放疗与免疫治疗相结合治疗IV期非小细胞肺癌的现状和治疗前景
Current Status and Therapeutic Prospects of Combining Radiotherapy and Immunotherapy for the Treatment of Stage IV Non-Small Cell Lung Cancer
DOI: 10.12677/ACM.2023.13122714, PDF,   
作者: 伍 敏：青海大学研究生院，青海 西宁；姜 军*：青海大学附属医院肿瘤内科三病区，青海 西宁
关键词: 非小细胞肺癌；免疫检查点抑制剂；放射治疗；综述；Non-Small Cell Lung Cancer； Immune Checkpoint Inhibitors； Radiotherapy； Review
摘要: 免疫疗法使转移性非小细胞肺癌(NSCLC)的治疗发生了革命性变化。与广泛性转移性疾病相比，少转移性肿瘤预后更好，可通过放射治疗治愈。放射治疗(RT)可激发免疫原性抗肿瘤活性，当与免疫检查点抑制剂(ICIS)等免疫治疗相结合时，这种活性可进一步增强。因此，它与免疫疗法的结合被认为是一种有希望的治疗选择，特别是在转移的环境中。然而，RT与免疫治疗相结合的最优方法仍然存在争议，早期临床证据正在出现。在这里，我们回顾了目前支持RT联合免疫疗法治疗转移性非小细胞肺癌的临床证据。此外，我们还讨论了当前的争议和与该治疗策略相关的进一步探索的领域。
Abstract: Immunotherapy has revolutionised the treatment of metastatic non-small cell lung cancer (NSCLC). Less metastatic tumours have a better prognosis than extensive metastatic disease and can be cured by radiotherapy. Radiation therapy (RT) stimulates immunogenic anti-tumour activity, which can be further enhanced when combined with immunotherapy such as immune checkpoint inhibi-tors (ICIS). Therefore, its combination with immunotherapy is considered a promising therapeutic option, especially in the setting of metastasis. However, the optimal approach to combining RT with immunotherapy remains controversial and early clinical evidence is emerging. Here, we review the current clinical evidence supporting the combination of RT with immunotherapy for metastatic non-small cell lung cancer. In addition, we discuss current controversies and areas for further ex-ploration related to this treatment strategy.
文章引用：伍敏, 姜军. 放疗与免疫治疗相结合治疗IV期非小细胞肺癌的现状和治疗前景[J]. 临床医学进展, 2023, 13(12): 19282-19288. https://doi.org/10.12677/ACM.2023.13122714

参考文献

[1] Ganti, A.K., Klein, A.B., Cotarla, I., Seal, B. and Chou, E. (2021) Update of Incidence, Prevalence, Survival, and Initial Treatment in Patients with Non-Small Cell Lung Cancer in the US. JAMA Oncology, 7, 1824-1832. [Google Scholar] [CrossRef] [PubMed]
[2] Hellmann, M.D., Paz-Ares, L., Bernabe Caro, R., Zurawski, B., Kim, S.-W., Carcereny Costa, E., et al. (2019) Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. The New England Journal of Medicine, 381, 2020-2031. [Google Scholar] [CrossRef] 
[3] Nestle, U., Adebahr, S., Kaier, K., Gkika, E., Schimek-Jasch, T., Hechtner, M., et al. (2020) Quality of Life after Pulmonary Stereo-tactic Fractionated Radiotherapy (SBRT): Results of the Phase II STRIPE Trial. Radiotherapy and Oncology, 148, 82-88. [Google Scholar] [CrossRef] [PubMed]
[4] Chi, A. and Nguyen, N.P. (2022) Rationale for Combing Stere-otactic Body Radiation Therapy with Immune Checkpoint Inhibitors in Medically Inoperable Early-Stage Non-Small Cell Lung Cancer. Cancers, 14, Article 3144. [Google Scholar] [CrossRef] [PubMed]
[5] Plá, M., Beltrán, D.D. and Albiach, E.F. (2021) Immune Check-points Inhibitors and SRS/SBRT Synergy in Metastatic Non-Small-Cell Lung Cancer and Melanoma: A Systematic Re-view. International Journal of Molecular Sciences, 22, Article 11621. [Google Scholar] [CrossRef] [PubMed]
[6] Abdulhaleem, M., et al. (2022) Local Control Outcomes for Combina-tion of Stereotactic Radiosurgery and Immunotherapy for Non-Small Cell Lung Cancer Brain Metastases. Journal of Neuro-Oncology, 157, 101-107. [Google Scholar] [CrossRef] [PubMed]
[7] Borghaei, H., Paz-Ares, L., Horn, L., Spigel, D.R., Steins, M., Ready, N.E., et al. (2015) Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. The New England Journal of Medicine, 373, 1627-1639. [Google Scholar] [CrossRef] 
