Jurnal Internasional Kasus untuk terapi sel T CAR pada limfoma folikel
Enthusiasm for investigating CAR T cells in treatment haematological malignancies (and to some extent, solid tumors) continue to increase beyond indications approved by the current US Food and Drug Administration regarding acute lymphocytic leukemia and diffuse large B cell lymphoma (DLBCL), as evidenced by the increasing number of reports and therapeutic trials this. Most of these trials use anti-CD19 CARs for a number of biological, clinical and practical reasons. Because FL is the second most frequent NHL and the results of patients with R / R FL are relatively poor, investigating CAR T cells in this entity is logical. Indeed, one of the first reports about the use of anti-CD19 T-CAR cell therapy in NHL was in patients with FL, as reported by Kochenderfer and colleagues 2 at the National Cancer Institute. Their group then reported on 22 patients with NHL R / R, including 2 patients with FL and 4 patients with tFL, who were treated with modified CAR-CD19 modified T cells. 3 All 6 patients with FL or tFL responded, including 5 complete remissions (CR), all of which were maintained. Most reports with anti-CD19 CAR T cells focus on DLBCL. 4 5 However, Schuster and colleagues 6 at the University of Pennsylvania reported 28 patients with R / R NHL, including 14 patients with FL, with anti-CD19 CAR T-cell products -CD19 them. The article did not mention whether there were patients who had tFL. Among 14 FL patients, 10 (71%) achieved CR, and 89% of patients who responded retained their response without further therapy.
Article by Hirayama and colleagues from the Fred Hutchinson Cancer Research Center added to the clinical experience of anti-T CAR cells -CD19 in patients with FL. They analyzed the results of 21 patients, 8 with FL and 13 with tFL, who participated in phase 1/2 trials using CD8 ratios + and CD4 + CD19-specific T cell modification CAR . 7 Similar to reports from the University of Pennsylvania, response rates among FL patients are high (88%) all of which also persist. In contrast, the response rate among patients with tFL was only 46%, although all were CR; The average duration of response in this group was 10.2 months. These latest results appear to be relatively consistent with the results of the ZUMA-1 and JULIET clinical trials, which included 16 and 19 patients with tFL, respectively. The ZUMA-1 trial reported tFL results in patients with primary mediastinal B cell lymphoma, and the JULIET trial reported results 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 are important differences in the 2 patient cohorts in the article by Hirayama et al. Patients with tFL have a higher tumor burden, average lactate dehydrogenase, and International Prognostic Index (FLIPI) Follicular Lymphoma). Another difference is in the intensity of lymphodepleting chemotherapy used before infusion. The majority of patients with FL (62%) received a regimen containing approximately twice the amount of cyclophosphamide compared to the other 2 regimens used. Although there is no difference in CAR T cell expansion among the 3 lymphodep depletion regimens, intensity can affect the overall response rate. Hirayama et al. Have previously reported that development-free survival is superior in patients receiving high-intensity lymphodepleting chemotherapy, although that also depends on achieving a favorable cytokine profile. 8
There was a significant difference in the intensity of lymphodepleting chemotherapy used in the ZUMA-1 and JULIET trials, which might explain the significant difference in the overall response rate in the 2 trials. In fact, 7 patients in the JULIET trial did not receive lymphodepleting chemotherapy before the CAR T cell infusion. The overall response rate in this patient is only 29%; 4 patients (57%) were observed to have progressive disease as their best response compared to 23% in the group who received lymphodepoint chemotherapy. This important observation contributes to the increasing amount of data related to factors influencing the efficacy and toxicity of CD19 T-CAR cell therapy, which also includes differences in CAR construction and health and T cell function in which they are introduced. 9 Together, they will help researchers develop trials and trials to understand the resistance and enhancement of CAR T cell therapy.
The results reported by Hirayama et al add data from a previous article by Kochenderfer et al 2 3 and Schuster et al 5 6 showed that CAR-CD19 T cell therapy can produce very high and continuous remission rates in patients with R / R FL and that also support observations on ZUMA-1 and JULIET about the benefits in patients with tFL. There are several ongoing trials specifically investigating anti-CD19 CAR T cells in FL, and the preliminary results are encouraging. Although the number of patients is currently small, there is growing evidence that anti-CD19 CAR T cell therapy will ultimately provide a very effective option for patients with R / R FL.
Conflict-of-expression of interest: MRB is a consultant and has received honorarium and research support from Novartis, Kite / Gilead, Juno Therapeutics, Celgene, and CRISPR Therapeutics.
- © 2019 by The American Society of Hematology