Volume 14 Issue 4
Jul.  2023
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ZENG Xinying, WEN Xuejun, GUO Zhide, ZHANG Xianzhong. Advances in Synergistic Antitumor Effects of Radiopharmaceuticals Combined with Immune Checkpoint Inhibitors[J]. Medical Journal of Peking Union Medical College Hospital, 2023, 14(4): 680-690. doi: 10.12290/xhyxzz.2023-0159
Citation: ZENG Xinying, WEN Xuejun, GUO Zhide, ZHANG Xianzhong. Advances in Synergistic Antitumor Effects of Radiopharmaceuticals Combined with Immune Checkpoint Inhibitors[J]. Medical Journal of Peking Union Medical College Hospital, 2023, 14(4): 680-690. doi: 10.12290/xhyxzz.2023-0159

Advances in Synergistic Antitumor Effects of Radiopharmaceuticals Combined with Immune Checkpoint Inhibitors

doi: 10.12290/xhyxzz.2023-0159

National Natural Science Foundation of China 81901805

National Natural Science Foundation of China 21976150

National Natural Science Foundation of China 21906135

National High Level Hospital Clinical Research Funding 2022-PUMCH-B-071

National High Level Hospital Clinical Research Funding 2023-PUMCH-E-007

More Information
  • Corresponding author: GUO Zhide, E-mail: gzd666888@xmu.edu.cn; ZHANG Xianzhong, E-mail: zhangxzh@hotmail.com
  • Received Date: 2023-03-29
  • Accepted Date: 2023-04-17
  • Available Online: 2023-05-18
  • Publish Date: 2023-07-30
  • Targeted radionuclide therapy (TRT) provides an immunogenic microenvironment for immune checkpoint inhibitor (ICI) therapy by inducing DNA double-strand break, activating the cGAS-STING, NF-κB/IRF3 and STAT1/3-IRF1 pathways, up-regulating the expression of PD-L1, and increasing the infiltration of pro-inflammatory cytokines, CD8+ T cells and CD4+ T cells in tumors. The combined therapy could increase the infiltration of memory effector T cells, M1 macrophages and dendritic cells which positively regulate immune response, and downregulate immunosuppressive regulatory T cells, M2 macrophages and myeloid-derived suppressor cells. Partial complete remission and immune memory were achieved in tumor-bearing mice treated with combined therapy. It is worth noting that radiodiagnostic agent 2-[18F]FDG combined with anti-PD-L1 mAb could also reprogram the immune microenvironment and significantly improve therapeutic effect. This review presents typical combination therapy strategies, emphasizes the time window of combination therapy and different combinations of therapy that may improve the therapeutic effect, and proposes that radiodiagnostic agents combined with tumor immunotherapy are expected to become a new paradigm and a direction for further research in the future.
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  • [1] FDA approves anti-LAG3 checkpoint[J]. Nat Biotechnol, 2022, 40: 625.
    [2] Yi M, Zheng X, Niu M, et al. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions[J]. Mol Cancer, 2022, 21: 28. doi:  10.1186/s12943-021-01489-2
    [3] de Miguel M, Calvo E. Clinical Challenges of Immune Checkpoint Inhibitors[J]. Cancer Cell, 2020, 38: 326-333. doi:  10.1016/j.ccell.2020.07.004
    [4] Fradet Y, Bellmunt J, Vaughn DJ, et al. Randomized phase Ⅲ KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up[J]. Ann Oncol, 2019, 30: 970-976. doi:  10.1093/annonc/mdz127
    [5] McLaughlin M, Patin EC, Pedersen M, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy[J]. Nat Rev Cancer, 2020, 20: 203-217. doi:  10.1038/s41568-020-0246-1
    [6] Pouget JP, Lozza C, Deshayes E, et al. Introduction to radiobiology of targeted radionuclide therapy[J]. Front Med (Lausanne), 2015, 2: 12.
    [7] Deng L, Liang H, Xu M, et al. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type Ⅰ Interferon-Dependent Antitumor Immunity in Immunogenic Tumors[J]. Immunity, 2014, 41: 843-852. doi:  10.1016/j.immuni.2014.10.019