[8] Brahmer, J., Reckamp, K.L., Baas, P., Crinò, L., Eberhardt, W.E.E., Poddubskaya, E., et al. (2015) Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. The New England Journal of Medicine, 373, 123-135. [Google Scholar] [CrossRef] 
[9] Borghaei, H., Gettinger, S., Vokes, E.E., Chow, L.Q.M., Burgio, M.A., de Castro Carpeno, J., et al. (2021) Five-Year Outcomes from the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 39, 723-733. [Google Scholar] [CrossRef] 
[10] Wu, Y.-L., Lu, S., Cheng, Y., Zhou, C., Wang, J., Mok, T., et al. (2019) Nivolumab versus Docetaxel in a Predominantly Chinese Patient Population with Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial. Journal of Thoracic Oncology, 14, 867-875. [Google Scholar] [CrossRef] [PubMed]
[11] Paz-Ares, L., Ciuleanu, T.-E., Cobo, M., Schenker, M., Zurawski, B., Menezes, J., et al. (2021) First-Line Nivolumab plus Ipilimumab Combined with Two Cycles of Chemotherapy in Patients with Non-Small-Cell Lung Cancer (CheckMate 9LA): An International, Randomised, Open-Label, Phase 3 Trial. The Lancet Oncology, 22, 198-211. [Google Scholar] [CrossRef] 
[12] Brahmer, J.R., Lee, J.-S., Ciuleanu, T.-E., Bernabe Caro, R., Nishio, M., Urban, L., et al. (2023) Five-Year Survival Outcomes with Nivolumab plus Ipilimumab versus Chemother-apy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227. Journal of Clinical Oncology, 41, 1200-1212. [Google Scholar] [CrossRef] 
[13] Rittmeyer, A., Barlesi, F., Waterkamp, D., Park, K., Ciardiello, F., von Pawel, J., et al. (2017) Atezolizumab versus Docetaxel in Patients with Previously Treated Non-Small-Cell Lung Cancer (OAK): A Phase 3, Open-Label, Multicentre Randomised Controlled Trial. The Lancet, 389, 255-265. [Google Scholar] [CrossRef] 
[14] Jassem, J., de Marinis, F., Giaccone, G., Vergnenegre, A., Barrios, C.H., Morise, M., et al. (2021) Updated Overall Survival Analysis from IMpower110: Ate-zolizumab versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1-Selected NSCLC. Journal of Thoracic Oncology, 16, 1872-1882. [Google Scholar] [CrossRef] [PubMed]
[15] Socinski, M.A., et al. (2023) Association of Immune-Related Ad-verse Events with Efficacy of Atezolizumab in Patients with Non-Small Cell Lung Cancer: Pooled Analyses of the Phase 3 IMpower130, IMpower132, and IMpower150 Randomized Clinical Trials. JAMA Oncology, 9, 527-535. [Google Scholar] [CrossRef] [PubMed]
[16] Socinski, M.A., Nishio, M., Jotte, R.M., Cappuzzo, F., Orlandi, F., Stroyakovskiy, D., et al. (2021) IMpower150 Final Overall Survival Analyses for Atezolizumab plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC. Journal of Thoracic Oncology, 16, 1909-1924. [Google Scholar] [CrossRef] [PubMed]
[17] Yang, Y., Sun, J., Wang, Z., Fang, J., Yu, Q., Han, B., et al. (2021) Updated Overall Survival Data and Predictive Biomarkers of Sintilimab plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC in the Phase 3 ORIENT-11 Study. Journal of Thoracic Oncology 16, 2109-2120. [Google Scholar] [CrossRef] [PubMed]
[18] Zhou, C., Wu, L., Fan, Y., Wang, Z., Liu, L., Chen, G., et al. (2021) Sintilimab plus Platinum and Gemcitabine as First-Line Treatment for Advanced or Metastatic Squamous NSCLC: Re-sults from a Randomized, Double-Blind, Phase 3 Trial (ORIENT-12). Journal of Thoracic Oncology, 16, 1501-1511. [Google Scholar] [CrossRef] [PubMed]
[19] Zhou, .F, Qiao, M. and Zhou, C. (2021) The Cutting-Edge Progress of Immune-Checkpoint Blockade in Lung Cancer. Cellular & Molecular Immunology, 18, 279-293. [Google Scholar] [CrossRef] [PubMed]
