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Immune checkpoint blockade (ICB) monotherapy has produced limited benefit in breast cancer (BC) with response rates (RR) ranging from 5 to 23%. Combination ICB improved RR and progression free survival (PFS) resulting in atezolizumab + nab-paclitaxel receiving FDA accelerated approval for programmed cell death ligand 1 (PD-L1) positive, triple negative breast cancers (TNBC). BC has historically been considered immunologically quiet with most having a low mutational burden, low PD-L1 expression, defective antigen presentation machinery, and immuosuppressive signals in the tumor microenvironment (TME). An approach using a combination of immuno-oncology (IO) agents including ICB, immunomodulators and vaccines may shift the TME to allow for improved antigen presentation, the release of immunostimulatory cytokines, more immunogenic cell death and increased PD-L1 expression. The transcription factor brachyury plays an important role in breast tumor plasticity. High brachyury expression is associated with treatment resistance and a worse prognosis. Entinostat is a histone deacetylase inhibitor that has activity in multiple breast cancer subtypes. Preclinical data demonstrates entinostat upregulates MHC, enhances immune-mediated lysis and upregulates PD-L1 expression through epigenetic modification. Bintrafusp alfa is a bifunctional protein composed of the extracellular domain of the TGF-βRII receptor (TGF-β“trap”) fused to a human IgG1. Preclinical data shows bintrafusp alpha treatment increases T-cell trafficking, antigen-specific CD8+ T-cell lysis and NK cell activation. Monotherapy clinical studies with these agents have produced modest results in solid tumors, including BC. Preclinical data evaluating combinations of these agents shows a reduction in in tumor size, improved antigen-specific T-cell responses, reduced regulatory T cells, increased CD8+T-cells, and increased PD-L1 expression. We propose the stepwise addition of BN-Brachyury, Bintrafusp alfa, T-DM1 and Entinostat in advanced BC. This phase Ib study will assess efficacy and safety of the regimen and has three cohorts: Cohort 1(TNBC) will receive BN-Brachyury + Bintrafusp alfa. Cohort 2 (HER2+) will receive T-DM1 + BN-Brachyury + Bintrafusp alfa +/- entinostat. After safety is established in Cohort 2, patients in Cohort 3 (HER2+) will be assigned to receive T-DM1 + BN-Brachyury + Bintrafusp alfa +/- entinostat. Responses are evaluated every 2 cycles (6 weeks). Patients in Cohorts 2 and 3 will undergo research biopsies -baseline and after 2 cycles to evaluate changes within TME. Peripheral immune responses will be evaluated at selected time points. All patients must have measurable disease and HER2+ patients must have biopsiable disease. >1 prior treatment is required. Asymptomatic or brain metastases treated > 6 weeks are allowed. Well controlled HIV, HBV or treated HCV is allowed. Exclusion criteria include symptomatic brain metastases or clinically significant bleeding ( Citation Format: Margaret E Gatti-Mays, Claudia Palena, Sofia R Gameiro, Renee N Donahue, Caroline Jochems, Seth Steinberg, Stan Lipkowitz, Alexandra Zimmer, Deneise Francis, Julius Strauss, Houssein Abdul Sater, Lisa Cordes, Jason Redman, Fatima Karzai, Marijo Bilusic, Ravi A Madan, James L Gulley, Jeffrey Schlom. A phase Ib trial of sequential combinations of BN-brachyury, entinostat, ado-trastuzumab emtansine (T-DM1) and bintrafusp alfa (M7824) in advanced stage breast cancer (BrEAsT) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-01.

