Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity.
Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity.
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间皮素靶向 CAR T 细胞疗法的区域递送可产生有效且持久的 CD4 依赖性肿瘤免疫。
DOI：
10.1126/scitranslmed.3010162
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发表时间：
2014-11-05
影响因子：
17.1
通讯作者：
Sadelain M
中科院分区：
文献类型：
--
作者：
Adusumilli PS;Cherkassky L;Villena-Vargas J;Colovos C;Servais E;Plotkin J;Jones DR;Sadelain M
将嵌合抗原受体（CAR） T细胞治疗血液系统恶性肿瘤的最新成功转化为实体肿瘤，需要克服几个障碍，包括T细胞肿瘤浸润效率低和功能持久性不足。利用真实模拟人类胸膜恶性肿瘤的原位模型，我们评估了使用M28z CAR给药间皮素靶向T细胞的两种途径。我们发现胸腔内给药的CAR - T细胞大大优于全身输注的T细胞，诱导长期完全缓解所需的M28z T细胞减少了30倍。在胸膜内注射T细胞后，体内抗原诱导的T细胞迅速激活，使CAR - T细胞扩增和效应分化强大，从而增强了抗肿瘤疗效和功能性T细胞持久性200天。局部T细胞给药也促进胸外肿瘤部位的有效消除。这种治疗效果依赖于与较高的肿瘤内CD4/CD8细胞比率和cd28依赖性CD4+ T细胞介导的细胞毒性相关的早期CD4+ T细胞活化。相比之下，静脉注射CAR - T细胞，即使在胸膜肿瘤中积累了相同数量的CAR - T细胞，也没有达到类似的激活、肿瘤根除或持久性。胸腔内注射T细胞循环和持续的卓越能力支持了通过“区域分配中心”提供最佳CAR - T细胞治疗的概念。基于这些结果，我们正在开展一项I期临床试验，以评估原发性或继发性胸膜恶性肿瘤患者胸膜内给药间皮素靶向CAR - T细胞的安全性。
Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intra-pleurally administered CAR T cells vastly out-performed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. Following intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced anti-tumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4+ T cell activation associated with a higher intra-tumoral CD4/CD8 cell ratios and CD28-dependent CD4+ T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication or persistence. The remarkable ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through “regional distribution centers.” Based on these results, we are opening a phase I clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies.
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DOI：
10.1097/cji.0b013e318194a6e8
发表时间：
2009-02
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Hollyman D;Stefanski J;Przybylowski M;Bartido S;Borquez-Ojeda O;Taylor C;Yeh R;Capacio V;Olszewska M;Hosey J;Sadelain M;Brentjens RJ;Rivière I
通讯作者：
Rivière I
影响因子：
5.7
作者：
Feng Y;Xiao X;Zhu Z;Streaker E;Ho M;Pastan I;Dimitrov DS
通讯作者：
Dimitrov DS
影响因子：
17.1
作者：
Fedorov VD;Themeli M;Sadelain M
通讯作者：
Sadelain M
影响因子：
4
作者：
Carpenter SG;Carson J;Fong Y
通讯作者：
Fong Y
影响因子：
8.8
作者：
Einama T;Homma S;Kamachi H;Kawamata F;Takahashi K;Takahashi N;Taniguchi M;Kamiyama T;Furukawa H;Matsuno Y;Tanaka S;Nishihara H;Taketomi A;Todo S
通讯作者：
Todo S