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European Journal of Nuclear Medicine and Molecular Imaging

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Open Access 15-10-2022 | Melanoma | Original Article

Enhanced antitumor immune responses via a new agent [¹³¹I]-labeled dual-target immunosuppressant

Authors: Chunjuan Jiang, Qiwei Tian, Xiaoping Xu, Panli Li, Simin He, Jian Chen, Bolin Yao, Jianping Zhang, Ziyi Yang, Shaoli Song

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 2/2023

Abstract

Radionuclides theranostic are ideal “partners” for bispecific antibodies to explore the immune response of patients and synergistic treatment. A bispecific single-domain antibody-Fc fusion protein, KN046, exhibits a good treatment effect by binding to programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). An ionizing-radiation stimulus mediated by a low-dose of [¹³¹I] may be used for immunopotentiation. In this study, we established [¹³¹I]-labeled KN046 as a novel radioimmunotherapy agent to treat malignant melanoma and explored the mechanism.

Methods

After intravenous injection of [¹³¹I]-KN046, SPECT/CT imaging was applied to identify candidate targets for KN046 immunotherapy. [¹⁸F]-FDG and [⁶⁸ Ga]-NOTA-GZP (granzyme B-specific PET imaging agent) micro-PET/CT imaging was used to assess the immune response in vivo after [¹³¹I]-KN046 treatment. The synergistic treatment effect of [¹³¹I]-KN046 was evaluated by exploring the [¹³¹I]-based radionuclide-induced release of tumor immunogenicity-related antigens as well as the histology and survival of tumor-bearing mice after treatment.

Results

The constructed [¹³¹I]-KN046 exhibited high affinity and specificity for PD-L1/CTLA-4 immune targets and had excellent in vivo intratumoral retention capability so as to achieve good antitumor efficacy. More importantly, the combination of low-dose [¹³¹I] and KN046-enhanced immunosensitivity increased the immunotherapy response rates significantly. Exposure of tumor cells to [¹³¹I]-KN046 led to upregulated expression of MHC-I and Fas surface molecules and significant increases in the degree of T-cell activation and counts of tumor-infiltrating immunocytes.

Conclusion

Use of low-dose [¹³¹I] combined with a dual-target immunosuppressant could be exploited to identify the subset of treatment responders but also exhibited great potential for enhancing antitumor immune responses.

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Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33:1889–94. https://doi.org/10.1200/JCO.2014.56.2736.CrossRef

Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390:1853–62. https://doi.org/10.1016/S0140-6736(17)31601-X.CrossRef

Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377:1345–56. https://doi.org/10.1056/NEJMoa1709684.CrossRef

Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:1480–92. https://doi.org/10.1016/S1470-2045(18)30700-9.CrossRef

Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17:1558–68. https://doi.org/10.1016/S1470-2045(16)30366-7.CrossRef

Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34. https://doi.org/10.1056/NEJMoa1504030.CrossRef

Jiang C, Zhang L, Xu X, Qi M, Zhang J, He S, et al. Engineering a smart agent for enhanced immunotherapy effect by simultaneously blocking PD-L1 and CTLA-4. Adv Sci (Weinh). 2021;8:e2102500. https://doi.org/10.1002/advs.202102500.CrossRef

Kozlovskaya V, Alford A, Dolmat M, Ducharme M, Caviedes R, Radford L, et al. Multilayer microcapsules with shell-chelated (89)Zr for PET imaging and controlled delivery. ACS Appl Mater Interfaces. 2020;12:56792–804. https://doi.org/10.1021/acsami.0c17456.CrossRef

Ballal S, Yadav MP, Kramer V, Moon ES, Roesch F, Tripathi M, et al. A theranostic approach of [(68)Ga]Ga-DOTA.SA.FAPi PET/CT-guided [(177)Lu]Lu-DOTA.SA.FAPi radionuclide therapy in an end-stage breast cancer patient: new frontier in targeted radionuclide therapy. Eur J Nucl Med Mol Imaging. 2021;48:942–4. https://doi.org/10.1007/s00259-020-04990-w.CrossRef

10.

Jungels C, Karfis I. 131I-metaiodobenzylguanidine and peptide receptor radionuclide therapy in pheochromocytoma and paraganglioma. Curr Opin Oncol. 2021;33:33–9. https://doi.org/10.1097/CCO.0000000000000691.CrossRef

11.

Keinanen O, Fung K, Brennan JM, Zia N, Harris M, van Dam E, et al. Harnessing (64)Cu/(67)Cu for a theranostic approach to pretargeted radioimmunotherapy. Proc Natl Acad Sci U S A. 2020;117:28316–27. https://doi.org/10.1073/pnas.2009960117.CrossRef

12.

