2018Nature Medicine：過繼性移植識別體細胞突變的腫瘤浸潤性T細胞治癒1例轉移性乳腺癌

本周五我們JC討論了Steven Rosenburg課題組最近發表在Nature Medicine的研究論文「Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer」。

通訊作者簡介

論文摘要

Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations—such as melanoma, smoking-induced lung cancers and bladder cancer—with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary. Adoptive transfer of autologous lymphocytes that specifically target proteins encoded by somatically mutated genes has mediated substantial objective clinical regressions in patients with metastatic bile duct, colon and cervical cancers. We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins—SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing for > 22 months, and it represents a new immunotherapy approach for the treatment of these patients.

過繼性細胞移植TIL（腫瘤浸潤性T細胞）的流程示意圖

Graph source: Science 2015

1. Clinical History of Patients:

Patient 4136—a 49-year-old woman with metastatic ER+HER2–breast cancer—was initially diagnosed with ductal carcinoma in situ (marker status unknown) with no invasive component identified after a left modified radical mastectomy.

Aftera disease-free interval of 10 years, recurrence was identified inmultiplelymph nodes(axillary,supraclavicular, mediastinal and paratracheal)and confirmedby biopsy (100% ER+, 40% PR+, HER2–). After ashort response tonanoparticle-albumin-bound(nab)-paclitaxeltreatment, persistent disease was foundto berefractoryto multiple endocrine therapies and chemotherapies (capecitabine, vinorelbine, docetaxel, doxorubicin and cyclophosphamide), and biopsy (Fig. 2d, top) of a chestwall mass was > 50% ER+, PR–and HER2–.

A metastatic right breast subcutaneous lesion was resected (ER–PR–HER2–) and processed for identification of nonsynonymous somatic mutations in the tumor and for the generation of TILs. In the 4 months between resection and treatment, the patient receivedeverolimusand demonstrated clinical andradiologic progression before receiving the clinical treatment described below.

The patient never received radiation therapy and did not harbor known germline mutations in the BRCA1and BRCA2 oncogenes, or other known deleterious somatic mutations in high penetrance genes involved in breast cancer susceptibility.

2. Key Representative Data:Adoptive transfer of autologous TILs targeting immunogenic tumor mutations mediated tumor regression

a, Treatment schema, with characteristics of the infusion product. Initial gating for flow cytometry analysis was done on live CD3+ cells.

b, Interferon (IFN)-γ production, as determined by ELISPOT assay, showing that the infusion product, consisting of TILs expanded from fragments 8, 12 and 13 maintained their reactivity to mutSLC3A2 and mutKIAA0368.

c, Top, response curves of target lesions (tumor size measurements). All lesions resolved 1 year after TIL transfer, and the patient continued to demonstrate complete response 22 months after cell infusion and 20 months after the last dose of pembrolizumab. Bottom, crosssectional imaging was obtained 1 week before cell infusion (pre-treatment) and 22 months after infusion (22 months post-treatment). Arrows indicate target lesions (from top to bottom: retrosternal mediastinum, left axilla with clinical brachial plexopathy and compressed axillary vein, and multiple liver segments). SubQ, subcutaneous.

d, Top, images showing pre-treatment tumor biopsy of a left chest wall mass (present at time of treatment), demonstrating ductal breast adenocarcinoma with scattered peripheral PD-1+ lymphocytes and few intratumoral lymphocytes (magnification: 40× ). Bottom, images showing the subcutaneous tumor that served as the source of TILs, with intratumoral PD-1+ lymphocytes and PD-L1+ stroma. Tumor cells were negative for PD-L1 expression (magnification: H&E-stained images, 10× ; CD3-, PD-1- or PD-L1-stained images, 20× ).

Graph source: Nature Medicine 2018

評論

1. Grabeel：

本篇paper講述了一個神奇的治療案例—將複發轉移性乳腺癌患者免疫系統經過調整後完全消除了癌細胞，為所有常規治療無效的晚期癌症提供了一種可能的治療方法。在筆者眼中，本篇文章有兩點十分具有創新性，一是在體外實現了T的培養並進行了大規模的擴增，在我們的理解中，T細胞在體外很難培養很容易凋亡，研究人員描述的這種添加大劑量的IL-2的培養方法讓人眼前一亮。二是從患者腫瘤中篩選出了特異性識別腫瘤細胞突變多肽的腫瘤浸潤性淋巴細胞（TILs）。這兩點也是這種自體免疫療法的亮點和核心，非常值得我們學習。當然這種字體免疫療法也有局限性，一旦腫瘤細胞的突變不夠或沒有突變，這種療法也失去了作用，並且某些腫瘤的異質性也對這種自體免疫療法造成了挑戰，所以構建具有不同多肽識別能力的腫瘤浸潤性淋巴細胞或體細胞也是今後努力的方向。

2.丶NI々N：

此研究貼近臨床病例，闡述了個體腫瘤組織中的特異性突變激發產生的針對該突變的免疫T淋巴細胞，再採用此類免疫細胞體外擴增進行免疫細胞的過繼治療，從而達到治療腫瘤的目的。文章角度比較獨特，巧妙地從單個病人大量突變中篩選出具有新抗原特性的突變，然後針對該突變進行類似CAR-T的治療。同時，文章體外分離擴增CD8 T淋巴細胞的方法也值得參考。本文也有問題亟待解決：首先文章例病較少，而且同期進行的治療的其它病人並沒有在具有此類突變的病人中取得很好的治療效果，因此該治療方案可能對患者特異性要求比較高，即使具有同類的篩選突變病人也並不一定適合相同治療方案，如此一來，治療費用也會非常高，臨床適用效率和實用性也成問題。

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