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Molecular Diagnostics

Biomarkers of response to camrelizumab combined with apatinib: an analysis from a phase II trial in recurrent/metastatic nasopharyngeal carcinoma

Abstract

Background

This study aims to develop a peripheral blood-based model that can predict the response to the combination therapy of camrelizumab and apatinib as a second-line or later-line treatment regimen in patients with recurrent/metastatic nasopharyngeal carcinoma (R/M-NPC).

Methods

We collected peripheral blood routine data from 72 patients with R/M-NPC from two clinical trial studies (NCT04547088, NCT04548271). Utilising the least absolute shrinkage and selection operator Cox regression model, we built a peripheral blood signature and developed a prognostic nomogram through multivariable analysis. Spectral flow cytometry analysed peripheral blood mononuclear cell immunophenotyping.

Results

Six indicators (WBC, MCV, HCT, MCHC, P-LCR, MLR) were included to construct the peripheral blood signature. By combining this signature with Epstein–Barr virus DNA, distant lymph node metastasis and previous PD-1 inhibitor treatment, we constructed a peripheral blood-based nomogram that showed favourable performance. High-risk individuals had lower overall survival than low-risk individuals (P < 0.05). Immunophenotyping revealed that the high-risk individuals had increased monocytic myeloid-derived suppressor cells, Tregs and decreased CD8 effector memory cells (P < 0.05).

Conclusions

We established a model that could predict the prognosis of combined therapy. The model could predict outcomes and reflect the systemic immune and inflammatory status, which is beneficial for risk stratification and therapeutic modification.

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Fig. 1: Correlation between Peripheral blood immune inflammation indices and survival (n = 72).
Fig. 2: Development of peripheral blood signature in R/M-NPC patients (n = 72).
Fig. 3: Nomogram2 based on peripheral blood signature and clinical characteristics (n = 72).
Fig. 4: Comparison of immune cell populations in peripheral blood samples between high- and low-risk R/M-NPC patients stratified by Nomogram2 score (n = 61).

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Data availability

All data included in this study are available upon request by contact with the corresponding author.

References

  1. Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet. 2019;394:64–80.

    Article  PubMed  Google Scholar 

  2. Prawira A, Oosting SF, Chen TW, Delos Santos KA, Saluja R, Wang L, et al. Systemic therapies for recurrent or metastatic nasopharyngeal carcinoma: a systematic review. Br J Cancer. 2017;117:1743–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Sun Q, Hong Z, Zhang C, Wang L, Han Z, Ma D. Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends. Signal Transduct Target Ther. 2023;8:320.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Adkins DR, Haddad RI. Clinical trial data of Anti-PD-1/PD-L1 therapy for recurrent or metastatic nasopharyngeal Carcinoma: a review. Cancer Treat Rev. 2022;109:102428.

    Article  CAS  PubMed  Google Scholar 

  5. Fang W, Zhang J, Hong S, Zhan J, Chen N, Qin T, et al. EBV-driven LMP1 and IFN-gamma up-regulate PD-L1 in nasopharyngeal carcinoma: implications for oncotargeted therapy. Oncotarget. 2014;5:12189–202.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Zhang J, Fang W, Qin T, Yang Y, Hong S, Liang W, et al. Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma. Med Oncol. 2015;32:86.

    Article  PubMed  Google Scholar 

  7. Yang Y, Qu S, Li J, Hu C, Xu M, Li W, et al. Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2021;22:1162–74.

    Article  CAS  PubMed  Google Scholar 

  8. Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, et al. Toripalimab plus chemotherapy for recurrent or metastatic nasopharyngeal carcinoma: the JUPITER-02 randomized clinical trial. JAMA. 2023;330:1961–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Jiang J, Ying H. Revealing the crosstalk between nasopharyngeal carcinoma and immune cells in the tumor microenvironment. J Exp Clin Cancer Res. 2022;41:244.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Liu Q, Bode AM, Chen X, Luo X. Metabolic reprogramming in nasopharyngeal carcinoma: mechanisms and therapeutic opportunities. Biochim Biophys Acta Rev Cancer. 2023;1878:189023.

    Article  CAS  PubMed  Google Scholar 

  11. Huinen ZR, Huijbers EJM, van Beijnum JR, Nowak-Sliwinska P, Griffioen AW. Anti-angiogenic agents—overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Nat Rev Clin Oncol. 2021;18:527–40.

    Article  PubMed  Google Scholar 

  12. Zhao L, Ren Y, Zhang G, Zheng K, Wang J, Sha H, et al. Single-arm study of camrelizumab plus apatinib for patients with advanced mucosal melanoma. J Immunother Cancer. 2024;12:e008611.

