Chemotherapy may impair T cells』 potential to become effective CAR T cells
The researchers examined the T cells in 157 pediatric patients with blood cancers (ALL, chronic myelogenous leukemia, non-Hodgkin lymphoma, or Hodgkin lymphoma) or solid tumors (neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, or Ewing sarcoma) at diagnosis and after each cycle of chemotherapy.
The CAR T-cell potential of the T cells was very poor in all tumor types except ALL and Wilms tumor in the pre-chemotherapy samples, and there was a decline in CAR T-cell potential with cumulative chemotherapy in all cancer types. Nanostring RNA profiling of metabolic pathways revealed T cells with poor CAR T-cell potential were biased toward glycolysis as their fuel source instead of fatty acids.
Analysis of oxygen consumption rate also showed that certain classes of chemotherapies, particularly those regimens that had cyclophosphamide and doxorubicin, were harmful to the 「spare respiratory capacity」 (SRC) of T cells. 「SRC is a measure of the energy reserve of a cell, and is based on how many mitochondria are present and how healthy they are,」 Barrett explained. Having a poor energy reserve means the T cell is likely to either be inefficient to begin with or to die before it could kill the cancer cells.
「Based on these data, we have altered our practice for T-cell collection for children with leukemia, for children with high-risk disease … we will collect T cells early even if that patient is not currently eligible for CAR trial simply because we know that cumulative therapy is going to progressively deteriorate the likelihood that the cells will make a functional CAR product,」 Barrett noted in the webinar. 「We have been recommending that to other centers.」