In March 2017, James N. Kochenderfer from the National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA, and colleagues reported in the Journal of Clinical Oncology the results of a study treating R/R NHL patients with anti-CD19 CAR T-cells. The aim of the study was to investigate the effect of using low-dose rather than high-dose fludarabine and cyclophosphamide pre-CAR-T conditioning, which was previously reported.
- 22 pts recruited: DLBCL (incl. PMBCL) = 19 pts, FL = 2 pts, MCL = 1 pt
- Chemotherapy-refractory DLBCL = 11pts
- ASCT-relapsed DLBCL = 5 pts, FL = 1pt
- ORR = 73%, CR = 55%, PR = 18%
- DLBCL ORR = 68%, CR = 47%, PR = 21
- 12-month PFS = 63.3%
- DoR = 7+ to 24+ months
- Grade 3–4 AEs: 55% neurologic toxicities (2 pts received tocilizumab)
- Neurologic toxicities resolved within a “limited period of time”
- Low- vs. high-dose chemotherapy pre-treatment:
- Pts requiring platelet transfusions: n = 2/22 vs. n = 10/15 (P > 0.001)
- Shorter periods of neutropenia: median 0 days vs. 5 days (P > 0.001)
- Low-dose regimen increased IL-15 levels pre-CAR-T
- CAR+ and IL-15 levels:
- Median number CAR+ cells peaked at 8.5 days (6–35 days) post-infusion
- Peak CAR+ cell number higher in patients who went on to achieve CR
- Median peak CAR+ cell number: remission = 98/μl vs. non-remission = 15/μl (P = 0.027)
- IL-15 levels in pts blood plasma peaked at 2 days after CAR-T treatment
- IL-15 levels positively correlated with peak number of CAR+ cells (P = 0.001)
- Pts who achieved remission had larger IL-15 area-under-the-curve values than those who did not achieve remission (Day -5–14)
- Pts later achieving remission had higher IL-15 levels at Day 0 than those who did not (30 vs. 16 pg/mL; P = 0.010)
The authors concluded that their data suggests that IL-15 is associated with CD19 CAR T-cell efficacy, and that IL-15 level and peak CAR+ cell number are higher in patients who achieve remission following CD19 CAR T-cell therapy. The authors state that this study is “the first to show an association in humans between serum IL-15 levels and remission of lymphoma after adoptive T-cell therapy”. The authors suggest that future work should be conducted to better evaluate the ability of increasing IL-15 on CAR T-cell anti-lymphoma activity. Finally, the results presented here further support CAR T-cell therapy within chemotherapy-refractory lymphoma patients.
- Kochenderfer J.N. et al. Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels. Journal of Clinical Oncology. 2017 Mar 14. DOI: 1200/JCO.2016.71.3024. [Epub ahead of print: 2017 Mar 14].
Purpose. T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 (CAR-19) have potent activity against acute lymphoblastic leukemia, but fewer results supporting treatment of lymphoma with CAR-19 T cells have been published. Patients with lymphoma that is chemotherapy refractory or relapsed after autologous stem-cell transplantation have a grim prognosis, and new treatments for these patients are clearly needed. Chemotherapy administered before adoptive T-cell transfer has been shown to enhance the antimalignancy activity of adoptively transferred T cells. Patients and Methods. We treated 22 patients with advanced-stage lymphoma in a clinical trial of CAR-19 T cells preceded by low-dose chemotherapy. Nineteen patients had diffuse large B-cell lymphoma, two patients had follicular lymphoma, and one patient had mantle cell lymphoma. Patients received a single dose of CAR-19 T cells 2 days after a low-dose chemotherapy conditioning regimen of cyclophosphamide plus fludarabine. Results. The overall remission rate was 73% with 55% complete remissions and 18% partial remissions. Eleven of 12 complete remissions are ongoing. Fifty-five percent of patients had grade 3 or 4 neurologic toxicities that completely resolved. The low-dose chemotherapy conditioning regimen depleted blood lymphocytes and increased serum interleukin-15 (IL-15). Patients who achieved a remission had a median peak blood CAR+ cell level of 98/μL and those who did not achieve a remission had a median peak blood CAR+ cell level of 15/μL (P = .027). High serum IL-15 levels were associated with high peak blood CAR+ cell levels (P = .001) and remissions of lymphoma (P < .001). Conclusion. CAR-19 T cells preceded by low-dose chemotherapy induced remission of advanced-stage lymphoma, and high serum IL-15 levels were associated with the effectiveness of this treatment regimen. CAR-19 T cells will likely become an important treatment for patients with relapsed lymphoma.