    [8] Zhang X, Zhang H, Zhang J, et al. The paradoxical role of radiation-induced cGAS-STING signalling network in tumour immunity[J]. Immunology, 2023, 168: 375-388. doi:  10.1111/imm.13592
    [9] Lan Y, Moustafa M, Knoll M, et al. Simultaneous targeting of TGF-beta/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion[J]. Cancer Cell, 2021, 39: 1388-403. e10. doi:  10.1016/j.ccell.2021.08.008
    [10] Sha CM, Lehrer EJ, Hwang C, et al. Toxicity in combination immune checkpoint inhibitor and radiation therapy: A systematic review and meta-analysis[J]. Radiother Oncol, 2020, 151: 141-148. doi:  10.1016/j.radonc.2020.07.035
    [11] Procureur A, Simonaggio A, Bibault JE, et al. Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments[J]. Cancers (Basel), 2021, 13: 678. doi:  10.3390/cancers13040678
    [12] Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer[J]. Nature, 2015, 520: 373-377. doi:  10.1038/nature14292
    [13] Formenti SC, Demaria S. Systemic effects of local radiotherapy[J]. Lancet Oncol, 2009, 10: 718-726. doi:  10.1016/S1470-2045(09)70082-8
    [14] Formenti SC, Rudqvist NP, Golden E, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade[J]. Nat Med, 2018, 24: 1845-1851. doi:  10.1038/s41591-018-0232-2
    [15] Kleinendorst SC, Oosterwijk E, Bussink J, et al. Combining Targeted Radionuclide Therapy and Immune Checkpoint Inhibition for Cancer Treatment[J]. Clin Cancer Res, 2022, 28: 3652-3657. doi:  10.1158/1078-0432.CCR-21-4332
    [16] Sun Q, Li J, Ding Z, et al. Radiopharmaceuticals heat anti-tumor immunity[J]. Theranostics, 2023, 13: 767-786. doi:  10.7150/thno.79806
    [17] Rouanet J, Benboubker V, Akil H, et al. Immune checkpoint inhibitors reverse tolerogenic mechanisms induced by melanoma targeted radionuclide therapy[J]. Cancer Immunol Immunother, 2020, 69: 2075-2088. doi:  10.1007/s00262-020-02606-8
    [18] Jagodinsky JC, Jin WJ, Bates AM, et al. Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy[J]. Theranostics, 2021, 11: 6120-6137. doi:  10.7150/thno.54881
    [19] Patel RB, Hernandez R, Carlson P, et al. Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade[J]. Sci Transl Med, 2021, 13: eabb3631. doi:  10.1126/scitranslmed.abb3631
    [20] Grzmil M, Boersema P, Sharma A, et al. Comparative analysis of cancer cell responses to targeted radionuclide therapy (TRT) and external beam radiotherapy (EBRT)[J]. J Hematol Oncol, 2022, 15: 123. doi:  10.1186/s13045-022-01343-y
    [21] Zhang J, Yang M, Fan X, et al. Biomimetic radiosensitizers unlock radiogenetics for local interstitial radiotherapy to activate systematic immune responses and resist tumor metastasis[J]. J Nanobiotechnology, 2022, 20: 103. doi:  10.1186/s12951-022-01324-w
    [22] Brown R, Hernandez R, Grudzinski JJ, et al. Ability of Molecular Targeted Radionucleotide Therapy and Anti-CTLA-4 to Prevent Spontaneous Metastases in a Preclinical Lewis Lung Carcinoma Model[J]. Int J Radiat Oncol Biol Phys, 2019, 105: E498-E499.
    [23] Potluri HK, Ferreira CA, Grudzinski J, et al. Antitumor efficacy of 90Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors[J]. J Immunother Cancer, 2022, 10: e005060. doi:  10.1136/jitc-2022-005060
    [24] Lutetium (Lu-177) Dotatate Approved by FDA[J]. Cancer Discov, 2018, 8: OF2.
    [25] Fallah J, Agrawal S, Gittleman H, et al. FDA Approval Summary: lutetium (Lu-177) vipivotide tetraxetan for patients with metastatic castration-resistant prostate cancer[J]. Clin Cancer Res, 2023, 29: 1651-1657. doi:  10.1158/1078-0432.CCR-22-2875
    [26] Kim C, Liu SV, Subramaniam DS, et al. Phase Ⅰ study of the 177Lu-DOTA(0)-Tyr(3)-Octreotate (lutathera) in combination with nivolumab in patients with neuroendocrine tumors of the lung[J]. J Immunother Cancer, 2020, 8: e000980. doi:  10.1136/jitc-2020-000980
