Molecular pathways and cellular subsets associated with adverse clinical outcomes in overlapping immune-related myocarditis and myositis.

Immune checkpoint therapies (ICTs) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we obtained heart and skeletal muscle biopsies for single-cell RNA sequencing in living patients with cancers treated with ICTs admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n=10; myocarditis-only, n=1) compared to ICT-exposed patients ruled out for toxicity utilized as controls (n=9) within 96 hours of clinical presentation. Analyses of 58,523 cells revealed CD8+ T cells with a cytotoxic phenotype expressing activation/exhaustion markers in both myocarditis and myositis. Furthermore, the analyses identified a population of myeloid cells expressing tissue-resident signatures and FcγRIIIa (CD16a), which is known to bind IgG and regulate complement activation. Immunohistochemistry of affected cardiac and skeletal muscle tissues revealed protein expression of pan-IgG and complement product C4d that were associated with the presence of high-titer serum autoantibodies against muscle antigens in a subset of patients. We further identified a population of inflammatory IL-1B+TNF+ myeloid cells specifically enriched in myocarditis and associated with greater toxicity severity and poorer clinical outcomes. These results are the first to recognize these myeloid subsets in human immune-related myocarditis and myositis tissues and nominate new targets for investigation into rational treatments to overcome these high-mortality toxicities.

Monostotic Scapular Caffey Disease: A Case Report With MRI Correlate.

Caffey disease, also referred to as infantile cortical hyperostosis, is a self-limiting inflammatory disease of bone, typically diagnosed in infancy (ages less than five months). This disease is characterized by asymmetric, often polyostotic bony hyperostosis and expansion, with a predilection for the mandible (70-90%). We present a unique case of a two-month-old boy with monostotic scapular hyperostosis. The disease is primarily diagnosed on plain film and further evaluated with bone scintigraphy or skeletal survey to identify the extent of osseous involvement. Accompanying MR imaging is not usually obtained due to lack of specificity and diagnostic utility, and when pursued, can potentially confound the diagnosis. MR findings of this case are presented to re-iterate the benignity of this disease process and obviate the need for further invasive procedures.

Surgical Management and Considerations for Patients with Localized High-Risk Prostate Cancer.

OPINION STATEMENT: Localized high-risk (HR) prostate cancer (PCa) is a heterogenous disease state with a wide range of presentations and outcomes. Historically, non-surgical management with radiotherapy and androgen deprivation therapy was the treatment option of choice. However, surgical resection with radical prostatectomy (RP) and pelvic lymph node dissection (PLND) is increasingly utilized as a primary treatment modality for patients with HRPCa. Recent studies have demonstrated that surgery is an equivalent treatment option in select patients with the potential to avoid the side effects from androgen deprivation therapy and radiotherapy combined. Advances in imaging techniques and biomarkers have also improved staging and patient selection for surgical resection. Advances in robotic surgical technology grant surgeons various techniques to perform RP, even in patients with HR disease, which can reduce the morbidity of the procedure without sacrificing oncologic outcomes. Clinical trials are not only being performed to assess the safety and oncologic outcomes of these surgical techniques, but to also evaluate the role of surgical resection as a part of a multimodal treatment plan. Further research is needed to determine the ideal role of surgery to potentially provide a more personalized and tailored treatment plan for patients with localized HR PCa.

Development of a Strategic Initiative at MD Anderson Cancer Center to Improve Outcomes in Immune-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for many cancer types. The clinical use of ICIs is increasing rapidly, including in combinations associated with increased risk of toxicities, termed "immune-related adverse events" (irAEs). Therefore, MD Anderson Cancer Center (MDACC) in Houston, Texas has proactively responded by developing a priority endeavor known as the Immuno-Oncology Toxicity (IOTOX) initiative. This strategic initiative aims to facilitate the seamless integration of key domains: (1) standardized clinical practice and innovative decision toolsets; (2) patient and provider education; and (3) a comprehensive clinical and translational research platform. The ultimate goal of this initiative is to develop and disseminate clinical best practices and biologic insights into irAEs to improve outcomes of patients with irAEs at MDACC and in the wider oncology community.

