Image courtesy of NIAID
A new study suggests that having a certain type of cancer or receiving certain chemotherapeutic agents
can affect T-cell function and make patients ineligible for engineered T-cell therapy.
However, researchers found that proper timing of T-cell collection can increase the number of patients eiligible for the therapy.
And the team developed a culture technique that can boost T cells’ fitness for expansion, which can increase eligibility as well.
Nathan Singh, MD, of the University of Pennsylvania in Philadelphia, and his colleagues described this work in Science Translational Medicine.
The researchers set out to determine why some patients’ T cells fail to multiply in culture. The team studied T cells from children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) who were undergoing chemotherapy. (NHL subtypes included Burkitt lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, primary lymphoma of bone, and follicular lymphoma.)
The researchers found that T cells from patients with ALL expanded better in culture than those from patients with NHL.
The team said a threshold of greater than 5-fold expansion during test expansion was associated with a high likelihood of successful clinical expansion.
Nearly 80% of patients with ALL met this threshold at diagnosis, but the rate declined over the course of therapy, falling to about 40% during maintenance therapy.
About 25% of NHL patients met the threshold at diagnosis, but few samples demonstrated any expansion after therapy began (12.5% of samples at all remaining time points tested).
The researchers said the difference in the proportion of ALL and NHL samples that met the expansion threshold was significant at all time points tested.
Analysis revealed that ALL patients had higher numbers of naïve T cells and stem central memory T cells, T cell subtypes known to be highly potent and proliferative with an enhanced capacity for self-renewal.
The researchers also found that certain chemotherapy drugs—namely, cyclophosphamide and cytarabine—selectively depleted early lineage T cells.
Fortunately, the team discovered that poor expansion can be rescued by exposing T cells to signaling molecules that stimulate T-cell activity. Culture with IL-7 and IL-15 boosted the expansion capacity of T cells from patients with NHL and those with ALL.
The researchers therefore concluded that using this culture technique or collecting T cells prior to chemotherapy can increase the number of patients eligible for engineered T-cell therapy.