PURPOSE Despite decreased screening-based detection of clinically insignificant tumors, most diagnosed prostate cancers are still indolent, indicating a need for better strategies for detection of clinically significant disease before treatment. We hypothesized that patients with detectable circulating tumor DNA (ctDNA) were more likely to harbor aggressive disease. METHODS We applied ultra-low-pass whole-genome sequencing to profile cell-free DNA from 112 patients diagnosed with localized prostate cancer and performed targeted resequencing of plasma DNA for somatic mutations previously identified in matched solid tumor in nine cases. We also performed similar analyses of data from patients with metastatic prostate cancer. RESULTS In all cases of localized prostate cancer, even in clinically high-risk patients who subsequently had recurrent disease, ultra-low-pass whole-genome sequencing and targeted resequencing did not detect ctDNA in plasma acquired before surgery or before recurrence. In contrast, using both approaches, ctDNA was detected in patients with metastatic prostate cancer. CONCLUSION Our findings demonstrate clear differences between localized and advanced prostate cancer with respect to the dissemination and detectability of ctDNA. Because allele-specific alterations in ctDNA are below the threshold for detection in localized prostate cancer, other approaches to identify cell-free nucleic acids of tumor origin may demonstrate better specificity for aggressive disease.

SUMMARYPro-inflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution remain yet to be fully elucidated. Previously we identified a critical role for combined constitutive JAK/STAT and aberrant NF-κB pro-inflammatory signaling in myelofibrosis development. Using single-cell transcriptional and cytokine-secretion studies of primary MF patient cells and two separate murine models of myelofibrosis, we extend this previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. MF patient hematopoietic stem/progenitor cells are enriched in a CXCL8/CXCR2 gene signature and display dose-dependent proliferation and fitness in response to exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway in MF patients at risk for continued fibrotic progression.

BACKGROUND: Management of asymptomatic primary hyperparathyroidism (PHPT) in older patients (age >50) is controversial. The 4(th) International Workshop on the Management of Asymptomatic PHPT recommends surveillance for older patients who lack objective signs of disease, whereas The American Association of Endocrine Surgeons (AAES) guidelines recommend consideration of parathyroidectomy for patients of any age with subjective constitutional, neuropsychiatric, or cognitive symptoms. Therefore, the primary objective of this study was to evaluate the association between patient age and both practice patterns and outcomes in the management of patients with sporadic PHPT. METHODS: The Collaborative Endocrine Surgery Quality Improvement Program (CESQIP) database was queried for all adults (age ≥18) who underwent an index parathyroidectomy for sporadic primary hyperparathyroidism between 2014-2020. Associations between patient age (≤50 years vs. >50 years) and both practice patterns and outcomes were evaluated separately using adjusted multivariable logistic and multinomial regression models. RESULTS: Of 9,938 patients who underwent parathyroidectomy, 8,080 (81.3%) were >50 years old and 1,858 (18.7%) were ≤50. Of this cohort, 17% of older patients and 26% of younger patients presented with only subjective symptoms. Compared to younger patients, older patients were more likely to have an objective indication for parathyroidectomy (aOR=1.8, 95%CI: 1.6-2.0, p

