Safety, tolerability, and preliminary efficacy of nadunolimab, an anti-IL- 1 receptor accessory protein monoclonal antibody, in combination with pembrolizumab in patients with solid tumors

Bagchi S, Yuan R, Engleman EG (2021) Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol 16:223–249. https://doi.org/10.1146/annurev-pathol-042020-042741

Article  PubMed  CAS  Google Scholar 

Schoenfeld AJ, Hellmann MD (2020) Acquired resistance to immune checkpoint inhibitors. Cancer Cell 37:443–455. https://doi.org/10.1016/j.ccell.2020.03.017

Article  PubMed  PubMed Central  CAS  Google Scholar 

Khalili JS, Liu S, Rodriguez-Cruz TG, Whittington M, Wardell S, Liu C, Zhang M, Cooper ZA, Frederick DT, Li Y, Zhang M, Joseph RW, Bernatchez C, Ekmekcioglu S, Grimm E, Radvanyi LG, Davis RE, Davies MA, Wargo JA, Hwu P, Lizee G (2012) Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res 18:5329–5340. https://doi.org/10.1158/1078-0432.CCR-12-1632

Article  PubMed  PubMed Central  CAS  Google Scholar 

Li R, Ong SL, Tran LM, Jing Z, Liu B, Park SJ, Huang ZL, Walser TC, Heinrich EL, Lee G, Salehi-Rad R, Crosson WP, Pagano PC, Paul MK, Xu S, Herschman H, Krysan K, Dubinett S (2020) Chronic IL-1beta-induced inflammation regulates epithelial-to-mesenchymal transition memory phenotypes via epigenetic modifications in non-small cell lung cancer. Sci Rep 10:377. https://doi.org/10.1038/s41598-019-57285-y

Article  PubMed  PubMed Central  CAS  Google Scholar 

Lu X, Li Y, Yang W, Tao M, Dai Y, Xu J, Xu Q (2021) Inhibition of NF-kappaB is required for oleanolic acid to downregulate PD-L1 by promoting DNA demethylation in gastric cancer cells. J Biochem Mol Toxicol 35:e22621. https://doi.org/10.1002/jbt.22621

Article  PubMed  CAS  Google Scholar 

Cho NW, Guldberg SM, Nabet BY, Yu JZ, Kim EJ, Hiam-Galvez KJ, Yee JL, DeBarge R, Tenvooren I, Ashitey NA, Lynce F, Dillon DA, Rosenbluth JM, Spitzer MH (2025) T cells instruct immune checkpoint inhibitor therapy resistance in tumors responsive to IL1 and TNFalpha inflammation. Cancer Immunol Res 13:229–244. https://doi.org/10.1158/2326-6066.CIR-24-0416

Article  PubMed  CAS  Google Scholar 

Zhang D, Li L, Jiang H, Li Q, Wang-Gillam A, Yu J, Head R, Liu J, Ruzinova MB, Lim KH (2018) Tumor-stroma IL1beta-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer. Cancer Res 78:1700–1712. https://doi.org/10.1158/0008-5472.CAN-17-1366

Article  PubMed  PubMed Central  CAS  Google Scholar 

Zhang D, Li L, Jiang H, Knolhoff BL, Lockhart AC, Wang-Gillam A, DeNardo DG, Ruzinova MB, Lim KH (2017) Constitutive IRAK4 activation underlies poor prognosis and chemoresistance in pancreatic ductal adenocarcinoma. Clin Cancer Res 23:1748–1759. https://doi.org/10.1158/1078-0432.CCR-16-1121

Article  PubMed  CAS  Google Scholar 

Das S, Shapiro B, Vucic EA, Vogt S, Bar-Sagi D (2020) Tumor cell-derived IL1beta promotes desmoplasia and immune suppression in pancreatic cancer. Cancer Res 80:1088–1101. https://doi.org/10.1158/0008-5472.CAN-19-2080

Article  PubMed  PubMed Central  CAS  Google Scholar 

Wang D, Zhang S, Li L, Liu X, Mei K, Wang X (2010) Structural insights into the assembly and activation of IL-1beta with its receptors. Nat Immunol 11:905–911. https://doi.org/10.1038/ni.1925

Article  PubMed  CAS  Google Scholar 

Fields JK, Gunther S, Sundberg EJ (2019) Structural basis of IL-1 family cytokine signaling. Front Immunol 10:1412. https://doi.org/10.3389/fimmu.2019.01412

Article  PubMed  PubMed Central  CAS  Google Scholar 

Guo B, Fu S, Zhang J, Liu B, Li Z (2016) Targeting inflammasome/IL-1 pathways for cancer immunotherapy. Sci Rep 6:36107. https://doi.org/10.1038/srep36107

Article  PubMed  PubMed Central  Google Scholar 

Tengesdal IW, Dinarello A, Powers NE, Burchill MA, Joosten LAB, Marchetti C, Dinarello CA (2021) Tumor NLRP3-derived IL-1beta drives the IL-6/STAT3 axis resulting in sustained MDSC-mediated immunosuppression. Front Immunol 12:661323. https://doi.org/10.3389/fimmu.2021.661323