Lehner S, Todica A, Boning G, Buchholz S, Bartenstein P, Hacker M, et al. [68Ga]DOTA-TATE PET for the detection of early transplant rejection in a heterotopic allograft heart transplantation model of the rat. A pilot study. Q J Nucl Med Mol Imaging. 2021. https://doi.org/10.23736/S1824-4785.21.03387-2.

13.

van Helden EJ, Elias SG, Gerritse SL, van Es SC, Boon E, Huisman MC, et al. [(89)Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer. Eur J Nucl Med Mol Imaging. 2020;47:849–59. https://doi.org/10.1007/s00259-019-04555-6.CrossRef

14.

Larimer BM, Wehrenberg-Klee E, Dubois F, Mehta A, Kalomeris T, Flaherty K, et al. Granzyme B PET Imaging as a predictive biomarker of immunotherapy response. Cancer Res. 2017;77:2318–27. https://doi.org/10.1158/0008-5472.CAN-16-3346.CrossRef

15.

Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41:843–52. https://doi.org/10.1016/j.immuni.2014.10.019.CrossRef

16.

Rodriguez-Ruiz ME, Rodriguez I, Garasa S, Barbes B, Solorzano JL, Perez-Gracia JL, et al. Abscopal effects of radiotherapy are enhanced by combined immunostimulatory mAbs and are dependent on CD8 T cells and crosspriming. Cancer Res. 2016;76:5994–6005. https://doi.org/10.1158/0008-5472.CAN-16-0549.CrossRef

17.

Jiao R, Allen KJH, Malo ME, Rickles D, Dadachova E. Evaluating the combination of radioimmunotherapy and immunotherapy in a melanoma mouse model. Int J Mol Sci. 2020;21. https://doi.org/10.3390/ijms21030773.

18.

Chen H, Zhao L, Fu K, Lin Q, Wen X, Jacobson O, et al. Integrin alphavbeta3-targeted radionuclide therapy combined with immune checkpoint blockade immunotherapy synergistically enhances anti-tumor efficacy. Theranostics. 2019;9:7948–60. https://doi.org/10.7150/thno.39203.CrossRef

19.

Zhang Y, Kupferschlaeger J, Lang P, Reischl G, Handgretinger R, la Fougere C, et al. (131)Iodine-GD2-ch14.18 scintigraphy to evaluate option for radioimmunotherapy in patients with advanced tumors. J Nucl Med. 2021. https://doi.org/10.2967/jnumed.120.261854.

20.

Dillon JS, Bushnell D, Laux DE. High-specific-activity (131)iodine-metaiodobenzylguanidine for therapy of unresectable pheochromocytoma and paraganglioma. Future Oncol. 2021;17:1131–41. https://doi.org/10.2217/fon-2020-0625.CrossRef

21.

Chakraborty M, Wansley EK, Carrasquillo JA, Yu S, Paik CH, Camphausen K, et al. The use of chelated radionuclide (samarium-153-ethylenediaminetetramethylenephosphonate) to modulate phenotype of tumor cells and enhance T cell-mediated killing. Clin Cancer Res. 2008;14:4241–9. https://doi.org/10.1158/1078-0432.CCR-08-0335.CrossRef

22.

Jagodinsky JC, Jin WJ, Bates AM, Hernandez R, Grudzinski JJ, Marsh IR, et al. Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy. Theranostics. 2021;11:6120–37. https://doi.org/10.7150/thno.54881.CrossRef

23.

Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–7. https://doi.org/10.1038/nature14292.CrossRef

24.

Dudzinski SO, Cameron BD, Wang J, Rathmell JC, Giorgio TD, Kirschner AN. Combination immunotherapy and radiotherapy causes an abscopal treatment response in a mouse model of castration resistant prostate cancer. J Immunother Cancer. 2019;7:218. https://doi.org/10.1186/s40425-019-0704-z.CrossRef

25.

Hussien H, Goud AA, Amin AM, El-Sheikh R, Seddik U. Comparative study between chloramine-T and iodogen to prepare radioiodinated etodolac for inflammation imaging. J Radioanal Nucl Chem. 2011;288:9–15. https://doi.org/10.1007/s10967-010-0967-9.CrossRef

26.

Tavare R, McCracken MN, Zettlitz KA, Knowles SM, Salazar FB, Olafsen T, et al. Engineered antibody fragments for immuno-PET imaging of endogenous CD8+ T cells in vivo. Proc Natl Acad Sci U S A. 2014;111:1108–13. https://doi.org/10.1073/pnas.1316922111.CrossRef

27.

