Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment

Abstract

BackgroundImmune checkpoint therapy (ICT) has low response rates in patients with metastatic castration-resistant prostate cancer (mCRPC), in part due to few T cells in the tumor microenvironment (TME). Anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) promotes intratumoral T cell infiltration but induces upregulation of PD-1 and programmed death ligand-1 (PD-L1) within the prostate TME. Combined anti-CTLA-4 plus anti-PD-1 can partly overcome this adaptive resistance and was recently shown to augment responses in patients with mCRPC with measurable disease. Although bone is the most common site of metastasis in prostate cancer, patients with bone-predominant disease are frequently excluded from trials because they lack measurable disease, which limits assessment of disease progression and tissue sampling. We therefore designed this study to investigate combined ICT in mCRPC to bone.HypothesisCombined anti-CTLA-4 (tremelimumab) plus anti-PD-L1 (durvalumab) is safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone.Patients and methodsIn this single-arm pilot study, men with chemotherapy-naïve mCRPC to bone received tremelimumab (75 mg intravenous) plus durvalumab (1500 mg intravenous) every 4 weeks (up to four doses), followed by durvalumab (1500 mg intravenous) maintenance every 4 weeks (up to nine doses). The primary endpoint was incidence of adverse events. Secondary endpoints included serum prostate-specific antigen (PSA), progression-free survival (PFS), radiographic PFS (rPFS), and maximal PSA decline.ResultsTwenty-six patients were treated between August 8, 2017 and March 28, 2019. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 patients (42%), with no grade 4 or 5 events. TRAEs leading to discontinuation occurred in three patients (12%). PSA decline ≥50% occurred in three patients (12%). Six patients (24%) achieved stable disease for >6 months. At a median follow-up of 43.6 months, median rPFS was 3.7 months (95% CI: 1.9 to 5.7), and median overall survival was 28.1 months (95% CI: 14.5 to 37.3). Post-treatment evaluation of the bone microenvironment revealed transcriptional upregulation in myeloid and neutrophil immune subset signatures and increased expression of inhibitory immune checkpoints.ConclusionsTremelimumab plus durvalumab was safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone, with potential activity in a small number of patients as measured by rPFS. Combination of CTLA-4 and PD-L1 blockade with therapies targeting the myeloid compartment or other inhibitory immune receptors may be necessary to overcome mechanisms of resistance within prostate bone microenvironment.Trial registration numberNCT03204812.

Advancing Treatment of Bone Metastases through Novel Translational Approaches Targeting the Bone Microenvironment

“…Collaborative labs could then establish a biobank of primary bone stromal cells from patients with solid tumors, hematologic malignancies, and donors without cancer. Integration of defined workflows that preserve bone biopsies appropriate for genomic and transcriptomic analyses [95,[296][297][298][299][300] will be crucial to advance discovery of novel genomic alterations and gene signatures that reveal interactions between tumors and the bone microenvironment. We participated in a multiinstitution study to evaluate disseminated tumor cells (DTCs) in bone marrow from patients with localized or metastatic PC, compared to healthy controls [304].…”

“…This was recapitulated during inoculation of murine PC cells either in subcutaneous or intraosseous pockets of syngeneic mice [87]. Exploratory analysis of bone marrow aspirates in a single-arm phase I clinical trial of patients with metastatic PC receiving a dual checkpoint inhibitor with tremelimumab and durvalumab demonstrated upregulation of myeloid and neutrophil signatures after immunotherapy [95]. TGF-beta was highly enriched in both patient and murine bone marrow supernatant with BM.…”

Immunotherapy in Advanced Prostate Cancer—Light at the End of the Tunnel?

“…Median rPFS was 3.7 months (95% CI: 1.9 to 5.7), and median overall survival was 28.1 months (95% CI: 14.5 to 37.3). Of note, post-treatment evaluation of the bone microenvironment revealed transcriptional upregulation in myeloid and neutrophil immune subset signatures and increased the expression of inhibitory immune checkpoints indicating the development of immune resistance [ 135 ].…”

Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer

“…For example, we reported that restraint of Th1 anti-tumor responses by TGF-β and suppressive myeloid cells was a predominant feature of the bone TME, even after treatment with ICTs. 9 , 10 Future studies will be needed to address these and identify other mechanisms of resistance across disease sites.…”