Article  PubMed  PubMed Central  CAS  Google Scholar 

Garlanda C, Mantovani A (2021) Interleukin-1 in tumor progression, therapy, and prevention. Cancer Cell 39:1023–1027. https://doi.org/10.1016/j.ccell.2021.04.011

Article  PubMed  CAS  Google Scholar 

Frenay J, Bellaye PS, Oudot A, Helbling A, Petitot C, Ferrand C, Collin B, Dias AMM (2022) IL-1RAP, a key therapeutic target in cancer. Int J Mol Sci 23(23):14918. https://doi.org/10.3390/ijms232314918

Robbrecht D, Jungels C, Sorensen MM, Spanggaard I, Eskens F, Fretland SO, Guren TK, Aftimos P, Liberg D, Svedman C, Thorsson L, Steeghs N, Awada A (2022) First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours. Br J Cancer 126:1010–1017. https://doi.org/10.1038/s41416-021-01657-7

Article  PubMed  CAS  Google Scholar 

Gronberg C, Rattik S, Tran-Manh C, Zhou X, Rius Rigau A, Li YN, Gyorfi AH, Dickel N, Kunz M, Kreuter A, Matei EA, Zhu H, Skoog P, Liberg D, Distler JH, Trinh-Minh T (2024) Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis 83:1156–1168. https://doi.org/10.1136/ard-2023-225158

Article  PubMed  CAS  Google Scholar 

Mulholland M, Depuydt MAC, Jakobsson G, Ljungcrantz I, Grentzmann A, To F, Bengtsson E, JaenssonGyllenback E, Gronberg C, Rattik S, Liberg D, Schiopu A, Bjorkbacka H, Kuiper J, Bot I, Slutter B, Engelbertsen D (2024) Interleukin-1 receptor accessory protein blockade limits the development of atherosclerosis and reduces plaque inflammation. Cardiovasc Res 120:581–595. https://doi.org/10.1093/cvr/cvae046

Article  PubMed  PubMed Central  CAS  Google Scholar 

Kaplanov I, Carmi Y, Kornetsky R, Shemesh A, Shurin GV, Shurin MR, Dinarello CA, Voronov E, Apte RN (2019) Blocking IL-1beta reverses the immunosuppression in mouse breast cancer and synergizes with anti-PD-1 for tumor abrogation. Proc Natl Acad Sci U S A 116:1361–1369. https://doi.org/10.1073/pnas.1812266115

Article  PubMed  CAS  Google Scholar 

Fields JK, Kihn K, Birkedal GS, Klontz EH, Sjostrom K, Gunther S, Beadenkopf R, Forsberg G, Liberg D, Snyder GA, Deredge D, Sundberg EJ (2021) Molecular basis of selective cytokine signaling inhibition by antibodies targeting a shared receptor. Front Immunol 12:779100. https://doi.org/10.3389/fimmu.2021.779100

Article  PubMed  PubMed Central  CAS  Google Scholar 

Rydberg Millrud C, Deronic A, Gronberg C, JaenssonGyllenback E, von Wachenfeldt K, Forsberg G, Liberg D (2023) Blockade of IL-1alpha and IL-1beta signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy. Cancer Immunol Immunother 72:667–678. https://doi.org/10.1007/s00262-022-03277-3

Article  PubMed  CAS  Google Scholar 

Jaras M, Johnels P, Hansen N, Agerstam H, Tsapogas P, Rissler M, Lassen C, Olofsson T, Bjerrum OW, Richter J, Fioretos T (2010) Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein. Proc Natl Acad Sci U S A 107:16280–16285. https://doi.org/10.1073/pnas.1004408107

Article  PubMed  PubMed Central  Google Scholar 

Askmyr M, Agerstam H, Hansen N, Gordon S, Arvanitakis A, Rissler M, Juliusson G, Richter J, Jaras M, Fioretos T (2013) Selective killing of candidate AML stem cells by antibody targeting of IL1RAP. Blood 121:3709–3713. https://doi.org/10.1182/blood-2012-09-458935

Article  PubMed  CAS  Google Scholar 

Van Wagoner CM, Rivera-Escalera F, Jaimes-Delgadillo NC, Chu CC, Zent CS, Elliott MR (2023) Antibody-mediated phagocytosis in cancer immunotherapy. Immunol Rev 319:128–141. https://doi.org/10.1111/imr.13265

Article  PubMed  PubMed Central  CAS  Google Scholar 

Su S, Zhao J, Xing Y, Zhang X, Liu J, Ouyang Q, Chen J, Su F, Liu Q, Song E (2018) Immune checkpoint inhibition overcomes ADCP-induced immunosuppression by macrophages. Cell 175:442–57 e23. https://doi.org/10.1016/j.cell.2018.09.007

Article  PubMed  CAS  Google Scholar 

Comments (0)

No login
gif