Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels
Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels
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DOI：
10.1200/jco.2016.71.3024
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发表时间：
2017-06-01
影响因子：
45.3
通讯作者：
Rosenberg, Steven A.
中科院分区：
文献类型：
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作者：
Kochenderfer, James N.;Somerville, Robert P. T.;Rosenberg, Steven A.
目的表达靶向CD 19的嵌合抗原受体（CAR-19）的T细胞具有抗急性淋巴细胞白血病的活性，但支持CAR-19 T细胞治疗淋巴瘤的研究较少。化疗难治性或自体干细胞移植后复发的淋巴瘤患者预后很差，显然需要针对这些患者的新治疗方法。化疗前给予过继性T细胞转移已被证明，以提高过继性转移的T cells.Patients和MethodsWe治疗22例晚期淋巴瘤患者的CAR-19 T细胞的临床试验之前，低剂量化疗。19例患者患有弥漫性大B细胞淋巴瘤，2例患者患有滤泡性淋巴瘤，1例患者患有套细胞淋巴瘤。患者接受了单剂量的CAR-19 T细胞2天后，低剂量化疗预处理方案环磷酰胺加fludarabine.ResultsThe总体缓解率为73%，55%完全缓解和18%部分缓解。12例完全缓解中有11例正在进行中。55%的患者出现3级或4级神经毒性，并完全消退。低剂量化疗预处理方案使血淋巴细胞减少，血清白细胞介素-15（IL-15）升高。达到缓解的患者的中位峰值血液CAR（+）细胞水平为98/L，未达到缓解的患者的中位峰值血液CAR（+）细胞水平为15/L（P = .027）。高血清IL-15水平与高峰血CAR（+）细胞水平（P = .001）和淋巴瘤缓解相关（P < .001）。结论CAR-19 T细胞联合低剂量化疗可诱导晚期淋巴瘤缓解，高血清IL-15水平与该治疗方案的有效性相关。CAR-19 T细胞可能成为复发性淋巴瘤患者的重要治疗方法。
PurposeT 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 MethodsWe 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.ResultsThe 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/L and those who did not achieve a remission had a median peak blood CAR(+) cell level of 15/L (P = .027). High serum IL-15 levels were associated with high peak blood CAR(+) cell levels (P = .001) and remissions of lymphoma (P < .001).ConclusionCAR-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.