The effects of radium-223 on the immune system and the bone tumor microenvironment are incompletely understood. The authors describe mechanisms by which radium-223 may interact with the immune system, specifically through STAT-3 and impact on tumor and circulating lymphocyte populations. They review mechanisms through which effects of radium-223 and androgen-targeted therapy on bone microenvironment could be better elucidated. These knowledge gaps currently limit development of optimal combination therapy approaches for radium-223. Tissue based studies are currently underway in a prospective clinical trial to enhance therapeutic perspective on radium-223 treatment in the prostate cancer landscape.
Get full access to this article
View all access options for this article.
References
1.
LewingtonVJ, McEwanAJ, AckeryDM, et al.A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer Clin Oncol, 1991; 27:954.
2.
SartorO, ReidRH, HoskinPJ, et al.Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology, 2004; 63:940.
3.
ParkerC, NilssonS, HeinrichD, et al.Alpha-emitter Radium-223 and survival in metastatic prostate cancer. N Engl J Med, 2013; 369:213.
4.
SmithMR, ParkerC, SaadF, et al.Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA223): A randomized double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2019; 20:408.
5.
Dalla VoltaA, FormentiAM, BerrutA. Higher risk of fragility fractures in prostate cancer patients treated with combine radium-223 and abiraterone: Prednisone may be the culprit. Eur Urol, 2019; 75:894.
6.
TombalBF, LoriotY, SaadF, et al.Decreased fracture rate by mandating bone-protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: An interim safety analysis. J Clin Oncol, 2019; 37(suppl):5007.
7.
SuominenMI, FagerlundKM, RissanenJP, et al.Radium-223 inhibits osseous prostate cancer growth by dual targeting of cancer cells and bone microenvironment in mouse models. Clin Cancer Res, 2017; 23:4335.
8.
HarrisTJ, HipkissEL, BorzillaryS, et al.Radiotherapy augments the immune response to prostate cancer in a time-dependent manner. Prostate, 2008; 68:1319.
9.
KwonED, DrakeCG, ScherHI, et al.Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed on docetaxel chemotherapy (CA184-043): A multicenter, randomized double-blind phase 3 trial. Lancet, 2014; 15:700.
10.
ScherthanH, LeeJ-H, MausE, et al.Nanostructure of clustered DNA damage in leukocytes after in-solution irradiation with the alpha emitter Ra-223. Cancers, 2019; 11:1877.
11.
ConfinoH, HochmanI, EfratiM, et al.Tumor ablation by intratumoral Ra-224-loaded wires induces anti-tumor immunity against experimental metastatic tumors. Cancer Immunol Immunother, 2015; 64:191.
12.
BishopJL, SioA, AngelesA, et al.PD-L1 is highly expressed in enzalutamide resistant prostate cancer. Oncotarget, 2015; 6:234.
13.
CalcinottoA, SpataroC, ZagatoE, et al.IL23 secreted by myeloid cells drives castration resistant prostate cancer. Nature, 2018; 559:363.
14.
HossainDMS, PalSK, MoreiraD, et al.TLR9-targeted STAT3 silencing abrogates immunosuppressive activity of myeloid-derived suppressor cells from prostate cancer patients. Clin Cancer Res, 2015; 21:3771.
15.
ConfinoH, SchmidtM, EfratiM, et al.Inhibition of mouse breast adenocarcinoma growth by ablation with intra-tumoral alpha irradiation combined with inhibitors of immunosuppression and CpG. Cancer Immuonl Immunother, 2016; 65:1149.
16.
KortylewskiM. Regulation of the IL-23 and IL-12 blaance by Stat3 signaling in the tumor microenvironment. Cancer Cell, 2009; 15:114.
17.
Vasquez-DunddelD. STAT3 regulates arginase-l in myeloid derived suppressor cells from cancer patients. J Clin Invest, 2013; 123:1580.
18.
GaoC, KozlowskaA, NechaevS, et al.TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiotherapy. Cancer Res, 2013; 73:7211.
19.
SampathS. Combined modality radiation therapy promotes tolerogenic myeloid cell populations and STAT3-related gene expression in head and neck cancer patients. Oncotarget, 2018; 9:11279.
