TY - JOUR
T1 - Immune and pathologic responses in patients with localized prostate cancer who received daratumumab (anti-CD38) or edicotinib (CSF-1R inhibitor)
AU - Siddiqui, Bilal A.
AU - Chapin, Brian F.
AU - Jindal, Sonali
AU - Duan, Fei
AU - Basu, Sreyashi
AU - Yadav, Shalini S.
AU - Gu, Ai Di
AU - Espejo, Alexsandra B.
AU - Kinder, Michelle
AU - Pettaway, Curtis A.
AU - Ward, John F.
AU - Tidwell, Rebecca S.S.
AU - Troncoso, Patricia
AU - Corn, Paul G.
AU - Logothetis, Christopher J.
AU - Knoblauch, Roland
AU - Hutnick, Natalie
AU - Gottardis, Marco
AU - Drake, Charles G.
AU - Sharma, Padmanee
AU - Subudhi, Sumit K.
N1 - Funding Information:
These studies were supported in part by Janssen Research & Development. The research work was also supported by The University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program (PS and SS); National Institutes of Health (NIH)/National Cancer Institute (NCI) P50 CA140388 (Prostate Cancer SPORE) (SS, CJL, PS); and The V Foundation for Cancer Research’s Lloyd Family Clinical Oncology Scholar Award D2018-014 (SS). The Genitourinary Cancers Program of the Cancer Center Support Grant shared resources at The University of Texas M.D. Anderson Cancer Center. PS is a member of the Parker Institute for Cancer Immunotherapy at The University of Texas M.D. Anderson Cancer Center.
Publisher Copyright:
© 2023 BioMed Central Ltd.. All rights reserved.
PY - 2023/3/22
Y1 - 2023/3/22
N2 - 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.
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.
KW - Immunomodulation
KW - Immunotherapy
KW - Prostatic Neoplasms
KW - Tumor Microenvironment
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U2 - 10.1136/jitc-2022-006262
DO - 10.1136/jitc-2022-006262
M3 - Article
C2 - 36948506
AN - SCOPUS:85150785186
SN - 2051-1426
VL - 11
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 3
M1 - e006262
ER -