PMID- 36948506
OWN - NLM
STAT- MEDLINE
DCOM- 20230324
LR  - 20231223
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 11
IP  - 3
DP  - 2023 Mar
TI  - Immune and pathologic responses in patients with localized prostate cancer who 
      received daratumumab (anti-CD38) or edicotinib (CSF-1R inhibitor).
LID - 10.1136/jitc-2022-006262 [doi]
LID - e006262
AB  - BACKGROUND: The prostate tumor microenvironment (TME) is immunosuppressive, with 
      few effector T cells and enrichment of inhibitory immune populations, leading to 
      limited responses to treatments such as immune checkpoint therapies (ICTs). The 
      immune composition of the prostate TME differs across soft tissue and bone, the 
      most common site of treatment-refractory metastasis. Understanding 
      immunosuppressive mechanisms specific to prostate TMEs will enable rational 
      immunotherapy strategies to generate effective antitumor immune responses. 
      Daratumumab (anti-CD38 antibody) and edicotinib (colony-stimulating factor-1 
      receptor (CSF-1R) inhibitor) may alter the balance within the prostate TME to 
      promote antitumor immune responses. HYPOTHESIS: Daratumumab or edicotinib will be 
      safe and will alter the immune TME, leading to antitumor responses in localized 
      prostate cancer. PATIENTS AND METHODS: In this presurgical study, patients with 
      localized prostate cancer received 4 weekly doses of daratumumab or 4 weeks of 
      daily edicotinib prior to radical prostatectomy (RP). Treated and untreated 
      control (Gleason score >/=8 in prostate biopsy) prostatectomy specimens and 
      patient-matched pre- and post-treatment peripheral blood mononuclear cells 
      (PBMCs) and bone marrow samples were evaluated. The primary endpoint was 
      incidence of adverse events (AEs). The secondary endpoint was pathologic complete 
      remission (pCR) rate. RESULTS: Twenty-five patients were treated (daratumumab, 
      n=15; edicotinib, n=10). All patients underwent RP without delays. Grade 3 
      treatment-related AEs with daratumumab occurred in 3 patients (12%), and no 
      >/=grade 3 treatment-related AEs occurred with edicotinib. No changes in serum 
      prostate-specific antigen (PSA) levels or pCRs were observed. Daratumumab led to 
      a decreased frequency of CD38(+) T cells, natural killer cells, and myeloid cells 
      in prostate tumors, bone marrow, and PBMCs. There were no consistent changes in 
      CSF-1R(+) immune cells in prostate, bone marrow, or PBMCs with edicotinib. 
      Neither treatment induced T cell infiltration into the prostate TME. CONCLUSIONS: 
      Daratumumab and edicotinib treatment was safe and well-tolerated in patients with 
      localized prostate cancer but did not induce pCRs. Decreases in CD38(+) immune 
      cells were observed in prostate tumors, bone marrow, and PBMCs with daratumumab, 
      but changes in CSF-1R(+) immune cells were not consistently observed with 
      edicotinib. Neither myeloid-targeted agent alone was sufficient to generate 
      antitumor responses in prostate cancer; thus, combinations with agents to induce 
      T cell infiltration (eg, ICTs) will be needed to overcome the immunosuppressive 
      prostate TME.
CI  - (c) Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Siddiqui, Bilal A
AU  - Siddiqui BA
AUID- ORCID: 0000-0002-6806-1294
AD  - Department of Genitourinary Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas, USA.
FAU - Chapin, Brian F
AU  - Chapin BF
AD  - Department of Urology, The University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Jindal, Sonali
AU  - Jindal S
AD  - The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Duan, Fei
AU  - Duan F
AD  - The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Basu, Sreyashi
AU  - Basu S
AUID- ORCID: 0000-0002-5028-3833
AD  - The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Yadav, Shalini S
AU  - Yadav SS
AD  - The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Gu, Ai-Di
AU  - Gu AD
AD  - The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Espejo, Alexsandra B
AU  - Espejo AB
AUID- ORCID: 0000-0002-8841-7219
AD  - The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Kinder, Michelle
AU  - Kinder M
AD  - Janssen Research & Development, Spring House, Pennsylvania, USA.
FAU - Pettaway, Curtis A
AU  - Pettaway CA
AD  - Department of Urology, The University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Ward, John F
AU  - Ward JF
AD  - Department of Urology, The University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Tidwell, Rebecca S S
AU  - Tidwell RSS
AUID- ORCID: 0000-0003-3041-8582
AD  - Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Troncoso, Patricia
AU  - Troncoso P
AD  - Department of Pathology, The University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Corn, Paul G
AU  - Corn PG
AD  - Department of Genitourinary Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas, USA.
