Anti-CD19 CAR T-cell therapy: serum IL-15 levels associated with NHL patient response

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.

Key highlights:

• 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
• Efficacy:
  • ORR = 73%, CR = 55%, PR = 18%
  • DLBCL ORR = 68%, CR = 47%, PR = 21
  • 12-month PFS = 63.3%
  • DoR = 7+ to 24+ months
• Safety:
  • 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.

Abstract:

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.