BackgroundProstate cancer (PC) is the most common non-cutaneous diagnosed cancer among men in USA.1 Although clinical outcomes are favorable for patients with localized disease, 20–30% of patients will develop metastatic prostate cancer (mPC) and have poor prognosis. Immunotherapy, as a single agent, provides benefit to a small subset of PC patients, which is thought to be partially due to its known cold tumor immune microenvironment (TIME). Combination studies are needed to enhance benefit.2 Prostvac is a therapeutic cancer vaccine engineered to activate an immune response against prostate-specific Antigen (PSA).3 Prostvac alone could induce systemic immune response by increasing immune-cell infiltrates in and around the tumor.4 In this study, we are exploring the effect of Prostvac in combination with nivolumab in TIME in prostate cancer.MethodsWe treated locally advanced prostate cancer patients (n=6) undergoing radical prostatectomy (RP) with neoadjuvant Prostvac in combination with nivolumab, an immune checkpoint PD-1 inhibitor. Dynamic changes in TIME before and after treatment were studied using multiplex immunofluorescence (Opal Method). Formalin fixed paraffin-embedded sections from matched pre-treated prostate biopsies and post-treated RP samples were stained with a validated T cell panel (DAPI, CD4, CD8, FOXP3, Ki67, Pan CK and PD-L1). To analyze the data, TIME was segmented into 3 compartments: intratumoral, invasive margin and benign.ResultsCombination immunotherapy significantly increased CD4+ T cell density in the invasive margin (mean 211.5 cells/mm2 vs 592.2 cells/mm2, pConclusionsThe combination of Neoadjuvant Prostvac and nivolumab was associated with increased immune cell infiltration in a cohort of early prostate cancer patients. A broader examination of the TIME and the role immune cells undertake to control tumor growth is on-going.Trial RegistrationNCT02933255ReferencesSiegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin (Internet) 2020;70:7–3Zhao SG, Lehrer J, Chang SL, et al. The immune landscape of prostate cancer and nomination of PD-L2 as a potential therapeutic target. J Natl Cancer Inst 2018;111:301–10.Madan RA, Arlen PM, Mohebtash M, et al. Prostvac-VF: a vectorbased vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs 2009;18:1001–11Abdul Sater H, Marté JL, Donahue RN, et al. Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer. J Immunother Cancer 2020;8(1):655–64Ethics ApprovalThis study was performed in compliance with ethical standard and was approved by the NIH IRB, 17C-0007. All patients participating in this study gave an informed consent before taking part.

Metformin may have anticancer effects that are independent of its hypoglycemic effects. Retrospective studies have shown that metformin use is associated with decreased incidence of prostate cancer and prostate cancer-specific mortality. Preclinical studies suggesting additive anticancer effects of combining metformin and bicalutamide prompted this clinical trial (NCT02614859).This open-label, randomized, phase 2 trial enrolled non-diabetic patients with biochemically recurrent prostate cancer, a PSADT of 3-9 months, BMI 25 and normal testosterone. Patients were randomized 1:2 to observation for an initial 8 weeks (Arm A) or metformin 1000 mg twice daily (Arm B). Bicalutamide 50 mg/day was added after 8 weeks to both arms. The primary objective was to evaluate the number of patients with undetectable PSA ( 0.2 ng/mL) at the end of 32 weeks. Immune correlatives were assessed as exploratory endpoints.A total of 29 patients were enrolled from March 2015 to January 2020. No difference was seen between the 2 arms in the proportion of patients with undetectable PSA. Modest PSA decrease ranging from 4% to 24% were seen in 40.0% (95% CI: 19.1-64.0%) of patients with metformin monotherapy, compared to 11.1% (95% CI: 0.3-48.3%) in the observation arm. Metformin monotherapy reduced PD-1Although metformin plus bicalutamide was well tolerated, there was no improvement in rates of achieving undetectable PSA at 32 weeks. Metformin monotherapy induced modest PSA declines in 40% of patients after 8 weeks. Metformin, given alone and in combination with bicalutamide, displayed immune modifying effects, primarily within NK and T cells subsets.Trial Registration Number: NCT02614859.

BACKGROUND: The impact of the 2015 ATA guidelines on treatment for differentiated thyroid cancer (DTC) in older adults is unclear. METHODS: 60,567 adults (age≥18) with low-risk DTC diagnosed between 2010-2018 were identified using SEER-21. Annual rates of total thyroidectomy (TT), hemithyroidectomy (HT), and active surveillance (AS) were analyzed using interrupted time series stratified by age: younger adults (18-64), older adults (65-79), and the super-elderly (≥80). RESULTS: After 2015, annual rates of TT decreased by 2.6% and 1.9% in younger and older adults (p