  13. Qin S, Chan SL, Gu S, Bai Y, Ren Z, Lin X, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023;402:1133–46.

    Article  CAS  PubMed  Google Scholar 

  14. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1103–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Ding X, Zhang WJ, You R, Zou X, Wang ZQ, Ouyang YF, et al. Camrelizumab plus apatinib in patients with recurrent or metastatic nasopharyngeal carcinoma: an open-label, single-arm, phase II study. J Clin Oncol. 2023;41:2571–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Yuan L, Jia GD, Lv XF, Xie SY, Guo SS, Lin DF, et al. Camrelizumab combined with apatinib in patients with first-line platinum-resistant or PD-1 inhibitor resistant recurrent/metastatic nasopharyngeal carcinoma: a single-arm, phase 2 trial. Nat Commun. 2023;14:4893.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Bagaev A, Kotlov N, Nomie K, Svekolkin V, Gafurov A, Isaeva O, et al. Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell. 2021;39:845–865.e7.

    Article  CAS  PubMed  Google Scholar 

  18. Zaitsev A, Chelushkin M, Dyikanov D, Cheremushkin I, Shpak B, Nomie K, et al. Precise reconstruction of the TME using bulk RNA-seq and a machine learning algorithm trained on artificial transcriptomes. Cancer Cell. 2022;40:879–894 e16.

    Article  CAS  PubMed  Google Scholar 

  19. Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017;545:60–65.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Guida M, Bartolomeo N, Quaresmini D, Quaglino P, Madonna G, Pigozzo J, et al. Basal and one-month differed neutrophil, lymphocyte and platelet values and their ratios strongly predict the efficacy of checkpoint inhibitors immunotherapy in patients with advanced BRAF wild-type melanoma. J Transl Med. 2022;20:159.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Li C, Wu J, Jiang L, Zhang L, Huang J, Tian Y, et al. The predictive value of inflammatory biomarkers for major pathological response in non-small cell lung cancer patients receiving neoadjuvant chemoimmunotherapy and its association with the immune-related tumor microenvironment: a multi-center study. Cancer Immunol Immunother. 2023;72:783–94.

    Article  PubMed  Google Scholar 

  22. Park CK, Oh HJ, Kim MS, Koh BG, Cho HJ, Kim YC, et al. Comprehensive analysis of blood-based biomarkers for predicting immunotherapy benefits in patients with advanced non-small cell lung cancer. Transl Lung Cancer Res. 2021;10:2103–17.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Allen BM, Hiam KJ, Burnett CE, Venida A, DeBarge R, Tenvooren I, et al. Systemic dysfunction and plasticity of the immune macroenvironment in cancer models. Nat Med. 2020;26:1125–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Combes AJ, Samad B, Krummel MF. Defining and using immune archetypes to classify and treat cancer. Nat Rev Cancer. 2023;23:491–505.

    Article  CAS  PubMed  Google Scholar 

  25. Hirschhorn D, Budhu S, Kraehenbuehl L, Gigoux M, Schroder D, Chow A, et al. T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants. Cell. 2023;186:1432–1447.e17.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Cao D, Xu H, Xu X, Guo T, Ge W. A reliable and feasible way to predict the benefits of Nivolumab in patients with non-small cell lung cancer: a pooled analysis of 14 retrospective studies. Oncoimmunology. 2018;7:e1507262.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Taylor K, Zou J, Magalhaes M, Oliva M, Spreafico A, Hansen AR, et al. Circulating tumour DNA kinetics in recurrent/metastatic head and neck squamous cell cancer patients. Eur J Cancer. 2023;188:29–38.

    Article  CAS  PubMed  Google Scholar 

  28. Garcia-Leon MJ, Liboni C, Mittelheisser V, Bochler L, Follain G, Mouriaux C, et al. Platelets favor the outgrowth of established metastases. Nat Commun. 2024;15:3297.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Li Y, Wu H, Xing C, Hu X, Zhang F, Peng Y, et al. Prognostic evaluation of colorectal cancer using three new comprehensive indexes related to infection, anemia and coagulation derived from peripheral blood. J Cancer. 2020;11:3834–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Rui W, Li C, Da Q, Yue Y, Jing L, Ruirui G, et al. Analysis of the influencing factors in the long-term survival of esophageal cancer. Front Oncol. 2023;13:1274014.

    Article  CAS  PubMed  Google Scholar 

  31. Wang WY, Twu CW, Chen HH, Jiang RS, Wu CT, Liang KL, et al. Long-term survival analysis of nasopharyngeal carcinoma by plasma Epstein-Barr virus DNA levels. Cancer. 2013;119:963–70.

    Article  CAS  PubMed  Google Scholar 

  32. Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, et al. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med. 2004;350:2461–70.

    Article  CAS  PubMed  Google Scholar 

  33. Lam WKJ, King AD, Miller JA, Liu Z, Yu KJ, Chua MLK, et al. Recommendations for Epstein-Barr virus-based screening for nasopharyngeal cancer in high- and intermediate-risk regions. J Natl Cancer Inst. 2023;115:355–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Leung SF, Zee B, Ma BB, Hui EP, Mo F, Lai M, et al. Plasma Epstein-Barr viral deoxyribonucleic acid quantitation complements tumor-node-metastasis staging prognostication in nasopharyngeal carcinoma. J Clin Oncol. 2006;24:5414–8.