Evaluation of the Aggressive-Variant Prostate Cancer Molecular Signature in Clinical Laboratory Improvement Amendments (CLIA) Environments.

Aggressive-variant prostate cancers (AVPCs) are a subset of metastatic castrate-resistant prostate cancers (mCRPCs) characterized by defects in ≥ two of three of TP53, RB1, and PTEN (AVPCm), a profile linked to lineage plasticity, androgen indifference, and platinum sensitivity. Men with mCRPC undergoing biopsies for progression were assessed for AVPCm using immunohistochemistry (IHC), next-generation sequencing (NGS) of solid tumor DNA (stDNA), and NGS of circulating tumor DNA (ctDNA) assays in CLIA-certified labs. Biopsy characteristics, turnaround times, inter-reader concordance, and inter-assay concordance were assessed. AVPCm was detected in 13 (27%) patients via IHC, two (6%) based on stDNA, and seven (39%) based on ctDNA. The concordance of the IHC reads between pathologists was variable. IHC had a higher detection rate of AVPCm+ tumors with the shortest turnaround times. stDNA had challenges with copy number loss detection, limiting its detection rate. ctDNA detected the greatest proportion of AVPCm+ tumors but had a low tumor content in two thirds of patients. These data show the operational characteristics of AVPCm detection using various assays, and inform trial design using AVPCm as a criterion for patient selection or stratification.

Cancer Cell-Extrinsic Roles for the Androgen Receptor in Prostate Cancer.

Given the central role of the androgen receptor (AR) in prostate cancer cell biology, AR-targeted therapies have been the backbone of prostate cancer treatment for over 50 years. New data indicate that AR is expressed in additional cell types within the tumor microenvironment. Moreover, targeting AR for the treatment of prostate cancer has established side effects such as bone complications and an increased risk of developing cardiometabolic disease, indicating broader roles for AR. With the advent of novel technologies, such as single-cell approaches and advances in preclinical modeling, AR has been identified to have clinically significant functions in other cell types. In this mini-review, we describe new cancer cell-extrinsic roles for AR within the tumor microenvironment as well as systemic effects that collectively impact prostate cancer progression and patient outcomes.

Impact of Selective Immunosuppressive Therapy on Subsequent Immune-Related Adverse Events After Immune Checkpoint Inhibitor-Induced Colitis Treatment.

OBJECTIVES: Immune checkpoint inhibitors (ICI) can cause immune-related adverse events (irAEs) such as colitis. irAEs can be managed by selective immunosuppressive therapy (SIT) agents such as infliximab and vedolizumab. We aimed to elucidate the incidence of subsequent new irAEs after exposure to SIT by describing patients' clinical course. METHODS: We conducted a retrospective chart review of adult patients at a tertiary cancer center diagnosed with ICI-mediated colitis (IMC) treated with SIT from February 2013 through October 2021. Patients' clinical courses, treatments, and outcomes of new irAEs after SIT were collected and analyzed. RESULTS: The study included 156 patients. Most were male (67.3%), 44.8% had melanoma, and 43.5% received anti-PD1/L1 ICIs. For IMC treatment, 51.9% received infliximab and 37.8% received vedolizumab. Twenty-six patients (16.6%) resumed ICI treatment after their colitis event. Twenty-five patients (16%) developed a new irAE after receiving SIT. The most common new irAE involved skin (44%), and most (60%) were treated with steroids. Higher diarrhea grade and ≥2 doses of SIT were associated with lower incidence of post-SIT irAEs ( P =0.038, P =0.050). However, the type of SIT or individual dosage of infliximab did not affect the occurrence of subsequent irAEs. CONCLUSIONS: New irAEs usually occur more than 6 months after SIT completion for initial colitis event. Severe diarrhea grade and higher number of SIT infusions appeared to have protective effect to lower the occurrence of new irAEs. Otherwise, the type of SIT or individual dosage of infliximab did not affect the occurrence of subsequent irAEs.