    [27] Ferdinandus J, Fendler WP, Lueckerath K, et al. Response to Combined Peptide Receptor Radionuclide Therapy and Checkpoint Immunotherapy with Ipilimumab Plus Nivolumab in Metastatic Merkel Cell Carcinoma[J]. J Nucl Med, 2022, 63: 396-398. doi:  10.2967/jnumed.121.262344
    [28] Lin AL, Tabar V, Young RJ, et al. Synergism of Checkpoint Inhibitors and Peptide Receptor Radionuclide Therapy in the Treatment of Pituitary Carcinoma[J]. J Endocr Soc, 2021, 5: bvab133. doi:  10.1210/jendso/bvab133
    [29] Prasad V, Zengerling F, Steinacker JP, et al. First Experiences with 177Lu-PSMA Therapy in Combination with Pembrolizumab or After Pretreatment with Olaparib in Single Patients[J]. J Nucl Med, 2021, 62: 975-978. doi:  10.2967/jnumed.120.249029
    [30] Chen H, Zhao L, Fu K, et al. Integrin αυβ3-targeted radionuclide therapy combined with immune checkpoint blockade immunotherapy synergis-tically enhances anti-tumor efficacy[J]. Theranostics, 2019, 9: 7948-7960. doi:  10.7150/thno.39203
    [31] Wen XJ, Zeng XY, Shi CR, et al. Optimum combination of radiopharmaceuticals-based targeting-triggering-therapy effect and PD-L1 blockade immunotherapy[J]. Adv Ther, 2022, 6: 2200193.
    [32] Wen X, Zeng X, Liu J, et al. Synergism of 64Cu-Labeled RGD with Anti-PD-L1 Immunotherapy for the Long-Acting Antitumor Effect[J]. Bioconjug Chem, 2022, 33: 2170-2179. doi:  10.1021/acs.bioconjchem.2c00408
    [33] Guzik P, Siwowska K, Fang HY, et al. Promising potential of [177Lu]Lu-DOTA-folate to enhance tumor response to immunotherapy-a preclinical study using a syngeneic breast cancer model[J]. Eur J Nucl Med Mol Imaging, 2021, 48: 984-994. doi:  10.1007/s00259-020-05054-9
    [34] Ren J, Xu M, Chen J, et al. PET imaging facilitates antibody screening for synergistic radioimmunotherapy with a 177Lu-labeled alphaPD-L1 antibody[J]. Theranostics, 2021, 11: 304-315. doi:  10.7150/thno.45540
    [35] Malo ME, Allen KJH, Jiao R, et al. Mechanistic Insights into Synergy between Melanin-Targeting Radioimmun-otherapy and Immunotherapy in Experimental Melanoma[J]. Int J Mol Sci, 2020, 21: 8721. doi:  10.3390/ijms21228721
    [36] Choi J, Beaino W, Fecek RJ, et al. Combined VLA-4-Targeted Radionuclide Therapy and Immunotherapy in a Mouse Model of Melanoma[J]. J Nucl Med, 2018, 59: 1843-1849. doi:  10.2967/jnumed.118.209510
    [37] Vito A, Rathmann S, Mercanti N, et al. Combined Radionuclide Therapy and Immunotherapy for Treatment of Triple Negative Breast Cancer[J]. Int J Mol Sci, 2021, 22: 4843. doi:  10.3390/ijms22094843
    [38] Stap J, Krawczyk PM, Van Oven CH, et al. Induction of linear tracks of DNA double-strand breaks by alpha-particle irradiation of cells[J]. Nat Methods, 2008, 5: 261-266. doi:  10.1038/nmeth.f.206
    [39] Czernin J, Current K, Mona CE, et al. Immune-Checkpoint Blockade Enhances 225Ac-PSMA617 Efficacy in a Mouse Model of Prostate Cancer[J]. J Nucl Med, 2021, 62: 228-231. doi:  10.2967/jnumed.120.246041
    [40] Josefsson A, Nedrow JR, Park S, et al. Combining alpha-particle radiopharmaceutical therapy using Actinium-225 and immunotherapy with anti-PD-L1 antibodies in a murine immunocompetent metastatic breast cancer model[J]. Cancer Res, 2016, 76: 3052. doi:  10.1158/1538-7445.AM2016-3052
    [41] Dabagian H, Taghvaee T, Martorano P, et al. PARP Targeted Alpha-Particle Therapy Enhances Response to PD-1 Immune-Checkpoint Blockade in a Syngeneic Mouse Model of Glioblastoma[J]. ACS Pharmacol Transl Sci, 2021, 4: 344-351. doi:  10.1021/acsptsci.0c00206
    [42] Zhang J, Li F, Yin Y, et al. Alpha radionuclide-chelated radioimmunotherapy promoters enable local radiotherapy/chemodynamic therapy to discourage cancer progression[J]. Biomater Res, 2022, 26: 44. doi:  10.1186/s40824-022-00290-6