[20] MacManus, M. and Hegi-Johnson, F. (2022) Overcoming Im-munotherapy Resistance in NSCLC. The Lancet Oncology, 23, 191-193. [Google Scholar] [CrossRef] 
[21] Barbari, C., et al., (2020) Immunotherapies and Combination Strategies for Immuno-Oncology. International Journal of Molecular Sciences, 21, Article 5009. [Google Scholar] [CrossRef] [PubMed]
[22] Wu, G., Baine, M.J., Zhao, N., Li, S., Li, X. and Lin, C. (2019) Lym-phocyte-Sparing Effect of Stereotactic Body Radiation Therapy Compared to Conventional Fractionated Radiation Ther-apy in Patients with Locally Advanced Pancreatic Cancer. BMC Cancer, 19, Article No. 977. [Google Scholar] [CrossRef] [PubMed]
[23] Chen, D., Verma, V., Patel, R.R., Barsoumian, H.B., Cortez, M.A. and Welsh, J.W. (2020) Absolute Lymphocyte Count Predicts Abscopal Responses and Outcomes in Patients Receiving Combined Immunotherapy and Radiation Therapy: Analysis of 3 Phase 1/2 Trials. International Journal of Radiation Oncology, Biology, Physics, 108, 196-203. [Google Scholar] [CrossRef] [PubMed]
[24] Theelen, W.S.M.E., Chen, D., Verma, V., Hobbs, B.P., Peulen, H.M.U., Aerts, J.G.J.V., et al. (2021) Pembrolizumab with or without Radiotherapy for Metastatic Non-Small-Cell Lung Cancer: A Pooled Analysis of Two Randomised Trials. The Lancet Respiratory Medicine, 9, 467-475. [Google Scholar] [CrossRef] 
[25] Schoenfeld, J.D., Giobbie-Hurder, A., Ranasinghe, S., Kao, K.Z., Lako, A., Tsuji, J., et al. (2022) Durvalumab plus Tremelimumab Alone or in Combination with Low-Dose or Hypofractionated Radiotherapy in Metastatic Non-Small- Cell Lung Cancer Refractory to Previous PD(L)-1 Therapy: An Open-Label, Multicentre, Randomised, Phase 2 Trial. The Lancet Oncology, 23, 279-291. [Google Scholar] [CrossRef] 
[26] Bestvina, C.M., Pointer, K.B., Karrison, T., Al-Hallaq, H., Hoffman, P.C., Jelinek, M.J., et al. (2022) A Phase 1 Trial of Concurrent or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients with Stage IV NSCLC Study. Journal of Thoracic Oncology, 17, 130-140. [Google Scholar] [CrossRef] [PubMed]
[27] Welsh, J., Menon, H., Chen, D., Verma, V., Tang, C., Altan, M., et al. (2020) Pembrolizumab with or without Radiation Therapy for Metastatic Non-Small Cell Lung Cancer: A Random-ized Phase I/II Trial. The Journal for ImmunoTherapy of Cancer, 8, e001001. [Google Scholar] [CrossRef] [PubMed]
[28] Menon, H., Chen, D., Ramapriyan, R., Verma, V., Barsoumian, H.B., Cushman, T.R., et al. (2019) Influence of Low- Dose Radiation on Abscopal Responses in Patients Receiving High-Dose Radiation and Immunotherapy. The Journal for ImmunoTherapy of Cancer, 7, 237. [Google Scholar] [CrossRef] [PubMed]
[29] Yin, L., Xue, J., Li, R., Zhou, L., Deng, L., Chen, L., et al. (2020) Effect of Low-Dose Radiation Therapy on Abscopal Responses to Hypofractionated Radiation Therapy and Anti-PD1 in Mice and Patients with Non-Small Cell Lung Cancer. International Journal of Radiation Oncology, Biology, Physics, 108, 212-224. [Google Scholar] [CrossRef] [PubMed]
[30] Westcott, P.M.K., et al. (2023) Mismatch Repair Deficiency Is Not Sufficient to Elicit Tumor Immunogenicity. Nature Genetics, 55, 1686-1695. [Google Scholar] [CrossRef] [PubMed]
[31] Dovedi, S.J., Adlard, A.L., Lipowska-Bhalla, G., McKenna, C., Jones, S., Cheadle, E.J., et al. (2014) Acquired Resistance to Fractionated Radiotherapy Can Be Overcome by Concurrent PD-L1 Blockade. Cancer Research, 74, 5458- 5468. [Google Scholar] [CrossRef] 