20.
GraffJN, AlumkaiJJ, DrakeCG, et al.Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget, 2016; 7:52810.
21.
HansenAR, MassardC, OttPA, et al.Pembrolizumab for advanced prostate adenocarcinoma: Findings of the KEYNOTE-028 study. Ann Oncol, 2018; 29:1807.
22.
GorinJ-B, MenagerJ, GouardS, et al.Antitumor immunity induced after alpha irradiation. Neoplasia, 2014; 16:319.
23.
BarsegianV, MullerSP, MockelD, et al.Lymphocyte function following radium-223 therpay in patients with metastatic castration resistant prostate cancer. Eur J Nucl Med Mol Imaging, 2017; 44:242.
24.
KarjaV, AaltomaaS, LipponenP, et al.Tumour-infiltrating lymphocytes: A prognostic factor of PSA-free survival in patients with local prostate carcinoma treated by radical prostatectomy. Anticancer Res, 2005; 25:4435.
25.
WuAC, HeY, BroomfieldA, et al.CD169+ macrophages mediate pathological formation of woven bone in skeletal lesions of prostate cancer. J Pathol, 2016; 239:218.
26.
YlitaloEB, ThysellE, JernbergE, et al.Subgroups of castration-resistant prostate cancer bone metastases defined through an inverse relationship between androgen receptor activity and immune response. Eur Urol, 2017; 71:776.
27.
AlmeidaM, LaurentMR, DuboisV, et al.Estrogens and androgens in skeletal physiology and pathophysiology. Physiol Rev, 2017; 97:135.
28.
SaadF, GleasonD, MurrayR, et al.A randomized, placebo controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate cancer. J Natl Cancer Inst, 2002; 94:1458.
29.
FizaziK, CarducciM, SmithM, et al.Denosumab vs zoledronic acid for treatment of bone metastases in men with metastatic castration resistant prostate cancer: A randomized, double-blind study. Lancet, 2011; 377:813.
30.
FizaziK, ScherHI, MillerK, et al.Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: Results from the randomized, phase 3 AFFIRM trial. Lancet Oncol, 2014; 15:1147.
31.
SartorO, ColemanR, NilssonS, et al.Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: Results from a phase 3, double-blind, randomised trial. Lancet Oncol, 2014; 15:738.
32.
ChenG, SircarK, AprikianA, et al.Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation. Cancer, 2006; 107:289.
33.
CattriniC, RubagotiA, NuzzoPV, et al.Overexpression of periostin in tumor biopsy samples is associated with prostate cancer phenotype and clinical outcome. Clin Genitourin Cancer, 2018; 16:1257.
34.
RieunierG, WuX, MacaulayVM, et al.Bad to the bone: The role of the insulin-like growth factor axis in osseous metastasis. Clin Cancer Res, 2019; 25:3479.
35.
HiragaT, MyouiA, HashimotoN, et al.Bone-derived IGF mediates crosstalk between bone and breast cancer cells in bony metastases. Cancer Res, 2012; 72:4238.
36.
DasSK, PradhanAK, BhoopathiP, et al.The MDA-9/syntenin/IGF1R/STAT3 axis directs prostate cancer invasion. Cancer Res, 2018; 78:2852.
37.
ZongCS, ChanJ, LevyE, et al.Mechanism of STAT3 activation by insulin-like growth factor 1 receptor. J Biol Chem, 2000; 275:15099.
38.
HiganoCS, AlumkalJJ, RyanCJ, et al.A phase II study evaluating the efficacy and safety of single agent IMC A12, a monoclonal antibody, against the insulin-like growth factor-1 receptor, as monotherapy in patients with metastatic, asymptomatic castration-resistant prostate cancer. J Clin Oncol, 2009; 27(suppl):5142.
39.
YuEY, LiH, HiganoCS, et al.SWOG S0925: A randomized phase II study of androgen deprivation combined with cixutumumab versus androgen deprivation alone in patients with new metastatic hormone-sensitive prostate cancer. J Clin Oncol, 2015; 33:1601.