    Article  CAS  PubMed  Google Scholar 

  35. Chan AT, Lo YM, Zee B, Chan LY, Ma BB, Leung SF, et al. Plasma Epstein-Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst. 2002;94:1614–9.

    Article  CAS  PubMed  Google Scholar 

  36. Reticker-Flynn NE, Zhang W, Belk JA, Basto PA, Escalante NK, Pilarowski GOW, et al. Lymph node colonization induces tumor-immune tolerance to promote distant metastasis. Cell. 2022;185:1924–1942.e23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Binnewies M, Mujal AM, Pollack JL, Combes AJ, Hardison EA, Barry KC, et al. Unleashing type-2 dendritic cells to drive protective antitumor CD4(+) T cell immunity. Cell. 2019;177:556–571.e16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Ji H, Hu C, Yang X, Liu Y, Ji G, Ge S, et al. Lymph node metastasis in cancer progression: molecular mechanisms, clinical significance and therapeutic interventions. Signal Transduct Target Ther. 2023;8:367.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Wu TD, Madireddi S, de Almeida PE, Banchereau R, Chen YJ, Chitre AS, et al. Peripheral T cell expansion predicts tumour infiltration and clinical response. Nature. 2020;579:274–8.

    Article  CAS  PubMed  Google Scholar 

  40. Rahim MK, Okholm TLH, Jones KB, McCarthy EE, Liu CC, Yee JL, et al. Dynamic CD8(+) T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell. 2023;186:1127–1143.e18.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Han J, Duan J, Bai H, Wang Y, Wan R, Wang X, et al. TCR repertoire diversity of peripheral PD-1(+)CD8(+) T cells predicts clinical outcomes after immunotherapy in patients with non-small cell lung cancer. Cancer Immunol Res. 2020;8:146–54.

    Article  CAS  PubMed  Google Scholar 

  42. Dyikanov D, Zaitsev A, Vasileva T, Wang I, Sokolov AA, Bolshakov ES, et al. Comprehensive peripheral blood immunoprofiling reveals five immunotypes with immunotherapy response characteristics in patients with cancer. Cancer Cell. 2024;42:759–779.e12.

    Article  CAS  PubMed  Google Scholar 

  43. Tang Y, Cui G, Liu H, Han Y, Cai C, Feng Z, et al. Converting “cold” to “hot”: epigenetics strategies to improve immune therapy effect by regulating tumor-associated immune suppressive cells. Cancer Commun. 2024;44:601–36.

    Article  Google Scholar 

  44. Hopkins R, Xiang W, Marlier D, Au VB, Ching Q, Wu LX, et al. Monocytic myeloid-derived suppressor cells underpin resistance to adoptive T cell therapy in nasopharyngeal carcinoma. Mol Ther. 2021;29:734–43.

    Article  CAS  PubMed  Google Scholar 

  45. Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression—implications for anticancer therapy. Nat Rev Clin Oncol. 2019;16:356–71.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was funded by grants from the National Key Research and Development Program of China (2022YFC2505800, 2022YFC2705005), National Natural Science Foundation of China (No. 32200651, 82203776, 82203125, 82222050, 82272739, 82272882, 82203259, 82173287, 82073003, 82003267, 82002852, 82373258, 82372980, 82361168664, 8247101588, 82473038), Guangdong Basic and Applied Basic Research Foundation (2021B1515230002, 2023B1515120092, 2023A1515010398, 2024A1515013021), Science and Technology Program of Guangzhou (202201011561, 2023A04J2127, 2023A04J2246, 2024B03J1248), Sun Yat-sen University Clinical Research 5010 Program (No. 201315, 2015021, 2017010, 2019023), Innovative Research Team of High-level Local Universities in Shanghai (SSMU-ZLCX20180500), Postdoctoral Innovative Talent Support Program (BX20220361), Planned Science and Technology Project of Guangdong Province (2019B020230002), Science and Technology Projects in Guangzhou (202201011533), Key Youth Teacher Cultivating Program of Sun Yat-sen University (20ykzd24), and Fundamental Research Funds for the Central Universities.

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Authors

Contributions

LY and HM contributed to conceptualisation, funding acquisition, supervision and manuscript review and editing. KL, SL and GJ were responsible for data curation, formal analysis, conceptualisation, methodology and writing the original draft. SX and SL conducted data curation and formal analysis. LT performed data curation and methodology. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Haiqiang Mai or Li Yuan.

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The authors declare no competing interests.

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This study was approved by the Institutional Review Board of Sun Yat-sen University Cancer Center. All patients provided written informed consent prior to the collection of specimens. All methods were performed in accordance with the relevant guidelines and regulations.

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Lan, K., Li, S., Jia, G. et al. Biomarkers of response to camrelizumab combined with apatinib: an analysis from a phase II trial in recurrent/metastatic nasopharyngeal carcinoma. Br J Cancer (2025). https://doi.org/10.1038/s41416-025-03044-y

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