CAR-T免疫細胞療法的副作用和搶救過程之二:Emily的搶救方法成為CTL019臨床試驗的標準操作
話說神奇小姑娘Emily Whitehead的CTL019案例成功以後, 她的主治醫生Stephan Drupp開展了一個30人的CTL019臨床試驗, 下圖是原始文獻。
結果摘要裡面有些信息很重要:
A total of 30 children and adults received CTL019. Complete remission was
achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory
disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88)
and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability
that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92)
and the probability that a patient would have relapse-free B-cell aplasia was 73%
(95% CI, 57 to 94).
All the patients had the cytokine-release syndrome.
所有30位病人都出現細胞因子釋放綜合症的副作用。
Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti–interleukin-6 receptor antibody tocilizumab.
27%的病人細胞因子釋放綜合症的癥狀嚴重, 使用抗白介素-6受體的抗體托珠單抗可以有效緩解。
我看到這裡的時候可以感受到美國費城兒童醫院CHOP醫生團隊的誠實,是的,每個注射CD19 CART的病人都出現了細胞因子釋放綜合症的副作用,27%的病人情況很嚴重。而在中國主持CART臨床試驗的醫生中這樣的坦誠很少,患者和醫生的信息交流嚴重不對等。大多數參與CART臨床試驗的患者連細胞因子釋放綜合症是什麼都不知道就參與了臨床試驗,我個人認為這樣是不太合適的。
CTL019治療效果的圖我就不放了, FDA都批了,重點是下面的幾張圖. 第一張是外周血CTL019細胞的6個數量級的變化, 注意有的病人3個月不到CTL019的細胞就基本消失了。
第二張是B細胞缺乏的副作用
攜帶CD19的B細胞前體細胞都被CART細胞殺死了, 當然患者會出現B細胞缺乏。
很重要的一點,可以通過監測 白介素-6的水平來判斷細胞因子釋放綜合症的嚴重程度, 白介素-6水平見下圖:
這也是為什麼阻斷白介素-6信號途徑的托珠單抗可以有效緩解細胞因子釋放綜合症的原因。
如果你是一名患者,主持CART臨床試驗的醫生沒有告知你細胞因子釋放綜合症的副作用,我建議你不要參與這樣的臨床試驗
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