A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma.
A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma.
复制标题
DOI：
10.1126/scitranslmed.aaa0984
复制
发表时间：
2017-07-19
影响因子：
17.1
通讯作者：
Maus MV
中科院分区：
文献类型：
--
作者：
O'Rourke DM;Nasrallah MP;Desai A;Melenhorst JJ;Mansfield K;Morrissette JJD;Martinez-Lage M;Brem S;Maloney E;Shen A;Isaacs R;Mohan S;Plesa G;Lacey SF;Navenot JM;Zheng Z;Levine BL;Okada H;June CH;Brogdon JL;Maus MV
我们进行了一项首次人体研究，通过嵌合抗原受体（CAR）静脉递送单剂量的靶向表皮生长因子受体变体III （EGFRvIII）突变的自体T细胞。我们报告前10例复发性胶质母细胞瘤（GBM）患者的治疗结果。我们发现car修饰T细胞(CART) -EGFRvIII细胞的制造和输注是可行和安全的，没有证据表明肿瘤外毒性或细胞因子释放综合征。1例患者随访超过18个月，病情残余稳定。所有患者外周血均可检测到CART-EGFRvIII细胞的短暂扩增。7例患者接受了CART-EGFRvIII后手术干预，这允许对CART-EGFRvIII转运到肿瘤的组织特异性分析，肿瘤浸润T细胞和原位肿瘤微环境的表型分析，以及治疗后EGFRvIII靶抗原表达分析。CART免疫治疗后的影像学结果难以解释，这进一步加强了对输注患者进行病理取样的必要性。我们发现CART-EGFRvIII细胞运输到活性GBM区域，这7名患者中有5名患者的抗原减少。原位肿瘤环境评估显示，与CART-EGFRvIII输注前的肿瘤标本相比，CART-EGFRvIII输注后抑制分子的表达和调节性T细胞的浸润增加且强劲。我们在复发性GBM中CAR - T细胞的初步经验表明，尽管静脉输注会导致大脑中的靶向活性，但克服局部肿瘤微环境的适应性变化和解决抗原异质性可能会提高egfrviii导向策略在GBM中的疗效。
We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)–EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up. All patients demonstrated detectable transient expansion of CART-EGFRvIII cells in peripheral blood. Seven patients had post–CART-EGFRvIII surgical intervention, which allowed for tissue-specific analysis of CART-EGFRvIII trafficking to the tumor, phenotyping of tumor-infiltrating T cells and the tumor microenvironment in situ, and analysis of post-therapy EGFRvIII target antigen expression. Imaging findings after CART immunotherapy were complex to interpret, further reinforcing the need for pathologic sampling in infused patients. We found trafficking of CART-EGFRvIII cells to regions of active GBM, with antigen decrease in five of these seven patients. In situ evaluation of the tumor environment demonstrated increased and robust expression of inhibitory molecules and infiltration by regulatory T cells after CART-EGFRvIII infusion, compared to pre–CART-EGFRvIII infusion tumor specimens. Our initial experience with CAR T cells in recurrent GBM suggests that although intravenous infusion results in on-target activity in the brain, overcoming the adaptive changes in the local tumor microenvironment and addressing the antigen heterogeneity may improve the efficacy of EGFRvIII-directed strategies in GBM.
登录
查看更多内容
影响因子：
11.5
作者：
Kershaw, Michael H.;Westwood, Jennifer A.;Hwu, Patrick
通讯作者：
Hwu, Patrick
影响因子：
10.9
作者：
Ohno M;Ohkuri T;Kosaka A;Tanahashi K;June CH;Natsume A;Okada H
通讯作者：
Okada H
影响因子：
45.3
作者：
Hegi, Monika E.;Liu, Lili;Gilbert, Mark R.
通讯作者：
Gilbert, Mark R.
影响因子：
82.9
作者：
Long, Adrienne H.;Haso, Waleed M.;Shern, Jack F.;Wanhainen, Kelsey M.;Murgai, Meera;Ingaramo, Maria;Smith, Jillian P.;Walker, Alec J.;Kohler, M. Eric;Venkateshwara, Vikas R.;Kaplan, Rosandra N.;Patterson, George H.;Fry, Terry J.;Orentas, Rimas J.;Mackall, Crystal L.
通讯作者：
Mackall, Crystal L.
影响因子：
45.3
作者：
Ahmed, Nabil;Brawley, Vita S.;Gottschalk, Stephen
通讯作者：
Gottschalk, Stephen