CAR Therapy Achieves Durable Responses in Refractory Lymphoma

Published: Wednesday, Jun 08, 2016

James-Kochenderfer.jpg

James N. Kochenderfer, MD

Three-fourths of patients with advanced lymphoma achieved durable objective responses to treatment with chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 even after a low-dose chemotherapy conditioning regimen, data from an ongoing clinical study showed.1

Overall, 16 of 22 patients responded to the treatment, including complete responses (CRs) in 12 patients, with manageable toxicities, lead study author James N. Kochenderfer, MD, reported at the 2016 ASCO Annual Meeting.

In a subgroup of patients with diffuse large B-cell lymphoma (DLBCL), two-thirds responded to the treatment, with most achieving CRs. Ongoing CRs range from 7 months to more than 20 months in duration, said Kochenderfer.

The responses were achieved even though the patients in the study received low-dose chemotherapy conditioning as opposed to the high-dose regimen administered in a prior study that demonstrated the potential for CAR-T therapy.2

“The dominant toxicities in our patients were neurologic, and the toxicities resolved,” said Kochenderfer. “Both anti-lymphoma responses and neurologic toxicity were associated with higher blood levels of CAR T-cells.”

The findings support continued development of CD19-targeting CAR-T therapies, indicated Kochenderfer, a leading CAR-T researcher at the Experimental Transplantation and Immunology Branch of the National Cancer Institute.

“Anti-CD19 CAR-T cells have entered multicenter clinical trials and will probably become an important part of lymphoma therapy in the near future given the ability to salvage the patients who are refractory to chemotherapy and have very few other options,” he said.

Multiple groups had shown that T cells can be genetically modified to express CARs that target CD19. Studies have demonstrated that the resulting modified T cells have significant activity against B-cell malignancies.

The study that Kochenderfer reported was conducted under a research agreement between the NCI and Kite Pharma, a California-based company. The agent under study, called KTE-C19, is being evaluated in the phase I/II ZUMA-1 trial among patients with refractory aggressive non-Hodgkin lymphomas (NCT02348216).

“These early results are encouraging and served as the foundation for Kite’s ongoing C19 ZUMA-1 Study,” said Jeff Wiezorek, MD, MS, senior vice president of Clinical Development at Kite, in a statement referring to the ASCO presentation.

One of the goals of the latest study was to determine whether patients would respond to the CAR-T therapy with a modified chemotherapy conditioning regimen. Such conditioning is conducted to enhance leukocyte receptivity to the T-cells. NCI researchers theorized that a low-dose conditioning regimen might be less toxic and help improve outcomes.

The conditioning regimen used in the study consisted of cyclophosphamide 300 or 500 mg/m2 and fludarabine 30 mg/m2, both administered daily for 3 consecutive days, ending 3 days prior to infusion of the modified T-cells.

By contrast, the chemotherapy regimen used previously consisted of cyclophosphamide at a total dose of either 120 or 60 mg/kg, followed by 5 daily doses of fludarabine 25 mg/m2.2

Serum analysis before and after administration of the low-dose chemotherapy conditioning regimen revealed “striking changes” in multiple proteins, including interleukin (IL)-15, IL-7, MCP-1, and perforin (P <.0001 for all comparisons), said Kochenderfer.

Results for the 22 evaluable patients showed an objective response rate of 73%, consisting of CRs in 55% of the patients and partial responses in 18%. All but 3 patients had DLBCL, and in that predominant subgroup, the overall response rate was 68%, including CRs in 9 (47%) patients and partial responses in 4 (21%).

Of the remaining 3 patients, 2 had follicular lymphoma and 1 had mantle cell lymphoma. All 3 attained CRs with the CAR-T cell regimen with low-dose conditioning chemotherapy, said Kochenderfer.

Nine of the 12 patients who attained CRs have ongoing responses, the longest now approaching 2 years.

With regard to toxicity, all patients developed fever. Neurotoxicity has been most bothersome and also the most severe. Kochenderfer reported that 12 of the 22 patients developed grade 3 or 4 neurologic toxicity, including confusion, dysphasia, encephalopathy, and gait disturbances.

“All toxicities in these patients completely resolved, usually in less than 2 weeks,” he said.

Higher peak levels of CAR-T cells were associated with both remission (P = .026) and neurologic toxicity (P =.003). Additionally, patients who attained complete or partial remission had higher peak levels of serum IL-15 (P = .003) and IL-10 (P = .014) as compared with patients who had stable disease or progressive disease.

Higher levels of the same 2 proteins, plus Granzyme B, also had significant associations with grade 3/4 neurologic toxicity (P = .02 to P = .003).


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