PMID- 35121644
OWN - NLM
STAT- MEDLINE
DCOM- 20220323
LR  - 20230701
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 10
IP  - 2
DP  - 2022 Feb
TI  - Evaluating the efficacy of a priming dose of cyclophosphamide prior to 
      pembrolizumab to treat metastatic triple negative breast cancer.
LID - 10.1136/jitc-2021-003427 [doi]
LID - e003427
AB  - PURPOSE: Triple negative breast cancer (TNBC) is characterized by the presence of 
      immune cells in the tumor microenvironment, however, the response to single-agent 
      immune checkpoint inhibitor (ICI) therapy is modest. Preclinical models have 
      demonstrated that intratumoral regulatory T cells (T(regs)) dampen the antitumor 
      response to ICI. We performed a single-arm phase II trial to evaluate the 
      efficacy of a single low dose of cyclophosphamide (Cy) to deplete T(regs) 
      administered before initiating pembrolizumab. PATIENTS AND METHODS: 40 patients 
      with pretreated metastatic TNBC were enrolled. The primary endpoints were 
      progression-free survival (PFS) and change in peripheral blood T(regs) after Cy. 
      Secondary endpoints included overall response rate (ORR), duration of response, 
      overall survival, treatment-related adverse events (AEs), and correlative 
      evaluations. RESULTS: Median PFS was 1.8 months, and the ORR was 21%. T(regs) 
      were not significantly decreased after Cy prior to ICI (-3.3%, p=0.19), and 
      increased significantly after the first cycle of therapy (+21% between cycles 1 
      and 2, p=0.005). Immune-related AEs were similar to historical pembrolizumab 
      monotherapy, and were associated with response to therapy (p=0.02). Patients with 
      pretreatment tumors harboring increased expression of B cell metagene signatures 
      and increased circulating B cell receptor repertoire diversity were associated 
      with clinical response and immune-related toxicity (IRT). CONCLUSIONS: Among 
      patients with heavily pretreated TNBC, Cy prior to pembrolizumab did not 
      significantly deplete T(regs), and in those with decreased numbers there was 
      rapid recovery following therapy. Increased B cell gene expression in baseline 
      samples was associated with clinical response and IRT.
CI  - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Anders, Carey K
AU  - Anders CK
AD  - Duke Cancer Institute, Durham, North Carolina, USA.
FAU - Woodcock, Mark G
AU  - Woodcock MG
AUID- ORCID: 0000-0001-7348-4980
AD  - Division of Medical Oncology, University of North Carolina School of Medicine, 
      Chapel Hill, North Carolina, USA.
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Van Swearingen, Amanda E D
AU  - Van Swearingen AED
AUID- ORCID: 0000-0002-4287-9741
AD  - Duke Cancer Institute, Durham, North Carolina, USA.
FAU - Moore, Dominic T
AU  - Moore DT
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Sambade, Maria J
AU  - Sambade MJ
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Laurie, Sonia
AU  - Laurie S
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Robeson, Alexander
AU  - Robeson A
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Kolupaev, Oleg
AU  - Kolupaev O
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Cuaboy, Luz A
AU  - Cuaboy LA
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Garrett, Amy L
AU  - Garrett AL
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - McKinnon, Karen
AU  - McKinnon K
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
AD  - Division of Microbiology and Immunology, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Cowens, Kristen
AU  - Cowens K
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Bortone, Dante
AU  - Bortone D
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Calhoun, Benjamin C
AU  - Calhoun BC
AD  - Department of Pathology and Laboratory Medicine, University of North Carolina 
      School of Medicine, Chapel Hill, North Carolina, USA.
FAU - Wilkinson, Alec D
AU  - Wilkinson AD
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Carey, Lisa
AU  - Carey L
AD  - Division of Medical Oncology, University of North Carolina School of Medicine, 
      Chapel Hill, North Carolina, USA.
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Jolly, Trevor
AU  - Jolly T
AD  - Division of Medical Oncology, University of North Carolina School of Medicine, 
      Chapel Hill, North Carolina, USA.
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Muss, Hyman
AU  - Muss H
AD  - Division of Medical Oncology, University of North Carolina School of Medicine, 
      Chapel Hill, North Carolina, USA.
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Reeder-Hayes, Katherine
AU  - Reeder-Hayes K
AD  - Division of Medical Oncology, University of North Carolina School of Medicine, 
      Chapel Hill, North Carolina, USA.
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Kaltman, Rebecca
AU  - Kaltman R
AD  - Department of Hematology and Oncology, George Washington Cancer Center, 
      Washington, District of Columbia, USA.
