如何正確使用PD1抗體進行精準癌症治療之八（宮頸癌)

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來自專欄基於基因組學診斷的癌症靶向治療6 人贊了文章

現在寫稍微早了點，因為已經公開發表的數據有限，而未公開的數據我是不能在知乎上發表的。先說說FDA今年6月批准Keytruda這藥用於晚期宮頸癌的原因，MERCK 的官網給出的資料比較詳盡：

FDA Approves Merck』s KEYTRUDA? (pembrolizumab) for Previously Treated Patients with Recurrent or Metastatic Cervical Cancer Whose Tumors Express PD-L1 (CPS Greater Than or Equal to 1) | Merck Newsroom Home?

www.mrknewsroom.com

FDA批准這藥用於宮頸癌有三個小前提，第一是複發或者轉移，第二是已經接受過化療，第三是表達PD-L1. 我需要說明一下背景。

第一，PD-1不是宮頸癌的一線方案，一線方案是鉑類藥物加Avastin貝伐珠單抗。一線治療無效以後才應該使用二線藥物，比如PD1抗體Keytruda.

第二，為什麼需要有PD-L1 表達？這是基於KEYNOTE-158二期臨床試驗的結果。

For the 77 patients whose tumors expressed PD-L1 with a CPS ≥1, the ORR was 14.3 percent (95% CI, 7.4-24.1), with a complete response rate of 2.6 percent and partial response rate of 11.7 percent. Among the 11 responding patients, median DOR was not yet reached (range, 4.1 to 18.6+ months) and 91 percent experienced a duration of response of six months or longer. The median follow-up time was 11.7 months (range, 0.6 to 22.7 months). No responses were observed in patients whose tumors did not have PD-L1 expression (CPS<1).

沒有PD-L1表達，有效率為0，而有PD-L1表達，藥物響應率是14.3%.

結論就是沒有PD-L1, 就不需要用藥，反正沒有效果。有PD-L1, 七分之一的人會有反應。注意，這一結論僅對最常見的鱗癌適用，對宮頸癌裡面少見的腺癌並不適用。

還有一點需要特別注意， CTLA-4抗體對宮頸癌的效果很差，我目前不推薦使用，見下面的臨床試驗結果。

JAMA Oncol. 2018 Jul 12;4(7):e173776. doi: 10.1001/jamaoncol.2017.3776. Epub 2018 Jul 12.

Association of Ipilimumab With Safety and Antitumor Activity in Women With Metastatic or Recurrent Human Papillomavirus-Related Cervical Carcinoma.

Lheureux S1, Butler MO1,2, Clarke B3, Cristea MC4, Martin LP5, Tonkin K6, Fleming GF7, Tinker AV8, Hirte HW9, Tsoref D1, Mackay H1, Dhani NC1, Ghatage P10, Weberpals J11, Welch S12, Pham NA13, Motta V2, Sotov V2, Wang L1,14, Karakasis K1, Udagani S1, Kamel-Reid S15, Streicher HZ16, Shaw P2, Oza AM1.

Author information

Abstract

IMPORTANCE:

Based on evidence of human papillomavirus (HPV)-induced immune evasion, immunotherapy may be an attractive strategy in cervical cancer. Ipilimumab is a fully humanized monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), which acts to downregulate the T-cell immune response.

OBJECTIVE:

To assess the safety and antitumor activity of ipilimumab in recurrent cervical cancer.

DESIGN, SETTING, AND PARTICIPANTS:

A multicenter trial was designed for patients with metastatic cervical cancer (squamous cell carcinoma or adenocarcinoma) with measurable disease and progression after at least 1 line of platinum chemotherapy. A run-in safety cohort using ipilimumab, 3 mg/kg, every 21 days for 4 cycles in 6 patients was followed by a phase II cohort of ipilimumab, 10 mg/kg, every 21 days for 4 cycles and then 4 cycles of maintenance therapy every 12 weeks for patients demonstrating radiologic response or stabilization. Immune correlative studies were performed on peripheral blood before and after therapy on archival tissue and fresh tumor obtained prior to registration and 7 days after cycle 2. The study was conducted from December 3, 2012, to September 15, 2014. The data were analyzed from April 2016 to June 2016 and in July 2017.

MAIN OUTCOMES AND MEASURES:

The primary end points were safety and objective response rate. Immune analyses were performed on blood and tumor tissue.

RESULTS:

A total of 42 women (median age, 49 years; range, 23-78 years) were enrolled (29 [69%] squamous cell cervical cancer and 13 [31%] adenocarcinoma; 37 [93%] of 40 patients with tissue available for analysis had HPV-positive confirmation; there was no archival tissue for 2 women). Grade 3 toxic effects included diarrhea in 4 patients, 3 of whom had colitis. Of 34 patients evaluated for best response (Response Evaluation Criteria in Solid Tumors, version 1.1), 1 patient had partial response and 10 had stable disease. The median progression-free survival and overall survival were 2.5 months (95% CI, 2.1-3.2 months) and 8.5 months (95% CI, 3.6-not reached; 1 patient was still alive), respectively. Intratumoral pretreatment CD3, CD4, CD8, FoxP3, indoleamine 2,3-dioxygenase, and programmed cell death ligand 1 (PD-L1) expression was not predictive of benefit and did not significantly change with treatment. Multicolor flow cytometry on peripheral lymphocytes revealed a treatment-dependent increase of inducible T-cell costimulator, human leukocyte antigen-antigen D related, and PD-1 during initial treatment, which returned to baseline during maintenance.

CONCLUSIONS AND RELEVANCE:

Ipilimumab was tolerable in this population but did not show significant single-agent activity. Immune changes were induced by anti-CTLA-4 therapy but did not correlate with clinical activity. Changes in these markers may guide further treatment strategies.

最後寫寫精準治療的點，我只是點一下。宮頸癌是HPV病毒誘發的，而HPV病毒有不同的株系，有幾個株系可以誘導PD-L1的表達。所以，在不具備做PD-L1免疫組合的情況下，可以使用簡單的ELISA方法鑒定病人攜帶的HPV病毒亞型來幫助做出免疫治療決策。

HPV -> PD-L1這一點其實還可以擴展到其他HPV相關癌症的免疫治療，比如頭頸癌，肛門癌和更加罕見的婦科癌症, 這裡就不多說了。前提是你需要知道哪幾個HPV毒株可以誘導PD-L1表達。