Immune checkpoint therapy-current perspectives and future directions.

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.

Immune and pathologic responses in patients with localized prostate cancer who received daratumumab (anti-CD38) or edicotinib (CSF-1R inhibitor).

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.

International multicenter study comparing COVID-19 in patients with cancer to patients without cancer: Impact of risk factors and treatment modalities on survivorship.

Background: In this international multicenter study, we aimed to determine the independent risk factors associated with increased 30 day mortality and the impact of cancer and novel treatment modalities in a large group of patients with and without cancer with COVID-19 from multiple countries. Methods: We retrospectively collected de-identified data on a cohort of patients with and without cancer diagnosed with COVID-19 between January and November 2020 from 16 international centers. Results: We analyzed 3966 COVID-19 confirmed patients, 1115 with cancer and 2851 without cancer patients. Patients with cancer were more likely to be pancytopenic and have a smoking history, pulmonary disorders, hypertension, diabetes mellitus, and corticosteroid use in the preceding 2 wk (p≤0.01). In addition, they were more likely to present with higher inflammatory biomarkers (D-dimer, ferritin, and procalcitonin) but were less likely to present with clinical symptoms (p≤0.01). By country-adjusted multivariable logistic regression analyses, cancer was not found to be an independent risk factor for 30 day mortality (p=0.18), whereas lymphopenia was independently associated with increased mortality in all patients and in patients with cancer. Older age (≥65y) was the strongest predictor of 30 day mortality in all patients (OR = 4.47, p<0.0001). Remdesivir was the only therapeutic agent independently associated with decreased 30 day mortality (OR = 0.64, p=0.036). Among patients on low-flow oxygen at admission, patients who received remdesivir had a lower 30 day mortality rate than those who did not (5.9 vs 17.6%; p=0.03). Conclusions: Increased 30 day all-cause mortality from COVID-19 was not independently associated with cancer but was independently associated with lymphopenia often observed in hematolgic malignancy. Remdesivir, particularly in patients with cancer receiving low-flow oxygen, can reduce 30 day all-cause mortality. Funding: National Cancer Institute and National Institutes of Health.

Characteristics and outcomes of cancer patients with pre-existing microscopic colitis after exposure to PD-1 and PD-L1 inhibitors.

PURPOSE: Immune checkpoint inhibitors (ICIs) are frequently associated with adverse events, often affecting the gastrointestinal tract. We conducted this study to determine the characteristics and outcomes of cancer patients with pre-existing microscopic colitis (MC) who underwent ICI treatment. METHODS: In this retrospective study, we identified 10 patients with pre-existing MC who received ICIs at our center 01/2010-06/2020. Clinical characteristics and disease outcomes were recorded. RESULTS: Of 124 screened patients with MC before ICI exposure, 10 had sufficient data to be included in the study. Melanoma (40%) and lung cancer (30%) were the most prevalent cancer types, with 70% of stage IV cancer. Patients received either anti-programmed death 1 regimen (8, 80%) or anti-programmed death ligand 1 agent (2, 20%). Six patients (60%) had collagenous colitis, and 4 (40%) had lymphocytic colitis. The median time from MC diagnosis to ICI initiation was 4 years, with 1 patient on budesonide within 2 months of ICI initiation. Eight patients (80%) developed colitis exacerbations after ICI  and required selective immunosuppression. One patient received a compassionate-use fecal transplantation. The median time from ICI to colitis exacerbation was 14 days, with 40% and 50% of patients experiencing grade 3 diarrhea and grade 2 colitis, respectively, leading to hospitalization in 3 patients. Six patients received steroids and vedolizumab with no colitis recurrence. Of 8 patients who had colitis exacerbation, 6 resumed ICI therapy afterward; with 5 receiving concomitant vedolizumab for secondary prophylaxis. CONCLUSION: Our findings suggest that ICI exposure increases the risk of exacerbation of underlying colitis necessitating and responding to potent immunosuppression therapy.

Use of behavioural change taxonomies in systematic reviews and meta-analyses regarding obesity management.

