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Prior exposure to chemotherapy blunted the expansion of chimeric antigen receptor (CAR) T cells and subsequent clinical activity in pediatric cancers, serial analysis of peripheral T cells showed.

Cumulative chemotherapy exposure correlated with a decline in the modified T cells' expansion potential. Moreover, specific types of chemotherapy -- those containing doxorubicin or cyclophosphamide -- depleted T cells' spare respiratory capacity (SRC), or energy reserve, a portent of poor clinical performance.

The analysis also showed that T cells that depended on glutamine and fatty acid pathways for fuel had good CAR T-cell expansion potential, whereas those that depended on glycolysis were poorly suited for the CAR T-cell manufacturing process.

Collectively, the findings emphasized that the success of CAR T-cell therapy in an individual patient depended on the quality of the starting material, David M. Barrett, MD, PhD, of Children’s Hospital of Pennsylvania in Philadelphia, said during a press briefing prior to the (AACR) meeting.

"We've been diving really deep into why these T cells don't make good CAR-T cells," said Barrett. "We're investigating what goes into the best starting material, so that we can alter our approaches to make sure that we make a highly functional CAR T-cell product, not only for kids with leukemia but also for potentially solid-tumor CARs, as we try to develop those in the future."

The research offers a good example of the intersection of immunotherapy, immuno-oncology, and precision medicine to solve clinical problems in oncology, said AACR president Michael Caligiuri, MD.

"We're looking at immune response and immunotherapy to discover what could be wrong and how to fix it. In this instance we see these T cells aren't working, and [Barrett] uses gene expression profiling and finds a pathway, an energy pathway. The cells seem to be exhausted by the tumor or the chemo. We can now predict -- the precision medicine angle -- who's going to do well and who's not."

During early clinical experience with CAR T-cell therapy, Barrett and colleagues noticed that T cells collected from some patients appeared "exhausted." Those cells inevitably did not survive the production process or performed poorly after infusion into patients. The investigators previously reported in that new-lineage (younger) T-cells performed best, as well as those with little or no exposure to chemotherapy.

To study factors leading to poor-quality T cells, investigators prospectively collected T cells from 157 patients with acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia, Hodgkin and non-Hodgkin lymphoma (NHL), neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, or Ewing sarcoma. The cells were obtained at diagnosis and after each cycle of chemotherapy.

Laboratory analysis using a validated model involving normal human T cells showed that all of the T cell samples had poor-quality expansion potential except for T cells from patients with ALL or Wilms tumor. Subsequent analyses showed continual decline in the expansion potential of all the samples as total chemotherapy exposure increased, particularly in children younger than 3.

In vitro assays showed that doxorubicin- and cyclophosphamide-containing chemotherapy regimens were especially toxic to T cells with no prior exposure to chemotherapy. Those chemotherapeutic agents attack the mitochondria, which are cells' energy generators, Barrett explained. Mitochondrial destruction led to depletion of cells' SRC.

However, that did not explain why some T cells had poor CAR potential prior to chemotherapy. Additional laboratory studies showed that T cells with poor baseline CAR potential tended to rely on glycolysis as a fuel source rather than fatty acids.

Using a laboratory model of T cells, Barrett and colleagues found they could "force" glycolysis-biased T cells to use fatty acids for energy, at least chemotherapy-exposed T cells. He cautioned that the findings relative cells' metabolic pathway preference have yet to be confirmed in T cells obtained from patients with cancer.

Fundamental differences in the quality of the starting material could explain why CAR T-cell therapy results in objective responses in about 90% of pediatric patients with ALL, as compared with about a 50% response rate with the same CAR T-cell product in adults with NHL, said Barrett. The findings also suggested that different production or processing strategies might be required to develop effective CAR T-cell products for solid tumors.

The AACR annual meeting begins April 14 in Chicago and continues through April 18.

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