Could CAR-T Therapy Be Moving Into Lymphoma?


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Stephen J. Schuster, MD

CAR-T cells targeting CD19 have achieved potent antitumor effects in relapsed/refractory acute lymphoblastic leukemia and chronic lymphocytic leukemia. It is not a stretch to hypothesize that CAR-T would be active in non-Hodgkin lymphomas that express CD19.

—Stephen J. Schuster, MD

The use of T cells that are genetically engineered to express chimeric antigen receptor (CAR-T) has made headway as an approach to hematologic malignancies, with the best results achieved in leukemia. At the 2015 American Society of Hematology (ASH) Annual Meeting and Exposition, a preliminary study explored the use of CAR-T cells in lymphoma.1

Durable remissions were observed following a single infusion of CAR-T cells directed against CD19 in very sick, heavily pretreated patients with CD19-positive diffuse large B-cell lymphoma and follicular lymphoma. All patients who achieved complete remission remained in remission at a median follow-up of about 1 year. Only two patients with mantle cell lymphoma were treated, with one complete remission.

“CAR-T cells targeting CD19 have achieved potent antitumor effects in relapsed/refractory acute lymphoblastic leukemia and chronic lymphocytic leukemia. It is not a stretch to hypothesize that CAR-T would be active in non-Hodgkin lymphomas that express CD19,” said lead author Stephen J. Schuster, MD, Director of the Lymphoma Program at the Abramson Cancer Center, University of Pennsylvania, Philadelphia.

“We found durable responses in extensively pretreated patients with active non-Hodgkin lymphoma treated with CAR-T, with less toxicity than is reported with other therapies,” he said.

Study Eligibility

Patients enrolled in the trial (n = 43 at the time of the ASH meeting) had no available curative therapies and an expected survival of 3 months or longer. They included patients with diffuse large B-cell lymphoma, either after transplant or transplant-ineligible; patients with follicular lymphoma for whom at least two prior immunotherapy regimens had failed and who had progressive disease within 2 years of treatment; and patients with mantle cell lymphoma who had relapsed or had persistent disease after first-line rituximab (Rituxan) chemotherapy and were transplant-ineligible or relapsed after transplant.

Once eligibility for the study was determined, apheresis and manufacturing of CAR-T cells were initiated. Patients were restaged by computed tomography (CT) scan and bone marrow analysis and then given lymphodepleting chemotherapy on an individualized basis according to histology, past response, and blood counts. Chemotherapy ended 1 to 4 days before the CAR-T infusion was administered.

Of the 43 patients enrolled, 30 patients got the protocol-determined dose of CAR-T (15 diffuse large B-cell lymphoma, 13 follicular lymphoma, 2 mantle cell lymphoma); 6 patients failed to produce CAR-T sufficient for infusion.

Diffuse Large B-Cell Lymphoma

Patients with diffuse large B-cell lymphoma were very sick and heavily pretreated. At the first response assessment 3 months after infusion, response rates using anatomic criteria were as follows: overall response rate of 47%, with complete response in three patients, partial response in four, and progressive disease in eight. Best response was complete remission in six, partial response in one, and progressive disease in eight. Three of the patients with a partial response at 3 months converted to complete remission by 6 months; one patient with a partial response developed progressive disease.

No patients who achieved a complete remission have relapsed at a median follow-up of 14.5 months, Dr. ­Schuster told listeners.

“Most of the disease progression [on CAR-T] occurs before 3 months. You don’t need a CT scan to show progressive disease. However, those who achieve complete remission by 6 months stay in remission. We have 1 patient in [complete remission] for 18 months,” he said.

“In [diffuse large B-cell lymphoma], the peak in vivo expansion of T cells doesn’t correlate with response rates,” he added.

Durable responses were observed with a single infusion of CAR-T cells, and persistence of T cells was seen on flow cytometry out to 1 year. In seven responding patients, the median overall response rate had not been reached at 14.5 months.

“These results in primary refractory [diffuse large B-cell lymphoma] are quite impressive,” Dr. Schuster said.

Follicular and Mantle Cell Lymphoma

Patients with follicular lymphoma had a median age of 59 and had received a median of five prior therapies. One-third had undergone prior stem cell transplant, 71% had increased LDH, and 29% had more than one extranodal site.

In 11 evaluable follicular lymphoma patients, the 3-month overall response rate was 73%; there were 4 patients with complete remission, 4 with partial response, and 3 patients with progressive disease. Best response rate was 73%, with seven complete remissions, one partial response, and three patients with progressive disease. Three of the patients with a partial response converted to complete remission by 6 months.

The majority of patients who responded have continued to maintain a response at 1 year. As in the patients with diffuse large B-cell lymphoma, the peak in vivo expansion of CAR-T cells did not correlate with remission. A median follow-up of 14.3 months showed durable responses in those who achieved partial response or complete remission, he said.

Safety

Looking at overall toxicity, cytokine-release syndrome—mostly grade 2—was reported as ≥ grade 3 in four patients. Also, reversible central nervous system toxicity was reported, including agitation and delirium. One case of encephalitis was fatal.

Based on these promising results, investigators conducting a phase II trial called JULIET are planning to enroll adults with diffuse large B-cell lymphoma early in 2016. ■

Disclosure: Dr. Schuster has received consultant fees and/or research funding from Pharmacyclics, Novartis, Janssen, Nordic Nanovector, Celgene, Genentech, and Hoffmann-La Roche.

Reference

1. Schuster SJ, Svoboda J, Nasta SD, et al: Sustained remission following chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. 2015 ASH Annual Meeting. Abstract 183. Presented December 6, 2015.

 


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