We investigated the prevalence of behavioural change taxonomies in systematic reviews and meta-analyses related to obesity management. In addition, we analysed the funding sources, author conflicts of interest statements, risk of bias, and favorability of the results in such studies to determine if there was a relationship between methodological quality and taxonomy use. We searched several databases including MEDLINE, Epistemonikos, Cochrane EDSR, Pubmed and Embase for systematic reviews and meta-analyses regarding the behavioural treatment of obesity. Screening and data extraction was performed in a masked, duplicate fashion. We performed statistical analyses to determine any significant association between use of taxonomy and study characteristics. Fifteen (of 186; 8.06%) systematic reviews used a taxonomy-nine used the BCTTv1, three used OXFAB, two used the CALO-RE and one used "Taxonomy of choice architecture techniques." Most interventions that referenced a taxonomy were self-mediated (6/60, 10%). Behavioural change taxonomies were mentioned in 10 (of 87, 11.49%) studies with a public funding source. Of the studies with favourable results, 14 studies (of 181, 7.73%) referred to a taxonomy. We found no statistically significant relationships between use of taxonomy and study characteristics. We found that systematic reviews regarding the management of obesity rarely mention a behavioural change taxonomy. Given the global burden of obesity, it is crucial that behavioural change techniques are reproducible and translatable. We recommend that researchers look further into how taxonomies affect the quality and reproducibility of behavioural interventions in an effort to improve patient outcomes.

International Multicenter Study Comparing Cancer to Non-Cancer Patients with COVID-19: Impact of Risk Factors and Treatment Modalities on Survivorship.

Background: In this international multicenter study we aimed to determine the independent risk factors associated with increased 30-day mortality and the impact of novel treatment modalities in a large group of cancer and non-cancer patients with COVID-19 from multiple countries. Methods: We retrospectively collected de-identified data on a cohort of cancer and non-cancer patients diagnosed with COVID-19 between January and November 2020, from 16 international centers. Results: We analyzed 3966 COVID-19 confirmed patients, 1115 cancer and 2851 non-cancer patients. Cancer patients were more likely to be pancytopenic, and have a smoking history, pulmonary disorders, hypertension, diabetes mellitus, and corticosteroid use in the preceding two weeks (p≤0.01). In addition, they were more likely to present with higher inflammatory biomarkers (D-dimer, ferritin and procalcitonin), but were less likely to present with clinical symptoms (p≤0.01). By multivariable logistic regression analysis, cancer was an independent risk factor for 30-day mortality (OR 1.46; 95% CI 1.03 to 2.07; p=0.035). Older age (≥65 years) was the strongest predictor of 30-day mortality in all patients (OR 4.55; 95% CI 3.34 to6.20; p< 0.0001). Remdesivir was the only therapeutic agent independently associated with decreased 30-day mortality (OR 0.58; CI 0.39-0.88; p=0.009). Among patients on low-flow oxygen at admission, patients who received remdesivir had a lower 30-day mortality rate than those who did not (5.9% vs 17.6%; p=0.03). Conclusions: Cancer is an independent risk factor for increased 30-day all-cause mortality from COVID-19. Remdesivir, particularly in patients receiving low-flow oxygen, can reduce 30-day all-cause mortality. Condensed Abstract: In this large multicenter worldwide study of 4015 patients with COVID-19 that included 1115 patients with cancer, we found that cancer is an independent risk factor for increased 30-day all-cause mortality. Remdesivir is a promising treatment modality to reduce 30-day all-cause mortality.

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

The addition of atezolizumab (anti-PD-L1) to enzalutamide (androgen receptor antagonist) did not prolong survival in metastatic prostate cancer.1 Efficacy with immunotherapies in prostate cancer will require additional studies to elucidate and target mechanisms of resistance within the prostate tumor microenvironment.

A composite T cell biomarker in pre-treatment blood samples correlates with detection of immune-related adverse events.

