Pre-existing effector T-cell levels and augmented myeloid cell composition denote response to CDK4/6 inhibitor palbociclib and pembrolizumab in hormone receptor-positive metastatic breast cancer
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ..
BACKGROUND: Single-agent pembrolizumab treatment of hormone receptor-positive metastatic breast cancer (MBC) has demonstrated modest clinical responses. Little is known about potential biomarkers or mechanisms of response to immune checkpoint inhibitors (ICIs) in patients with HR+ MBC. The present study presents novel immune correlates of clinical responses to combined treatment with CDK4/6i and ICI.
METHODS: A combined analysis of two independent phase I clinical trials treating patients with HR+ MBC was performed. Patients treated with the combination of the CDK4/6i palbociclib+the ICI pembrolizumab+the aromatase inhibitor (AI) letrozole (palbo+pembro+AI) were compared with patients treated with pembrolizumab+AI (pembro+AI). Peripheral blood mononuclear cells collected at pretreatment, 3 weeks (cycle 2 day 1) and 9 weeks (cycle 4 day 1) were characterized by high-parameter flow cytometry to assess baseline immune subset composition and longitudinal changes in response to therapy.
RESULTS: In the peripheral blood, higher pretreatment frequencies of effector memory CD45RA+ CD8+ T cells and effector memory CD4+ T cells were observed in responders to palbo+pembro+AI. In contrast, this was not observed in pembro+AI-treated patients. We further characterized T-cell subsets of effector-like killer cell lectin-like receptor subfamily G member 1 (KLRG1+) ICOS+ CD4+ T cells and KLRG1+ CD45RA+ CD8+ T cells as baseline biomarkers of response. In comparison, pretreatment levels of tumor-infiltrating lymphocyte, tumor mutation burden, tumor programmed death-ligand 1 expression, and overall immune composition did not associate with clinical responses. Over the course of treatment, significant shifts in myeloid cell composition and phenotype were observed in palbo+pembro+AI-treated patients, but not in those treated with pembro+AI. We identified increased fractions of type 1 conventional dendritic cells (cDC1s) within circulating dendritic cells and decreased classical monocytes (cMO) within circulating monocytes only in patients treated with palbociclib. We also demonstrated that in palbociclib-treated patients, cDC1 and cMO displayed increased CD83 and human leukocyte antigen-DR isotype (HLA-DR) expression, respectively, suggesting increased maturation and antigen presentation capacity.
CONCLUSIONS: Pre-existing circulating effector CD8+ and CD4+ T cells and dynamic modulation of circulating myeloid cell composition denote response to combined pembrolizumab and palbociclib therapy for patients with HR+ MBC.
TRIAL REGISTRATION NUMBER: NCT02778685 and NCI02648477.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Journal for immunotherapy of cancer - 9(2021), 3 vom: 23. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Egelston, Colt [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.12.2021 Date Revised 31.03.2024 published: Print ClinicalTrials.gov: NCT02778685 Citation Status MEDLINE |
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| doi: |
10.1136/jitc-2020-002084 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM323142389 |
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| 245 | 1 | 0 | |a Pre-existing effector T-cell levels and augmented myeloid cell composition denote response to CDK4/6 inhibitor palbociclib and pembrolizumab in hormone receptor-positive metastatic breast cancer |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Revised 31.03.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT02778685 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a BACKGROUND: Single-agent pembrolizumab treatment of hormone receptor-positive metastatic breast cancer (MBC) has demonstrated modest clinical responses. Little is known about potential biomarkers or mechanisms of response to immune checkpoint inhibitors (ICIs) in patients with HR+ MBC. The present study presents novel immune correlates of clinical responses to combined treatment with CDK4/6i and ICI | ||
| 520 | |a METHODS: A combined analysis of two independent phase I clinical trials treating patients with HR+ MBC was performed. Patients treated with the combination of the CDK4/6i palbociclib+the ICI pembrolizumab+the aromatase inhibitor (AI) letrozole (palbo+pembro+AI) were compared with patients treated with pembrolizumab+AI (pembro+AI). Peripheral blood mononuclear cells collected at pretreatment, 3 weeks (cycle 2 day 1) and 9 weeks (cycle 4 day 1) were characterized by high-parameter flow cytometry to assess baseline immune subset composition and longitudinal changes in response to therapy | ||
| 520 | |a RESULTS: In the peripheral blood, higher pretreatment frequencies of effector memory CD45RA+ CD8+ T cells and effector memory CD4+ T cells were observed in responders to palbo+pembro+AI. In contrast, this was not observed in pembro+AI-treated patients. We further characterized T-cell subsets of effector-like killer cell lectin-like receptor subfamily G member 1 (KLRG1+) ICOS+ CD4+ T cells and KLRG1+ CD45RA+ CD8+ T cells as baseline biomarkers of response. In comparison, pretreatment levels of tumor-infiltrating lymphocyte, tumor mutation burden, tumor programmed death-ligand 1 expression, and overall immune composition did not associate with clinical responses. Over the course of treatment, significant shifts in myeloid cell composition and phenotype were observed in palbo+pembro+AI-treated patients, but not in those treated with pembro+AI. We identified increased fractions of type 1 conventional dendritic cells (cDC1s) within circulating dendritic cells and decreased classical monocytes (cMO) within circulating monocytes only in patients treated with palbociclib. We also demonstrated that in palbociclib-treated patients, cDC1 and cMO displayed increased CD83 and human leukocyte antigen-DR isotype (HLA-DR) expression, respectively, suggesting increased maturation and antigen presentation capacity | ||
| 520 | |a CONCLUSIONS: Pre-existing circulating effector CD8+ and CD4+ T cells and dynamic modulation of circulating myeloid cell composition denote response to combined pembrolizumab and palbociclib therapy for patients with HR+ MBC | ||
| 520 | |a TRIAL REGISTRATION NUMBER: NCT02778685 and NCI02648477 | ||
| 650 | 4 | |a Comparative Study | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a CD4-positive T-lymphocytes | |
| 650 | 4 | |a CD8-positive T-lymphocytes | |
| 650 | 4 | |a breast neoplasms | |
| 650 | 4 | |a immunotherapy | |
| 650 | 7 | |a Antibodies, Monoclonal, Humanized |2 NLM | |
| 650 | 7 | |a Aromatase Inhibitors |2 NLM | |
| 650 | 7 | |a Immune Checkpoint Inhibitors |2 NLM | |
| 650 | 7 | |a Piperazines |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
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| 650 | 7 | |a Letrozole |2 NLM | |
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| 700 | 1 | |a Guo, Weihua |e verfasserin |4 aut | |
| 700 | 1 | |a Yost, Susan |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Jin Sun |e verfasserin |4 aut | |
| 700 | 1 | |a Rose, David |e verfasserin |4 aut | |
| 700 | 1 | |a Avalos, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Frankel, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Schmolze, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Waisman, James |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Yuan |e verfasserin |4 aut | |
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