    [43] Malamas AS, Gameiro SR, Knudson KM, et al. Sublethal exposure to alpha radiation 223Ra dichloride) enhances various carcinomas' sensitivity to lysis by antigen-specific cytotoxic T lymphocytes through calreticulin-mediated immunogenic modulation[J]. Oncotarget, 2016, 7: 86937-86947. doi:  10.18632/oncotarget.13520
    [44] Creemers JHA, van der Doelen MJ, van Wilpe S, et al. Immunophenotyping Reveals Longitudinal Changes in Circulating Immune Cells During Radium-223 Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer[J]. Front Oncol, 2021, 11: 667658. doi:  10.3389/fonc.2021.667658
    [45] Vardaki I, Corn P, Gentile E, et al. Radium-223 Treatment Increases Immune Checkpoint Expression in Extracellular Vesicles from the Metastatic Prostate Cancer Bone Microenvironment[J]. Clin Cancer Res, 2021, 27: 3253-3264. doi:  10.1158/1078-0432.CCR-20-4790
    [46] Fong L, Morris MJ, Sartor O, et al. A Phase Ib Study of Atezolizumab with Radium-223 Dichloride in Men with Metastatic Castration-Resistant Prostate Cancer[J]. Clin Cancer Res, 2021, 27: 4746-4756. doi:  10.1158/1078-0432.CCR-21-0063
    [47] Li M, Liu D, Lee D, et al. Targeted Alpha-Particle Radiotherapy and Immune Checkpoint Inhibitors Induces Cooperative Inhibition on Tumor Growth of Malignant Melanoma[J]. Cancers (Basel), 2021, 13: 3676. doi:  10.3390/cancers13153676
    [48] Nosanchuk JD, Jeyakumar A, Ray A, et al. Structure-function analysis and therapeutic efficacy of antibodies to fungal melanin for melanoma radioimmunotherapy[J]. Sci Rep, 2018, 8: 5466. doi:  10.1038/s41598-018-23889-z
    [49] Perrin J, Capitao M, Allard M, et al. Targeted Alpha Particle Therapy Remodels the Tumor Microenvironment and Improves Efficacy of Immunotherapy[J]. Int J Radiat Oncol Biol Phys, 2022, 112: 790-801. doi:  10.1016/j.ijrobp.2021.10.013
    [50] Gorin JB, Menager J, Gouard S, et al. Antitumor immunity induced after alpha irradiation[J]. Neoplasia, 2014, 16: 319-328. doi:  10.1016/j.neo.2014.04.002
    [51] Lejeune P, Cruciani V, Berg-Larsen A, et al. Immunostimulatory effects of targeted thorium-227 conjugates as single agent and in combination with anti-PD-L1 therapy[J]. J Immunother Cancer, 2021, 9: e002387. doi:  10.1136/jitc-2021-002387
    [52] Hagemann UB, Ellingsen C, Schuhmacher J, et al. Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers[J]. Clin Cancer Res, 2019, 25: 4723-4734. doi:  10.1158/1078-0432.CCR-18-3476
    [53] Moadel RM, Nguyen AV, Lin EY, et al. Positron emission tomography agent 2-deoxy-2-[18F]fluoro-D-glucose has a therapeutic potential in breast cancer[J]. Breast Cancer Res, 2003, 5: R199-R205. doi:  10.1186/bcr643
    [54] Moadel RM, Weldon RH, Katz EB, et al. Positherapy: targeted nuclear therapy of breast cancer with 18F-2-deoxy-2-fluoro-D-glucose[J]. Cancer Res, 2005, 65: 698-702. doi:  10.1158/0008-5472.698.65.3
    [55] Fang S, Wang J, Jiang H, et al. Experimental study on the therapeutic effect of positron emission tomography agent[18F]-labeled 2-deoxy-2-fluoro-d-glucose in a colon cancer mouse model[J]. Cancer Biother Radiopharm, 2010, 25: 733-740.
    [56] Wen X, Shi C, Zeng X, et al. A Paradigm of Cancer Immunotherapy Based on 2-[18F]FDG and Anti-PD-L1 mAb Combination to Enhance the Antitumor Effect[J]. Clin Cancer Res, 2022, 28: 2923-2937. doi:  10.1158/1078-0432.CCR-22-0159
    [57] 文雪君, 周吴昊, 郭志德, 等. 整合素αυβ3靶向放射性药物99mTc-RGD联合抗PD-L1肿瘤免疫治疗增强抗肿瘤效果的研究[J]. 协和医学杂志, 2023, 14: 766-773. doi:  10.12290/xhyxzz.2023-0155
    [58] Wen X, Zeng X, Cheng X, et al. PD-L1-Targeted Radionuclide Therapy Combined with alpha PD-L1 Antibody Immunotherapy Synergistically Improves the Antitumor Effect[J]. Mol Pharm, 2022, 19: 3612-3622. doi:  10.1021/acs.molpharmaceut.2c00281
    [59] Gutfilen B, Souza SA, Valentini G. Copper-64: a real theranostic agent[J]. Drug Des Devel Ther, 2018, 12: 3235-3245. doi:  10.2147/DDDT.S170879
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