Uniform CAR-T Cells Help Tweak Lymphoma Therapy


By David Douglas

NEW YORK (Reuters Health) - Standardized CD19-specific chimeric antigen receptor (CAR)-modified T cells along with chemotherapy can more effectively guide treatment and improve response in patients with relapsed and refractory B cell non-Hodgkin's lymphoma, according to a new study.

"The main message is that you can treat patients with non-Hodgkin's lymphoma with CAR-T cells and get very good response rates with optimization of the CAR-T-cell dose and lymphodepletion," lead author Dr. Cameron J. Turtle said in a statement.

In a paper online September 7 in Science Translational Medicine, Dr. Turtle of Fred Hutchinson Cancer Research Center in Seattle and colleagues note that CAR-T cells are known to have antitumor activity in B cell malignancies.

However, differences in lymphodepletion regimens and heterogeneity of cells given to individual patients have made it difficult to define factors that affect toxicity and efficacy.

By selecting and transducing individual T cell subsets, the team produced a CAR-T cell product with a 1:1 CD4+/CD8+ ratio of CAR-T cells, which helped clarify relationships between cell doses and patient outcomes. The researchers evaluated three CAR-T cell dose levels administered 36 to 96 hours after lymphodepleting chemotherapy.

The study involved 20 patients who had had cyclophosphamide-based lymphodepletion chemotherapy along with fludarabine and a further 12 patients who had received such chemotherapy without fludarabine.

The combination group had a 72% overall response rate and 50% remission rate compared to a 50% overall response rate and 8% complete remission in those not given fludarabine.

In the 11 patients given combination chemotherapy at the maximum tolerated dose, the overall response rate was 82% and complete remission was seen in 64%. This, say the researchers, "compares favorably to the 45% complete remission rate observed in a recent report."

The combination lymphodepletion regimen led to higher peak expansion and longer duration of CAR-T cell persistence in the blood and a greater probability of tumor regression. The addition of fludarabine was also associated with improvement in the depth of response.

No serious acute toxicity was seen in the first two hours after CAR-T cell infusion, but most patients developed toxicities expected with cytotoxic chemotherapy, including bone marrow suppression and neutropenic fever.

Overall, severe cytokine release syndrome (sCRS) was seen in 13% of the patients and severe neurotoxicity, which was more common in those who received fludarabine, was observed in 28%. CAR-T cell dose was related to the development of sCRS and neurotoxicity and was predominantly seen at the highest doses.

The results "show that delivery of a consistent CAR-T cell product is feasible in an overwhelming majority of heavily pretreated patients, provides high overall response and complete remission rates, and allows identification of factors that are important for optimizing CAR-T cell proliferation and persistence and for reducing toxicity."

Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Maryland, who was not involved in the work, characterized the paper as "excellent" and noted that it "extends earlier results from the NCI that first reported the effectiveness of anti-CD19 CAR-T cells against lymphoma."

"Anti-CD19 CAR-T cells," he told Reuters Health by email, "are likely to become an important standard therapy for lymphoma in the near future as results on the effectiveness of this approach accumulate from multiple academic groups and multiple companies."

Dr. Turtle did not respond to requests for comments.

SOURCE: http://bit.ly/2ctZHbt

Sci Transl Med 2016.

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