metabolic pathway and, if not, reversing that metabolic pathway.”

Some changes in clinical care have already occurred. “Based on this data, we have altered our practice for T-cell collection for children with leukemia, for children with high-risk disease,” noted Barrett. “We will collect T cells early, even if that patient is not currently eligible for a CAR T trial, simply because we know that cumulative chemotherapy is going to progressively deteriorate the likelihood that those cells will make a functional product, and we've been recommending that to other centers.” –Suzanne Rose

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