BackgroundMVA-BN-brachyury-TRICOM is a recombinant vector-based therapeutic cancer vaccine designed to induce an immune response against brachyury. Brachyury, a transcription factor overexpressed in advanced cancers, has been associated with treatment resistance, epithelial-to-mesenchymal transition, and metastatic potential. MVA-BN-brachyury-TRICOM has demonstrated immunogenicity and safety in previous clinical trials of subcutaneously administered vaccine. Preclinical studies have suggested that intravenous administration of therapeutic vaccines can induce superior CD8+ T cell responses, higher levels of systemic cytokine release, and stronger natural killer cell activation and proliferation. This is the first-in-human study of the intravenous administration of MVA-BN-brachyury-TRICOM.MethodsBetween January 2020 and March 2021, 13 patients were treated on a phase 1, open-label, 3+3 design, dose-escalation study at the National Institutes of Health Clinical Center. The study population was adults with advanced solid tumors and was enriched for chordoma, a rare sarcoma of the notochord that overexpresses brachyury. Vaccine was administered intravenously at three DLs on days 1, 22, and 43. Blood samples were taken to assess drug pharmacokinetics and immune activation. Imaging was conducted at baseline, 1 month, and 3 months post-treatment. The primary endpoint was safety and tolerability as determined by the frequency of dose-limiting toxicities; a secondary endpoint was determination of the recommended phase 2 dose.ResultsNo dose-limiting toxicities were observed and no serious adverse events were attributed to the vaccine. Vaccine-related toxicities were consistent with class profile (ie, influenza-like symptoms). Cytokine release syndrome up to grade 2 was observed with no adverse outcomes. Dose-effect trend was observed for fever, chills/rigor, and hypotension. Efficacy analysis of objective response rate per RECIST 1.1 at the end of study showed one patient with a partial response, four with stable disease, and eight with progressive disease. Three patients with stable disease experienced clinical benefit in the form of improvement in pain. Immune correlatives showed T cell activation against brachyury and other tumor-associated cascade antigens.ConclusionsIntravenous administration of MVA-BN-brachyury-TRICOM vaccine was safe and tolerable. Maximum tolerated dose was not reached. The maximum administered dose was 109 infectious units every 3 weeks for three doses. This dose was selected as the recommended phase 2 dose.Trial registration numberNCT04134312.

Contains fulltext : 244115.pdf (Publisher’s version ) (Closed access) The novel coronavirus pandemic has radically changed the landscape of normal surgical practice. Lifesaving cancer surgery, however, remains a clinical priority, and there is an increasing need to fully define the optimal oncologic management of patients with varying stages of lung cancer, allowing prioritization of which thoracic procedures should be performed in the current era. Healthcare providers and managers should not ignore the risk of a bimodal peak of mortality in patients with lung cancer; an imminent spike due to mortality from acute coronavirus disease 2019 (COVID-19) infection, and a secondary peak reflecting an excess of cancer-related mortality among patients whose treatments were deemed less urgent, delayed, or cancelled. The European Association of Cardiothoracic Anaesthesiology and Intensive Care Thoracic Anesthesia Subspecialty group has considered these challenges and developed an updated set of expert recommendations concerning the infectious period, timing of surgery, vaccination, preoperative screening and evaluation, airway management, and ventilation of thoracic surgical patients during the COVID-19 pandemic.

BACKGROUND: The association between exposure to air pollution and papillary thyroid carcinoma (PTC) is unknown. We sought to estimate the relationship between long-term exposure to fine (diameter

SUMMARY The Borrelia spp. are tick-borne pathogenic spirochetes that include the agents of Lyme disease and relapsing fever. As part of their life cycle, the spirochetes traffic between the tick vector and the vertebrate host, which requires significant physiological changes and remodeling of their outer membranes and proteome. This crucial proteome resculpting is carried out by a diverse set of proteases, adaptor proteins, and related chaperones. Despite its small genome, Borrelia burgdorferi has dedicated a large percentage of its genome to proteolysis, including a full complement of ATP-dependent proteases. Energy-driven proteolysis appears to be an important physiological feature of this dual-life-cycle bacterium. The proteolytic arsenal of Borrelia is strategically deployed for disposal of proteins no longer required as they move from one stage to another or are transferred from one host to another. Likewise, the Borrelia spp. are systemic organisms that need to break down and move through host tissues and barriers, and so their unique proteolytic resources, both endogenous and borrowed, make movement more feasible. Both the Lyme disease and relapsing fever Borrelia spp. bind plasminogen as well as numerous components of the mammalian plasminogen-activating system. This recruitment capacity endows the spirochetes with a borrowed proteolytic competency that can lead to increased invasiveness.