[32] Twyman-Saint, V.C., Rech, A.J., Maity, A., Rengan, R., Pauken, K.E., Stelekati, E., et al. (2015) Radiation and Dual Checkpoint Blockade Activate Non-Redundant Immune Mechanisms in Cancer. Nature, 520, 373-377. [Google Scholar] [CrossRef] [PubMed]
[33] Anscher, M.S., Arora, S., Weinstock, C., Amatya, A., Bandaru, P., Tang, C., et al. (2022) Association of Radiation Therapy with Risk of Adverse Events in Patients Receiving Immunotherapy: A Pooled Analysis of Trials in the US Food and Drug Administration Database. JAMA Oncology, 8, 232-240. [Google Scholar] [CrossRef] [PubMed]
[34] Maher, V.E., Fernandes, L.L., Weinstock, C., Tang, S., Agarwal, S., Brave, M., et al. (2019) Analysis of the Association between Adverse Events and Outcome in Patients Receiving a Programmed Death Protein 1 or Programmed Death Ligand 1 Antibody. Journal of Clinical Oncology, 37, 2730-2737. [Google Scholar] [CrossRef] 
[35] Weichselbaum, R.R. (2018) The 46th David A. Karnofsky Memorial Award Lecture: Oligometastasis—From Conception to Treatment. Journal of Clinical Oncology, 36, 3240-3250. [Google Scholar] [CrossRef] 
[36] Brooks, E.D. and Chang, J.Y. (2019) Time to Abandon Single-Site Ir-radiation for Inducing Abscopal Effects. Nature Reviews Clinical Oncology, 16, 123-135. [Google Scholar] [CrossRef] [PubMed]
[37] Pitroda, S.P., Khodarev, N.N., Huang, L., Uppal, A., Wightman, S.C., Ganai, S., et al. (2018) Integrated Molecular Subtyping Defines a Curable Oligometastatic State in Colorectal Liver Metastasis. Nature Communications, 9, Article No. 1793. [Google Scholar] [CrossRef] [PubMed]
[38] Hegde, P.S., Karanikas, V. and Evers, S. (2016) The Where, the When, and the How of Immune Monitoring for Cancer Immu-notherapies in the Era of Checkpoint Inhibition. Clinical Cancer Research, 22, 1865-1874. [Google Scholar] [CrossRef] 
[39] Mariathasan, S., Turley, S.J., Nickles, D., Castiglioni, A., Yuen, K., Wang, Y., et al. (2018) TGFβ Attenuates Tumour Response to PD-L1 Blockade by Contributing to Exclusion of T Cells. Nature, 554, 544-548. [Google Scholar] [CrossRef] [PubMed]
[40] Salmon, H., Franciszkiewicz, K., Damotte, D., Dieu-Nosjean, M.C., Va-lidire, P., Trautmann, A., et al. (2012) Matrix Architecture Defines the Preferential Localization and Migration of T Cells into the Stroma of Human Lung Tumors. Journal of Clinical Investigation, 122, 899-910. [Google Scholar] [CrossRef] 
[41] Ene-Obong, A., Clear, A.J., Watt, J., Wang, J., Fatah, R., Riches, J.C., et al. (2013) Activated Pancreatic Stellate Cells Sequester CD8+ T Cells to Reduce Their Infiltration of the Juxtatumoral Com-partment of Pancreatic Ductal Adenocarcinoma. Gastroenterology, 145, 1121-1132. [Google Scholar] [CrossRef] [PubMed]
[42] Arina, A., Idel, C., Hyjek, E.M., Alegre, M.L., Wang, Y., Bin-dokas, V.P., et al. (2016) Tumor-Associated Fibroblasts Predominantly Come from Local and Not Circulating Precursors. Proceedings of the National Academy of Sciences of the United States of America, 113, 7551-7556. [Google Scholar] [CrossRef] [PubMed]
[43] Dominguez, C.X., Muller, S., Keerthivasan, S., Koeppen, H., Hung, J., Gierke, S., et al. (2019) Single-Cell RNA Sequencing Reveals Stromal Evolution into LRRC15+ Myofibroblasts as a Determinant of Patient Response to Cancer Immunotherapy. Cancer Discovery, 10, 232-253. [Google Scholar] [CrossRef] 
[44] Yost, K.E., Satpathy, A.T., Wells, D.K., Qi, Y., Wang, C., Kageyama, R., et al. (2019) Clonal Replacement of Tumor-Specific T Cells Following PD-1 Blockade. Nature Medicine, 25, 1251-5799. [Google Scholar] [CrossRef] [PubMed]

为你推荐