The radiopharmaceutical radium-223 has immunomodulatory effects in patients and facilitates anti-programmed death receptor-1 therapy in murine models of bone metastatic prostate cancer
Copyright © 2024 Elsevier B.V. All rights reserved..
BACKGROUND & PURPOSE: Radium-223 (Ra223) improves survival in metastatic prostate cancer (mPC), but its impact on systemic immunity is unclear, and biomarkers of response are lacking. We examined markers of immunomodulatory activity during standard clinical Ra223 and studied the impact of Ra223 on response to immune checkpoint inhibition (ICI) in preclinical models.
MATERIALS & METHODS: We conducted a single-arm biomarker study of Ra223 in 22 bone mPC patients. We measured circulating immune cell subsets and a panel of cytokines before and during Ra223 therapy and correlated them with overall survival (OS). Using two murine mPC models-orthotopic PtenSmad4-null and TRAMP-C1 grafts in syngeneic immunocompetent mice-we tested the efficacy of combining Ra223 with ICI.
RESULTS: Above-median level of IL-6 at baseline was associated with a median OS of 358 versus 947 days for below levels; p = 0.044, from the log-rank test. Baseline PlGF and PSA inversely correlated with OS (p = 0.018 and p = 0.037, respectively, from the Cox model). Ra223 treatment was associated with a mild decrease in some peripheral immune cell populations and a shift in the proportion of MDSCs from granulocytic to myeloid. In mice, Ra223 increased the proliferation of CD8+ and CD4+ helper T cells without leading to CD8+ T cell exhaustion in the mPC lesions. In one of the models, combining Ra223 and anti-PD-1 antibody significantly prolonged survival, which correlated with increased CD8+ T cell infiltration in tumor tissue.
CONCLUSION: The inflammatory cytokine IL-6 and the angiogenic biomarker PlGF at baseline were promising outcome biomarkers after standard Ra223 treatment. In mouse models, Ra223 increased intratumoral CD8+ T cell infiltration and proliferation and could improve OS when combined with anti-PD-1 ICI.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:192 |
|---|---|
| Enthalten in: |
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology - 192(2024) vom: 28. März, Seite 110091 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Saylor, Philip J [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 27.02.2024 Date Revised 05.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.radonc.2024.110091 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM367154706 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM367154706 | ||
| 003 | DE-627 | ||
| 005 | 20240305232215.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240116s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.radonc.2024.110091 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1317.xml |
| 035 | |a (DE-627)NLM367154706 | ||
| 035 | |a (NLM)38224917 | ||
| 035 | |a (PII)S0167-8140(24)00012-4 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Saylor, Philip J |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The radiopharmaceutical radium-223 has immunomodulatory effects in patients and facilitates anti-programmed death receptor-1 therapy in murine models of bone metastatic prostate cancer |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 27.02.2024 | ||
| 500 | |a Date Revised 05.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier B.V. All rights reserved. | ||
| 520 | |a BACKGROUND & PURPOSE: Radium-223 (Ra223) improves survival in metastatic prostate cancer (mPC), but its impact on systemic immunity is unclear, and biomarkers of response are lacking. We examined markers of immunomodulatory activity during standard clinical Ra223 and studied the impact of Ra223 on response to immune checkpoint inhibition (ICI) in preclinical models | ||
| 520 | |a MATERIALS & METHODS: We conducted a single-arm biomarker study of Ra223 in 22 bone mPC patients. We measured circulating immune cell subsets and a panel of cytokines before and during Ra223 therapy and correlated them with overall survival (OS). Using two murine mPC models-orthotopic PtenSmad4-null and TRAMP-C1 grafts in syngeneic immunocompetent mice-we tested the efficacy of combining Ra223 with ICI | ||
| 520 | |a RESULTS: Above-median level of IL-6 at baseline was associated with a median OS of 358 versus 947 days for below levels; p = 0.044, from the log-rank test. Baseline PlGF and PSA inversely correlated with OS (p = 0.018 and p = 0.037, respectively, from the Cox model). Ra223 treatment was associated with a mild decrease in some peripheral immune cell populations and a shift in the proportion of MDSCs from granulocytic to myeloid. In mice, Ra223 increased the proliferation of CD8+ and CD4+ helper T cells without leading to CD8+ T cell exhaustion in the mPC lesions. In one of the models, combining Ra223 and anti-PD-1 antibody significantly prolonged survival, which correlated with increased CD8+ T cell infiltration in tumor tissue | ||
| 520 | |a CONCLUSION: The inflammatory cytokine IL-6 and the angiogenic biomarker PlGF at baseline were promising outcome biomarkers after standard Ra223 treatment. In mouse models, Ra223 increased intratumoral CD8+ T cell infiltration and proliferation and could improve OS when combined with anti-PD-1 ICI | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Immune checkpoint blockade | |
| 650 | 4 | |a Immunomodulation | |
| 650 | 4 | |a Immunotherapy | |
| 650 | 4 | |a Prostate cancer | |
| 650 | 4 | |a Translational research | |
| 650 | 7 | |a Radium-223 |2 NLM | |
| 650 | 7 | |a 8BR2SOL3L1 |2 NLM | |
| 650 | 7 | |a Radiopharmaceuticals |2 NLM | |
| 650 | 7 | |a Interleukin-6 |2 NLM | |
| 650 | 7 | |a Cytokines |2 NLM | |
| 650 | 7 | |a Biomarkers |2 NLM | |
| 650 | 7 | |a Receptors, Death Domain |2 NLM | |
| 650 | 7 | |a Radium |2 NLM | |
| 650 | 7 | |a W90AYD6R3Q |2 NLM | |
| 700 | 1 | |a Kozin, Sergey V |e verfasserin |4 aut | |
| 700 | 1 | |a Matsui, Aya |e verfasserin |4 aut | |
| 700 | 1 | |a Goldberg, Saveli I |e verfasserin |4 aut | |
| 700 | 1 | |a Aoki, Shuichi |e verfasserin |4 aut | |
| 700 | 1 | |a Shigeta, Kohei |e verfasserin |4 aut | |
| 700 | 1 | |a Mamessier, Emilie |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Matthew R |e verfasserin |4 aut | |
| 700 | 1 | |a Michaelson, M Dror |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Richard J |e verfasserin |4 aut | |
| 700 | 1 | |a Duda, Dan G |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology |d 1993 |g 192(2024) vom: 28. März, Seite 110091 |w (DE-627)NLM012598305 |x 1879-0887 |7 nnns |
| 773 | 1 | 8 | |g volume:192 |g year:2024 |g day:28 |g month:03 |g pages:110091 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.radonc.2024.110091 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 192 |j 2024 |b 28 |c 03 |h 110091 | ||