FAU - Jankowitz, Rachel
AU  - Jankowitz R
AD  - Division of Hematology/Oncology, University of Pittsburgh, University of 
      Pittsburgh, Pittsburgh, Pennsylvania, USA.
AD  - Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, 
      Philadelphia, Pennsylvania, USA.
FAU - Gudena, Vinay
AU  - Gudena V
AD  - Division of Hematology/Oncology, Cone Health Cancer Center, Greensboro, North 
      Carolina, USA.
FAU - Olajide, Oludamilola
AU  - Olajide O
AD  - Rex Hematology Oncology Associates, Rex Cancer Care, Raleigh, North Carolina, 
      USA.
FAU - Perou, Charles
AU  - Perou C
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
AD  - Department of Genetics, University of North Carolina School of Medicine, Chapel 
      Hill, North Carolina, USA.
FAU - Dees, E Claire
AU  - Dees EC
AD  - Division of Medical Oncology, University of North Carolina School of Medicine, 
      Chapel Hill, North Carolina, USA.
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
FAU - Vincent, Benjamin G
AU  - Vincent BG
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
AD  - Division of Microbiology and Immunology, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
AD  - Department of Genetics, University of North Carolina School of Medicine, Chapel 
      Hill, North Carolina, USA.
AD  - Division of Hematology, University of North Carolina School of Medicine, Chapel 
      Hill, North Carolina, USA.
FAU - Serody, Jonathan S
AU  - Serody JS
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA jonathan_serody@med.unc.edu.
AD  - Division of Microbiology and Immunology, University of North Carolina School of 
      Medicine, Chapel Hill, North Carolina, USA.
AD  - Division of Hematology, University of North Carolina School of Medicine, Chapel 
      Hill, North Carolina, USA.
LA  - eng
GR  - P30 CA016086/CA/NCI NIH HHS/United States
GR  - P50 CA058223/CA/NCI NIH HHS/United States
GR  - T32 CA211056/CA/NCI NIH HHS/United States
GR  - K12 GM000678/GM/NIGMS NIH HHS/United States
GR  - P30 CA014236/CA/NCI NIH HHS/United States
GR  - R37 CA247676/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 8N3DW7272P (Cyclophosphamide)
RN  - DPT0O3T46P (pembrolizumab)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antibodies, Monoclonal, Humanized/pharmacology/*therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacology/*therapeutic use
MH  - Cyclophosphamide/pharmacology/*therapeutic use
MH  - Female
MH  - Humans
MH  - Immunotherapy/*methods
MH  - Middle Aged
MH  - Neoplasm Metastasis
MH  - Triple Negative Breast Neoplasms/*drug therapy
PMC - PMC8819787
OTO - NOTNLM
OT  - breast neoplasms
OT  - clinical trials
OT  - immunotherapy
OT  - phase II as topic
OT  - programmed cell death 1 receptor
COIS- Competing interests: CKA receives research funding from PUMA, Lilly, MSD, Seattle 
      Genetics, Nektar, Tesaro, and G1 Therapeutics, ZION, Novartis, Pfizer; 
      compensation for consulting from Genentech, Eisai, IPSEN, Seattle Genetics, 
      AstraZeneca, Novartis; and royalties from UpToDate and Jones and Bartlett. BV 
      holds equity in GeneCentric Therapeutics. CP is an equity stockholder and 
      consultant of BioClassifier, and an equity stock holder, consultant, and Board of 
      Directors member of GeneCentric Therapeutics. CP is also listed as an inventor on 
      patent applications for the Breast PAM50 assay. JS receives funding from MSD, 
      GSK, and Carisma, is a scientific consultant for PIQUE Therapeutics and has filed 
      IP for the use of STING agonists to enhance CAR T cell for breast cancer. The 
      other authors have no conflicts requiring disclosure.
EDAT- 2022/02/06 06:00
MHDA- 2022/03/24 06:00
PMCR- 2022/02/04
CRDT- 2022/02/05 05:48
PHST- 2021/11/16 00:00 [accepted]
PHST- 2022/02/05 05:48 [entrez]
PHST- 2022/02/06 06:00 [pubmed]
PHST- 2022/03/24 06:00 [medline]
PHST- 2022/02/04 00:00 [pmc-release]
AID - jitc-2021-003427 [pii]
AID - 10.1136/jitc-2021-003427 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2022 Feb;10(2):e003427. doi: 10.1136/jitc-2021-003427.