Lu Yong-Chen, Parker Linda L, Lu Tangying, Zheng Zhili, Toomey Mary Ann, White Donald E, Yao Xin, Li Yong F, Robbins Paul F, Feldman Steven A, van der Bruggen Pierre, Klebanoff Christopher A, Goff Stephanie L, Sherry Richard M, Kammula Udai S, Yang James C, Rosenberg Steven A
Yong-Chen Lu, Linda L. Parker, Tangying Lu, Zhili Zheng, Mary Ann Toomey, Donald E. White, Xin Yao, Yong F. Li, Paul F. Robbins, Steven A. Feldman, Christopher A. Klebanoff, Stephanie L. Goff, Richard M. Sherry, Udai S. Kammula, James C. Yang, and Steven A. Rosenberg, National Cancer Institute, Bethesda, MD; Pierre van der Bruggen, Ludwig Institute for Cancer Research; De Duve Institute, Université Catholique de Louvain, Brussels; and Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wallonia, Belgium; Christopher A. Klebanoff, Memorial Sloan Kettering Cancer Center, Parker Institute for Cancer Immunotherapy, New York, NY.
J Clin Oncol. 2017 Oct 10;35(29):3322-3329. doi: 10.1200/JCO.2017.74.5463. Epub 2017 Aug 15.
Purpose Adoptive transfer of genetically modified T cells is being explored as a treatment for patients with metastatic cancer. Most current strategies use genes that encode major histocompatibility complex (MHC) class I-restricted T-cell receptors (TCRs) or chimeric antigen receptors to genetically modify CD8 T cells or bulk T cells for treatment. Here, we evaluated the safety and efficacy of an adoptive CD4 T-cell therapy using an MHC class II-restricted, HLA-DPB1*0401-restricted TCR that recognized the cancer germline antigen, MAGE-A3 (melanoma-associated antigen-A3). Patients and Methods Patients received a lymphodepleting preparative regimen, followed by adoptive transfer of purified CD4 T cells, retrovirally transduced with MAGE-A3 TCR plus systemic high-dose IL-2. A cell dose escalation was conducted, starting at 10 total cells and escalating at half-log increments to approximately 10 cells. Nine patients were treated at the highest dose level (0.78 to 1.23 × 10 cells). Results Seventeen patients were treated. During the cell dose-escalation phase, an objective complete response was observed in a patient with metastatic cervical cancer who received 2.7 × 10 cells (ongoing at ≥ 29 months). Among nine patients who were treated at the highest dose level, objective partial responses were observed in a patient with esophageal cancer (duration, 4 months), a patient with urothelial cancer (ongoing at ≥ 19 months), and a patient with osteosarcoma (duration, 4 months). Most patients experienced transient fevers and the expected hematologic toxicities from lymphodepletion pretreatment. Two patients experienced transient grade 3 and 4 transaminase elevations. There were no treatment-related deaths. Conclusion These results demonstrate the safety and efficacy of administering autologous CD4 T cells that are genetically engineered to express an MHC class II-restricted antitumor TCR that targets MAGE-A3. This clinical trial extends the reach of TCR gene therapy for patients with metastatic cancer.
目的 探索基因改造T细胞的过继性转移作为转移性癌症患者的一种治疗方法。目前大多数策略使用编码主要组织相容性复合体（MHC）I类限制性T细胞受体（TCR）或嵌合抗原受体的基因来对CD8 T细胞或大量T细胞进行基因改造以用于治疗。在此，我们评估了一种过继性CD4 T细胞疗法的安全性和疗效，该疗法使用一种识别癌症种系抗原MAGE - A3（黑色素瘤相关抗原 - A3）的MHC II类限制性、HLA - DPB1*0401限制性TCR。
患者与方法 患者接受淋巴细胞清除预处理方案，随后过继性转移经逆转录病毒转导表达MAGE - A3 TCR并联合全身大剂量白细胞介素 - 2的纯化CD4 T细胞。进行了细胞剂量递增试验，起始剂量为10⁶个细胞，以半对数增量递增至约10⁷个细胞。9名患者接受了最高剂量水平（0.78至1.23×10⁷个细胞）的治疗。
结果 共治疗了17名患者。在细胞剂量递增阶段，一名接受2.7×10⁶个细胞的转移性宫颈癌患者出现客观完全缓解（持续≥29个月）。在接受最高剂量水平治疗的9名患者中，一名食管癌患者（持续时间4个月）、一名尿路上皮癌患者（持续≥19个月）和一名骨肉瘤患者（持续时间4个月）出现客观部分缓解。大多数患者经历了短暂发热以及淋巴细胞清除预处理预期的血液学毒性。两名患者出现短暂的3级和4级转氨酶升高。没有治疗相关死亡。
结论 这些结果证明了给予经基因工程改造以表达靶向MAGE - A3的MHC II类限制性抗肿瘤TCR的自体CD4 T细胞的安全性和疗效。这项临床试验扩展了TCR基因疗法对转移性癌症患者的应用范围。
