Harnessing the Immune System in Pancreatic Cancer.
Harnessing the Immune System in Pancreatic Cancer.
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DOI：
10.1007/s11864-018-0566-5
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发表时间：
2018-08-20
影响因子：
4.3
通讯作者：
Cardin D
中科院分区：
文献类型：
--
作者：
Das S;Berlin J;Cardin D
管理转移性胰腺癌（mPDA）患者对任何治疗肿瘤学家来说都是一个具有挑战性的命题。虽然一线治疗的效力随着FOLFIRINOX和吉西他滨+nab-紫杉醇的批准而有所改善，但许多患者在进展时无法从后续治疗中获得显著获益。临床试验入组仍然是所有治疗线中mPDA患者的最佳选择。在我们的机构，我们常规检查微卫星不稳定性（MSI-H），并在诊断时对所有表现良好的mPDA患者进行下一代测序（NGS）。尽管MSI-H状态仅见于1%的mPDA患者，但鉴于pembrolizumab在后期治疗中对MSI-H肿瘤的组织不可知性批准，在决定后续治疗时，这是一个可行的选择。在MSI-H环境之外，mPDA中使用任何免疫治疗都是研究性的。NGS可以识别患者的BRCA或其他DNA损伤反应（DDR）缺陷，这可以预测对铂类药物治疗的敏感性，并影响初始和后续治疗的选择。它还可以识别罕见的可操作的基因组改变，如HER 2（2%）和TRK融合（0.1%），并为患者提供参与临床试验的选择，这些药物靶向这些或其他已识别的改变。我们认为，在免疫调节剂的临床试验中招募mPDA患者对于确定MSI-H背景之外是否有其他患者亚群从这些方法中获益至关重要。免疫疗法的一般耐受性和产生持久反应的潜力使其对mPDA患者特别有吸引力。虽然单一模式的免疫疗法，如检查点抑制剂或疫苗尚未证明在这种疾病中的疗效，但针对PDA独特方面的组合策略，包括肿瘤微环境和促纤维增生基质，已显示出临床前或早期的成功。通过后期前瞻性研究验证这些治疗对于使免疫治疗成为mPDA患者治疗设备的常规组成部分至关重要。
Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab’s tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy’s general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor micro-environment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.
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DOI：
10.1158/1078-0432.ccr-16-2318
发表时间：
2017-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Johnson BA 3rd;Yarchoan M;Lee V;Laheru DA;Jaffee EM
通讯作者：
Jaffee EM
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM
影响因子：
11.5
作者：
Cioffi, Michele;Dorado, Jorge;Heeschen, Christopher
通讯作者：
Heeschen, Christopher
DOI：
10.1126/science.1198443
发表时间：
2011-03-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Beatty GL;Chiorean EG;Fishman MP;Saboury B;Teitelbaum UR;Sun W;Huhn RD;Song W;Li D;Sharp LL;Torigian DA;O'Dwyer PJ;Vonderheide RH
通讯作者：
Vonderheide RH
影响因子：
--
作者：
Cui R;Yue W;Lattime EC;Stein MN;Xu Q;Tan XL
通讯作者：
Tan XL