FAU - Logothetis, Christopher J
AU  - Logothetis CJ
AD  - Department of Genitourinary Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas, USA.
FAU - Knoblauch, Roland
AU  - Knoblauch R
AD  - Janssen Research & Development, Spring House, Pennsylvania, USA.
FAU - Hutnick, Natalie
AU  - Hutnick N
AD  - Janssen Research & Development, Spring House, Pennsylvania, USA.
FAU - Gottardis, Marco
AU  - Gottardis M
AD  - Janssen Research & Development, Spring House, Pennsylvania, USA.
FAU - Drake, Charles G
AU  - Drake CG
AD  - Janssen Research & Development, Spring House, Pennsylvania, USA.
AD  - Department of Medicine, Columbia University Medical Center, New York, New York, 
      USA.
AD  - Department of Urology, Columbia University Medical Center, New York, New York, 
      USA.
FAU - Sharma, Padmanee
AU  - Sharma P
AD  - Department of Genitourinary Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas, USA SKSubudhi@mdanderson.org 
      padsharma@mdanderson.org.
AD  - The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
AD  - Department of Immunology, The University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Subudhi, Sumit K
AU  - Subudhi SK
AD  - Department of Genitourinary Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas, USA SKSubudhi@mdanderson.org 
      padsharma@mdanderson.org.
LA  - eng
GR  - P50 CA140388/CA/NCI NIH HHS/United States
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  - 4Z63YK6E0E (daratumumab)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Immunosuppressive Agents)
SB  - IM
MH  - Male
MH  - Humans
MH  - Leukocytes, Mononuclear/pathology
MH  - *Antineoplastic Agents/therapeutic use
MH  - Antibodies, Monoclonal/pharmacology/therapeutic use
MH  - *Prostatic Neoplasms/drug therapy/pathology
MH  - Immunosuppressive Agents
MH  - Tumor Microenvironment
PMC - PMC10040066
OTO - NOTNLM
OT  - Immunomodulation
OT  - Immunotherapy
OT  - Prostatic Neoplasms
OT  - Tumor Microenvironment
COIS- Competing interests: BAS, FD, SB, SJ, ABE, A-DG, CAP, PCJ, JW, SSY, and RSST 
      report no competing interests. BFC reports Blue Earth Diagnostics - Scientific 
      study/Trial. Johnson and Johnson - Consultant/Advisor. CJL reports Honoraria: 
      Merck, Sharp & Dohme, Bayer, Amgen; Consulting/Advisory: Merck, Sharp & Dohme, 
      Exelixis, Bayer, Amgen; Clinical Grants: Janssen, ORIC Pharmaceuticals, Novartis, 
      Aragon Pharmaceuticals. CG and NH are employees of Janssen Research and 
      Development and report no other relevant disclosures. PS reports 
      Scientific/Advisory Committee Member: Achelois, BioAlta LLC, Candel Therapeutics, 
      Codiak Biosciences, Inc, C-Reveal Therapeutics, Dragonfly Therapeutics, formerly 
      called Equipoise Therapeutics Corporation, Earli Inc, InterVenn Biosciences, LAVA 
      Therapeutics, Lytix Biopharma, PBM Capital, Phenomic Al, Trained Therapeutix 
      Discovery, Xilis, Inc., Two Bear, Henlius/Hengenix. SKS reports Consulting or 
      Advisory Role: Amgen, Apricity Health LLC, AstraZeneca, Bayer, Bristol-Myers 
      Squibb, Cancer Expert Now, Dava Oncology, Dendreon, Exelixis, Kahr Medical Ltd., 
      Janssen Oncology, Javelin Oncology, and MD Education Limited, OncLive (owned by 
      Intellisphere, LLC); Research Funding: AstraZeneca, Bristol-Myers Squibb, and 
      Janssen Oncology; Other (Joint Scientific Committee): Amgen, Janssen Oncology, 
      and Polaris.
EDAT- 2023/03/23 06:00
MHDA- 2023/03/25 06:00
PMCR- 2023/03/22
CRDT- 2023/03/22 20:32
PHST- 2023/02/08 00:00 [accepted]
PHST- 2023/03/22 20:32 [entrez]
PHST- 2023/03/23 06:00 [pubmed]
PHST- 2023/03/25 06:00 [medline]
PHST- 2023/03/22 00:00 [pmc-release]
AID - jitc-2022-006262 [pii]
AID - 10.1136/jitc-2022-006262 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2023 Mar;11(3):e006262. doi: 10.1136/jitc-2022-006262.