Background Anaplastic prostate cancer has a poor prognosis with limited treatment options. Seven clinical features of anaplastic prostate cancer have been prospectively identified. In this phase II clinical trial, we identified mutations, including DNA-damage repair (DDR) mutations, in patients with metastatic castration-resistant prostate cancer (mCRPC), who were treated with durvalumab and olaparib, and determined how many of these patients can be described as anaplastic and the overlap between anaplastic features and DDR mutations. Methods Eligible patients with mCRPC received prior enzalutamide and/or abiraterone. Patients were treated with durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg p.o. every 12 hours until disease progression or unacceptable toxicity. Patients underwent mandatory baseline biopsies of metastatic lesions. Results Baseline characteristics were similar between anaplastic and non-anaplastic patients. Eleven patients (20%) displayed clear anaplastic features and 43 (78.2%) lacked anaplastic features. In the anaplastic group, 2/11 (18.2%) had germline DRR mutations and 4/11 (36.3%) had somatic DDR mutations. In the non-anaplastic group, 7/43 (16.3%) had germline mutations and 13/43 (30.2%) had somatic mutations. Median PFS in patients with anaplastic features (6.5 months) and without anaplastic features (5.1 months) were similar (hazard ratio [HR], 0.998, p=0.996). Conclusions Patients with and without anaplastic features appear to have similar total rates of DDR mutations and also have similar rates of somatic and germline DDR mutations. Patients with anaplastic features have a trend toward improved PFS when treated with olaparib and durvalumab compared to non-anaplastic patients. Micro-Abstract Relationships between DNA-damage repair (DDR) mutations and anaplastic features, which confers poor prognosis, are unknown. Fifty-five patients with mCRPC treated with olaparib and durvalumab were classified into anaplastic and non-anaplastic groups and had similar rates of DDR mutations. Anaplastic patients had a trend toward improved progression-free survival when treated with olaparib and durvalumab compared to non-anaplastic patients.

e17033 Background: M9241 is an immunocytokine that targets single- and double-stranded DNA which allows the treatment to localize IL-12 to necrotic tumor (Xu, CCR 2017). M9241 was well-tolerated as a monotherapy in a Phase I study with solid tumors (Strauss J, CCR 2019). Additional preclinical data has demonstrated synergy of M9241 with cytotoxic therapy. This is the first study to examine the safety of a novel combination of chemotherapy and immunocytokines in metastatic prostate cancer. Methods: This safety analysis included patients with mCSPC or mCRPC. Patients were enrolled in a 2-dose level (DL) escalation cohort of M9241 (DL 1: 12mcg/kg, DL 2: 16.8mcg/kg) combined with docetaxel (75mg/m2) with 6 patients planned per DL. A third DL of 8mcg/kg will enroll 6 more patients after the 16.8mcg/kg DL has fully enrolled. All patients were treated with ADT. Patients were initiated on treatment with docetaxel with a plan for mCSPC patients to receive six 3-week cycles of combined treatment and mCRPC patients to continue until progression or unacceptable toxicity. M9241 was given starting with the second cycle of treatment for each patient. Dose-limiting toxicity (DLT) was evaluated in the first 6 weeks after start of docetaxel (from cycle 1 day 1 through the end of the first cycle with M9241). Results: The study has enrolled 10 patients out of a planned 18 for the safety portion. Age range is 58-82 with a median of 69 years. Race distribution is 80% White and 20% Black. Gleason scores for patients were 8 (40%), 9 (40%), and 10 (20%). No DLTs were seen with either dose-level. Only 1 patient had a Grade 4 AE, neutropenia. Grade 3 toxicities included anemia, diarrhea, leukopenia, and hypotension (each occurring in 10% of the patients). The most frequent adverse events (AEs) of any grade were anemia (40%) and lymphopenia (40%), followed by fatigue (30%), diarrhea (20%), and fever (20%). Conclusions: We established a safe dose-level of M9241 at ≥ 12mcg/kg. Updated clinical data from the safety cohort (n = 18) will be presented. This demonstrates that an immunocytokine and chemotherapy can be safely combined for treatment in metastatic prostate cancer. Two planned expansion cohorts will evaluate docetaxel and M9241 in mCSPC and mCRPC, respectively. Clinical trial information: NCT04633252.

