The case for CAR T-cell therapy in follicular lymphomas

In this issue of Blood,Hirayama et al report high, sustained responses in patients with relapsed or refractory (R/R) follicular lymphoma (FL) treated with anti-CD19 chimeric antigen receptor (CAR)–modified T cells.¹  However, the variation in response, relative to patients with transformed FL (tFL), highlights the complexity of CAR T-cell therapy in the treatment of non-Hodgkin lymphoma (NHL).

Enthusiasm for the investigation of CAR T cells in the treatment of hematologic malignancies (and to a certain degree, solid tumors) continues to increase beyond the current US Food and Drug Administration–approved indications of acute lymphocytic leukemia and diffuse large B-cell lymphoma (DLBCL), as evidenced by the growing number of reports and trials of this therapy. The majority of these trials use an anti-CD19 CAR for a number of biologic, clinical, and practical reasons. Because FL is the second most frequent NHL and the outcomes of patients with R/R FL are relatively poor, the investigation of CAR T cells in this entity is logical. Indeed, one of the first reports on the use of anti-CD19 CAR T-cell therapy in NHL was in a patient with FL, as reported by Kochenderfer and colleagues²  at the National Cancer Institute. Their group subsequently reported on 22 patients with R/R NHL, including 2 patients with FL and 4 patients with tFL, who were treated with anti-CD19 CAR-modified T cells.³  All 6 of the patients with FL or tFL responded, including 5 complete remissions (CRs), all of which were sustained. The majority of reports with anti-CD19 CAR T cells have focused on DLBCL.^4,5  However, Schuster and colleagues⁶  at the University of Pennsylvania reported on 28 patients with R/R NHL, including 14 patients with FL, with their anti-CD19 CAR T-cell product CTL019. The article did not mention whether any of the patients had tFL. Among the 14 FL patients, 10 (71%) achieved a CR, and 89% of responding patients maintained their response without further therapy.

The article by Hirayama and colleagues from the Fred Hutchinson Cancer Research Center adds to the clinical experience of anti-CD19 CAR T cells in patients with FL. They analyzed the outcomes of 21 patients, 8 with FL and 13 with tFL, who participated in a phase 1/2 trial that used a defined ratio of CD8⁺ and CD4⁺ CD19-specific CAR-modified T cells.⁷  Similar to the report from the University of Pennsylvania, the response rate among the FL patients was high (88%) all of which were also sustained. In contrast, the response rate among the patients with tFL was only 46%, although all were CRs; the median duration of response in this cohort was 10.2 months. These latter results seem relatively consistent with results from the ZUMA-1 and JULIET clinical trials, which included 16 and 19 patients with tFL, respectively. The ZUMA-1 trial reported the outcomes of tFL in patients with primary mediastinal B-cell lymphoma, and the JULIET trial reported outcomes in their DLBCL population. Thus, an accurate assessment cannot be made regarding the efficacy of anti-CD19 CAR T-cell therapy in this unique disease entity.

There were important differences in the 2 patient cohorts in the article by Hirayama et al. Patients with tFL had a higher tumor burden, lactate dehydrogenase, and Follicular Lymphoma International Prognostic Index (FLIPI) score on average. Another difference was in regard to the intensity of the lymphodepleting chemotherapy that was used before infusion. The majority of the patients with FL (62%) received a regimen that contained approximately double the amount of cyclophosphamide compared with the other 2 regimens that were used. Although there was no difference in CAR T-cell expansion among the 3 lymphodepleting regimens, the intensity could have affected overall response rates. Hirayama et al have previously reported that progression-free survival was superior in patients who received higher-intensity lymphodepleting chemotherapy, although it was also dependent on achieving a favorable cytokine profile.⁸ 

There were significant differences in the intensity of the lymphodepleting chemotherapy used in the ZUMA-1 and JULIET trials, which might explain the significant differences in overall response rates in the 2 trials. In fact, 7 patients in the JULIET trial did not receive any lymphodepleting chemotherapy before CAR T-cell infusion. The overall response rate in these patients was only 29%; 4 patients (57%) were observed to have progressive disease as their best response compared with 23% in the cohort that did receive lymphodepleting chemotherapy. These important observations contribute to the increasing amount of data related to factors that affect the efficacy and toxicity of anti-CD19 CAR T-cell therapy, which also include differences in CAR constructs and the health and function of the T cells into which they are introduced.⁹  Taken together, they will help investigators develop experiments and trials to understand resistance to and enhancement of CAR T-cell therapies.

The results reported by Hirayama et al add to data from previous articles by Kochenderfer et al^2,3  and Schuster et al^5,6  showing that anti-CD19 CAR T-cell therapy can result in very high and sustained remission rates in patients with R/R FL and that also support observations in ZUMA-1 and JULIET of the benefit in patients with tFL. There are several ongoing trials specifically investigating anti-CD19 CAR T cells in FL, and preliminary results are encouraging. Although the number of patients at this time are small, there is growing evidence that anti-CD19 CAR T-cell therapy will eventually provide a highly efficacious option for patients with R/R FL.