The approach of using genetically engineered chimeric antigen receptor (CAR)-T cells has received much attention for treating leukemias, where it has achieved spectacular long-lasting complete remissions in some patients with no other treatment options. CAR-T cells are also being studied in lymphomas and other hematologic malignancies, and a new study suggests that CAR-T therapy can induce remissions in some patients who have progressed after allogeneic stem cell transplant.¹

This study, presented at the 57th American Society of Hematology Annual Meeting and Exposition by James Kochenderfer, MD, of the Center for Cancer Research at the National Cancer Institute, Bethesda, Maryland, used genetically engineered CAR-T cells from a transplant donor’s T cells. This approach differs from that of other studies, which have used a patient’s own T cells to manufacture CAR-T cells. Unlike other studies of CAR-T cells, Dr. Kochenderfer’s study used a single infusion of CAR-T cells with no additional chemotherapy.

“We need new therapies for progressive disease after allogeneic stem cell transplant. These patients are in a dire situation. A donor lymphocyte of unmanipulated origin has inconsistent efficacy and significantly more mortality and graft-vs-host disease. We aimed to improve efficacy in progressive disease after transplant by using anti-CD19 CAR-T cells. We are one of the only groups to use CAR-T cells for this purpose,” explained Dr. ­Kochenderfer, one of the first investigators to study these cells in lymphoma.

“In this small study, we used allogeneic donor T cells instead of the patient’s own T cells. We went back to the transplant donor to get more lymphocytes and genetically engineered them to make CAR-T cells,” he explained. “We used a gamma retroviral vector, and cell production took 8 days. This approach is feasible in all B-cell malignancies,” added Dr. Kochenderfer.

Study Details and Results

The phase I dose-escalation study enrolled 20 patients with B-cell malignancies that progressed post allogeneic stem cell transplant. Five had acute lymphocytic leukemia (ALL), five had chronic lymphocytic leukemia (CLL), and the remaining ten had lymphoma (five diffuse large B-cell lymphoma [DLBCL] and five with mantle cell lymphoma [MCL]).

Overall, 9 of 20 patients had a complete or partial response. The best responses were observed in ALL, with four of five patients achieving a complete response, although two of these patients later relapsed. Patients with CLL also had good responses: one in five had a complete response, one had a partial response, two had stable disease, and one had progressive disease.

One of five patients with MCL had an ongoing complete response, one had a partial response, and three had stable disease. In patients with DLBCL, one of five had a complete response, three had stable disease, and one had progressive disease.

“This approach is most successful in ALL,” he emphasized.

Responses were rapidly obtained, observed within 7 to 10 days of the single infusion of CAR-T cells. No acute graft-vs-host disease was reported. One patient had worsening of preexisting graft-vs-host disease after CAR-T cell infusion, and one developed mild chronic eye graft-vs-host disease more than a year after CAR-T cell infusion, “when the CAR-T cells were no longer around,” he said.

Patients with a higher disease burden developed cytokine release syndrome, which is actually a marker of activity. “In contrast to some other CAR-T cell studies, neurotoxicity was rare and mild,” Dr. Kochenderfer remarked.

Closer Look at Individual Patients

Dr. Kochenderfer provided examples of individual patients. In one patient with ALL, disease was completely eradicated by 1 month after treatment, with no additional chemotherapy necessary. One patient with CLL has been in complete remission for 36 months, and one patient with MCL has had a complete response at 31 months. In one photo of a patient with DLBCL, large masses completely disappeared 15 days after CAR-T cell infusion.

Dr. Kochenderfer explained that patients with B cells in the blood prior to CAR-T cell infusion had a higher number of CAR-T cells after infusion, “suggesting that B cells are causing the T cells to proliferate. Patients with a low B-cell count prior to infusion tend to have lower CAR-T cell levels after infusion,” he noted.

An Interesting Observation

“Another interesting observation is that PD-1 (programmed cell death protein 1) expression [on T cells] dramatically increases during infusion and CAR-T cell peak level. This provides a rationale for combining CAR-T cells with an anti–PD-1–blocking agent, such as nivolumab [Keytruda]. We are studying this in mice,” added Dr. Kochenderfer.

“CAR-T cells can be administered without prior chemotherapy for malignancies resistant to allogeneic stem cell transplant and standard donor lymphocyte infusion. Progressive disease after allogeneic stem cell transplant regressed after a single infusion of anti-CD19 CAR-T cells, with no graft-vs-host disease,” he stated. ■

Disclosure: Dr. Kochenderfer has received consultation fees from Bluebird Bio.

Reference

1. Brudno JN, Somerville R, Shi V, et al: Allogeneic T-cells expressing an anti-CD19 chimeric antigen receptor cause remissions of B-cell malignancies after allogeneic hematopoietic stem cell transplantation without causing graft-versus-host disease. ASH Annual Meeting. Abstract 99. Presented ­December 5, 2015.