e13556 Background: Precision oncology is gradually advancing into mainstream clinical practice. Despite the significant recent growth in the number of approved biomarkers for immune and targeted therapies, demonstrating significant survival benefits, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. Methods: We developed ENLIGHT - a transcriptomics-based computational platform that identifies and utilizes clinically relevant genetic interactions (GIs) to predict a patient’s response to cancer treatments. ENLIGHT markedly extends and improves upon SELECT, a previous GI-based framework for obtaining transcriptomics-based response biomarkers. In this study, we focus on three key translational aspects: (i) the number of drugs for which predictions can be obtained (ii) defining a biomarker-based test for Personalized Medicine (PM) that would identify favorable treatments for an individual; and (iii) Improving clinical trial design by excluding a sub-population of patients likely not to respond to the treatment. A key translational feature of the approach is that it does not require training on treatment response data. Thus, in addition to its ability to predict patients' response to approved and well-studied therapies, it can predict the response to new, unexplored treatments. Results: We first tested Enlight in the PM scenario, analyzing 21 patient cohorts from diverse indications, treated with a variety of targeted and immunotherapies. The ENLIGHT treatment matching score is associated with better response with an aggregate Odds Ratio (OR) of 2.59 (95% confidence interval [1.85, 3.55], p= 3.41 e-8). Applied to the WINTHER trial data, encompassing multiple indications and individualized treatments, ENLIGHT recommendations achieved a highly remarkable OR of 11.15 ([2.3, 54.5], p = 8 e-04), demonstrating ENLIGHT’s strong predictive power across a broad spectrum of treatments and cancer types. Second, using ENLIGHT to exclude patients from clinical trials increases the trial response rate, achieving more than 90% of the response rate attainable under an optimal exclusion strategy. Conclusions: ENLIGHT is a powerful transcriptomics-based precision oncology pipeline developed by Pangea Biomed that broadly predicts response to both extant and novel targeted and immune therapies in translationally oriented, clinical terms, going beyond case-specific biomarkers.