Finding biomarkers for predicting anti-tumor responses and immune-related adverse events (irAEs) with immune checkpoint therapy remains a challenge. Lozano et al. have developed a composite biomarker score that includes the frequency of effector-memory CD4 T cells and TCR clonality of CD4 T cells in peripheral blood as a potentially predictive biomarker of irAEs.

Analysis of Systematic Reviews in Clinical Practice Guidelines for Head and Neck Cancer.

OBJECTIVE: Clinical practice guidelines (CPGs) are essential to clinical decision-making as their recommendations are supported by published literature. Systematic reviews are considered the highest quality of evidence used to underpin these guidelines. However, research to support these recommendations may lack compliance to quality reporting among systematic reviews (SRs). Here, we aim to evaluate the quality of SRs underpinning CPG recommendations for the management of head and neck cancer (HNC). STUDY DESIGN: Retrospective cross-sectional analysis. METHODS: Using PubMed, we searched for CPGs pertinent to the management of head and neck cancer published between January 2017 and May 2021. Relevant guidelines were analyzed for all SRs. Cited SRs in CPGs were evaluated using A Measurement Tool to Assess Systematic Reviews-2 (AMSTAR-2) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) instruments. Study characteristics were extracted in a masked triplicate fashion. RESULTS: A total of 16 CPGs and 142 unique SRs were included in our study. PRISMA completion ranged from 67.15% to 87.65% across CPGs with a mean of 76.41% (SD = 16.9). AMSTAR-2 completion ranged from 34.38% to 84.38% across CPGs with a mean of 67.55% (SD = 20.9) among all SRs. The lowest rated items included funding sources and publication bias. A higher score was achieved in SR done by Cochrane group and it was only 2.11% (3/142) of all SR's quoted in CPG. CONCLUSION: Adherence to AMSTAR-2 and PRISMA items exhibits a variation among SRs cited in CPGs for the management of HNC. The mature underpinning CPG recommendation of SRs cited as supportive evidence could be enhanced in reporting quality. LEVEL OF EVIDENCE: NA Laryngoscope, 132:1976-1983, 2022.

Telemedicine for pediatric orthopedic visits: evaluating usability and satisfaction.

The purpose of this study is to evaluate usability and patient satisfaction with telemedicine in pediatric orthopedics using validated questionnaires and to identify demographic and clinical factors that may impact these ratings. All caregivers of patients who had telemedicine visits with a single fellowship-trained pediatric orthopedic surgeon between 23 March 2020 and 3 June 2020 were eligible to participate. Patient Satisfaction Questionnaire (PSQ) and the Telehealth Usability Questionnaire (TUQ) rated on a 4-point Likert scale (1 = poor, 2 = fair, 3 = good and 4 = excellent) were used. Additional information regarding the level of education, mode of transportation, technology usage, demographics, visit diagnosis and length of visit were collected. Quantitative analysis was performed. A total of 68.6% (83/121) of the visits were done via telemedicine. Around 46 surveys were completed with a response rate of 55.4% (46/83). The PSQ mean score was 3.63 ± 0.39 with non-English-speaking caregivers scoring lower compared to their English-speaking counterparts (3.4 ± 0.47 vs. 3.72 ± 0.33; P = 0.017). PSQ mean score increased with increasing length of visit (r = 0.352; P = 0.018). A total of 86.8% (839/966) of all TUQ's responses were good to excellent with 89.1% (41/46) of responders were satisfied with telemedicine and 91.3% (42/46) would use it again. Although the topic is an evolving one, and a lot of changes should be expected in the future, certain characteristics such as primary language and length of visit may affect the levels of satisfaction with the use of telemedicine in pediatric orthopedics. Knowledge regarding satisfaction ratings may allow orthopedic surgeons to improve patient care delivered through this technology. Level of Evidence: IV.

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.

BACKGROUND: Immune 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. HYPOTHESIS: Combined anti-CTLA-4 (tremelimumab) plus anti-PD-L1 (durvalumab) is safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone. PATIENTS AND METHODS: In 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. RESULTS: Twenty-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. CONCLUSIONS: Tremelimumab 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 NUMBER: NCT03204812.