Mah LJ, El-Osta A, Karagiannis TC. gammaH2AX: a sensitive molecular marker of DNA damage and repair. Leukemia. 2010;24:679–86. https://doi.org/10.1038/leu.2010.6.CrossRef

28.

Kojima H, Shinohara N, Hanaoka S, Someya-Shirota Y, Takagaki Y, Ohno H, et al. Two distinct pathways of specific killing revealed by perforin mutant cytotoxic T lymphocytes. Immunity. 1994;1:357–64. https://doi.org/10.1016/1074-7613(94)90066-3.CrossRef

29.

Garcia-Lora A, Algarra I, Garrido F. MHC class I antigens, immune surveillance, and tumor immune escape. J Cell Physiol. 2003;195:346–55. https://doi.org/10.1002/jcp.10290.CrossRef

30.

Bubenik J. Tumour MHC class I downregulation and immunotherapy (Review). Oncol Rep. 2003;10:2005–8.

31.

Jin WJ, Erbe AK, Schwarz CN, Jaquish AA, Anderson BR, Sriramaneni RN, et al. Tumor-specific antibody, cetuximab, enhances the in situ vaccine effect of radiation in immunologically cold head and neck squamous cell carcinoma. Front Immunol. 2020;11:591139. https://doi.org/10.3389/fimmu.2020.591139.CrossRef

32.

Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM, Schneider RJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618. https://doi.org/10.1038/ncomms15618.CrossRef

33.

Goping IS, Barry M, Liston P, Sawchuk T, Constantinescu G, Michalak KM, et al. Granzyme B-induced apoptosis requires both direct caspase activation and relief of caspase inhibition. Immunity. 2003;18:355–65. https://doi.org/10.1016/s1074-7613(03)00032-3.CrossRef

34.

Jeffrey JL, Lawson KV, Powers JP. Targeting metabolism of extracellular nucleotides via inhibition of ectonucleotidases CD73 and CD39. J Med Chem. 2020;63:13444–65. https://doi.org/10.1021/acs.jmedchem.0c01044.CrossRef

35.

Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26:2375–91. https://doi.org/10.1093/annonc/mdv383.CrossRef

36.

Nawaz S, Heindl A, Koelble K, Yuan Y. Beyond immune density: critical role of spatial heterogeneity in estrogen receptor-negative breast cancer. Mod Pathol. 2015;28:1621. https://doi.org/10.1038/modpathol.2015.133.CrossRef

37.

Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71. https://doi.org/10.1038/nature13954.CrossRef

38.

Vilain RE, Menzies AM, Wilmott JS, Kakavand H, Madore J, Guminski A, et al. Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in melanoma. Clin Cancer Res. 2017;23:5024–33. https://doi.org/10.1158/1078-0432.CCR-16-0698.CrossRef

39.

Chatterjee S, Lesniak WG, Gabrielson M, Lisok A, Wharram B, Sysa-Shah P, et al. A humanized antibody for imaging immune checkpoint ligand PD-L1 expression in tumors. Oncotarget. 2016;7:10215–27. https://doi.org/10.18632/oncotarget.7143.CrossRef

40.

Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74:5458–68. https://doi.org/10.1158/0008-5472.CAN-14-1258.CrossRef

41.

Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33:1974–82. https://doi.org/10.1200/JCO.2014.59.4358.CrossRef

42.

Carretero-Gonzalez A, Lora D, Ghanem I, Zugazagoitia J, Castellano D, Sepulveda JM, et al. Analysis of response rate with ANTI PD1/PD-L1 monoclonal antibodies in advanced solid tumors: a meta-analysis of randomized clinical trials. Oncotarget. 2018;9:8706–15. https://doi.org/10.18632/oncotarget.24283.CrossRef

Title: Enhanced antitumor immune responses via a new agent [131I]-labeled dual-target immunosuppressant
Authors: Chunjuan Jiang
Qiwei Tian
Xiaoping Xu
Panli Li
Simin He
Jian Chen
Bolin Yao
Jianping Zhang
Ziyi Yang
Shaoli Song
Publication date: 15-10-2022
Publisher: Springer Berlin Heidelberg
Keywords: Melanoma
Melanoma
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 2/2023
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-022-05986-4

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Enhanced antitumor immune responses via a new agent [¹³¹I]-labeled dual-target immunosuppressant

Abstract

Methods

Results

Conclusion

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Methods

Results

Conclusion

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