e17046 Background: Multiple treatment options combined with androgen deprivation therapy (ADT) provide a survival advantage in mCSPC. In this prospective study, mCSPC patients were treated with docetaxel and Prostvac, a therapeutic cancer vaccine. Since initiation of the study, a phase 3 trial of Prostvac did not show independent clinical activity in metastatic castration-resistant prostate cancer. Still, this study offers a chance to evaluate responses to docetaxel-based therapy in mCSPC. More specifically, with FDA approval of prostate-specific membrane antigen (PSMA) PET imaging in just the last year, there is a paucity of data regarding the use of this scan in long-term responders to therapies for mCSPC. Methods: Eligible patients included those with mCSPC and ECOG PS of ≤ 2. As per the CHAARTED regimen, patients started docetaxel within 4 months of initiating ADT with a plan to receive 75mg/m2 for 6 cycles. Patients were randomized to receive Prostvac prior to, concurrent with, or after docetaxel. Restaging was done annually with CT and Tc99 bone scan. The study was powered to evaluate immune responses, which is being reported separately. For this analysis, patients were evaluated as one group. Ten patients are in follow up with continued PSA values of ≤ 0.2 ng/mL and 7/10 were evaluated with 18F-DCFPyL PSMA PET. Results: Seventy-three patients enrolled. Median age was 63 years with a range of 41-86 years. Race distribution was 71.6% White, 20.3% Black, 4.1% other, and 4.1% unknown. Gleason 6, 7, and 8 to 10 was 4.1%, 21.6%, and 68.9% of patients, respectively, with 5.4% being unknown. Median pre-ADT PSA was 34.75 ng/mL. Low-volume disease represented 41.1% of patients and high-volume was 58.9%. After 2 years from the start of ADT, 22% of patients had PSA values of ≤ 0.2 ng/mL. This included 37% of the low-volume group and 12% of the high-volume group. Three years from starting ADT, 14% of patients had PSA values ≤ 0.2 ng/mL (20% of the low-volume group, 9% of the high-volume group). Of the 7 patients who remain in follow-up with PSA values ≤ 0.2 ng/mL and who were evaluated with PSMA PET, median time from start of ADT was 4 years with a range of 3.5-6 years. These patients either had no evidence of disease or minimal residual findings on CT/Tc99 bone scan. Four of the 7 patients still had residual areas of uptake on PSMA PET. Conclusions: Patients treated with docetaxel for mCSPC have the potential for long-term clinical responses. In these long-term responders, despite prolonged PSA response and minimal findings on conventional CT and Tc99 scans, more than half of patients still had findings on PSMA PET imaging. Further studies are required to better understand the clinical implications of these findings and the role of PSMA PET in mCSPC. Clinical trial information: NCT02649855.

Background Despite the clinical efficacy of enzalutamide monotherapy in patients with advanced prostate cancer, therapeutic resistance and disease progression are inevitable. We proposed a study to evaluate NLG207, a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor camptothecin, in combination with enzalutamide, in patients with metastatic castration-resistant prostate cancer (mCRPC) following progression on enzalutamide. Methods This was a single-arm, optimal two-stage, phase II study to evaluate the efficacy of NLG207 in combination with enzalutamide in patients with mCRPC who received prior enzalutamide. A lead-in dose escalation evaluated the recommended phase 2 dose of NLG207 in combination with enzalutamide. Patients received NLG207 via IV infusion every 2 weeks and enzalutamide 160 mg orally once daily. Results Between March 2019 and June 2021, four patients were accrued to the lead-in dose escalation. Two of the four patients were evaluable and both experienced DLTs at the NLG207 12 mg/m2 dose level; one DLT was related to a dose delay for noninfective cystitis and myelosuppression, the other a grade 3 noninfective cystitis. Further evaluation of NLG207 in combination with enzalutamide was halted and the study was ultimately terminated. PSA declines from baseline were observed in two patients. Conclusion NLG207 12 mg/m2 in combination with enzalutamide was not well tolerated in patients with mCRPC following several lines of the standard of care therapy. ClinicalTrials.gov Identifier NCT03531827.

Background Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations. Methods Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations. Results Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5–16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7–72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8–18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response. Conclusions Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities. Trial registration ClinicalTrials.gov identifier: NCT02484404. Electronic supplementary material The online version of this article (10.1186/s40425-018-0463-2) contains supplementary material, which is available to authorized users.

Breast tumors commonly harbor low mutational burden, low PD-L1 expression, defective antigen processing/presentation, and an immunosuppressive tumor microenvironment (TME). In a malignancy mostly refractory to checkpoint blockade, there is an unmet clinical need for novel combination approaches that increase tumor immune infiltration and tumor control. Preclinical data have guided the development of this clinical trial combining 1) BN-Brachyury (a poxvirus vaccine platform encoding the tumor associated antigen brachyury), 2) bintrafusp alfa (a bifunctional protein composed of the extracellular domain of the TGF-βRII receptor (TGFβ “trap”) fused to a human IgG1 anti-PD-L1), 3), entinostat (a class I histone deacetylase inhibitor), and 4) T-DM1 (ado-trastuzumab emtansine, a standard of care antibody-drug conjugate targeting HER2). We hypothesize that this tetratherapy will induce a robust immune response against HER2+ breast cancer with improved response rates through 1) expanding tumor antigen-specific effector T cells, natural killer cells, and immunostimulatory dendritic cells, 2) improving antigen presentation, and 3) decreasing inhibitory cytokines, regulatory T cells, and myeloid-derived suppressor cells. In an orthotopic HER2+ murine breast cancer model, tetratherapy induced high levels of antigen-specific T cell responses, tumor CD8+ T cell/Treg ratio, and augmented the presence of IFNγ- or TNFα-producing CD8+ T cells and IFNγ/TNFα bifunctional CD8+ T cells with increased cytokine production. Similar effects were observed in tumor CD4+ effector T cells. Based on this data, a phase 1b clinical trial evaluating the stepwise addition of BN-Brachyury, bintrafusp alfa, T-DM1 and entinostat in advanced breast cancer was designed. Arm 1 (TNBC) receives BN-Brachyury + bintrafusp alfa. Arm 2 (HER2+) receives T-DM1 + BN-Brachyury + bintrafusp alfa. After safety is established in Arm 2, Arm 3 (HER2+) will receive T-DM1 + BN-Brachyury + bintrafusp alfa + entinostat. Reimaging will occur every 2 cycles (1 cycle = 21 days). Arms 2 and 3 undergo research biopsies at baseline and after 2 cycles to evaluate changes within the TME. Peripheral immune responses will be evaluated. Co-primary objectives are response rate and safety. All arms employ a safety assessment in the initial six patients and a 2-stage Simon design for clinical efficacy (Arm 1 if ≥ three responses of eight then expand to 13 patients; Arms 2 and 3 if ≥ four responses of 14 then expand to 19 patients per arm). Secondary objectives include progression-free survival and changes in tumor infiltrating lymphocytes. Exploratory analyses include changes in peripheral immune cells and cytokines. To our knowledge, the combination of a vaccine, an anti-PD-L1 antibody, entinostat, and T-DM1 has not been previously evaluated in the preclinical or clinical setting. This trial (NCT04296942) is open at the National Cancer Institute (Bethesda, MD).

Background Tertiary hyperparathyroidism after kidney transplantation has been associated with graft dysfunction, cardiovascular morbidity, and osteopenia; however, its true prevalence is unclear. The objective of our study was to evaluate the prevalence of and risk factors for tertiary hyperparathyroidism. Methods A prospective cohort of 849 adult kidney transplantation recipients (December 2008–February 2020) was used to estimate the prevalence of hyperparathyroidism 1-year post-kidney transplant. Tertiary hyperparathyroidism was defined as hypercalcemia (≥10mg/dL) and hyperparathyroidism (parathyroid hormone≥70pg/mL) 1-year post-kidney transplantation. Modified Poisson regression models were used to evaluate risk factors associated with the development of both persistent hyperparathyroidism and tertiary hyperparathyroidism. Results Among kidney transplantation recipients, 524 (61.7%) had persistent hyperparathyroidism and 182 (21.5%) had tertiary hyperparathyroidism at 1-year post-kidney transplantation. Calcimimetic use before kidney transplantation was associated with 1.30-fold higher risk of persistent hyperparathyroidism (adjusted prevalence ratio = 1.30, 95% CI: 1.12–1.51) and 1.84-fold higher risk of tertiary hyperparathyroidism (adjusted prevalence ratio = 1.84, 95% CI: 1.25–2.72). Pre-kidney transplantation parathyroid hormone ≥300 pg/mL was associated with 1.49-fold higher risk of persistent hyperparathyroidism (adjusted prevalence ratio = 1.49, 95% CI = 1.19–1.85) and 2.21-fold higher risk of tertiary hyperparathyroidism (adjusted prevalence ratio = 2.21, 95% CI = 1.25-3.90). Pre–kidney transplantation tertiary hyperparathyroidism was associated with an increased risk of post-kidney transplantation tertiary hyperparathyroidism (adjusted prevalence ratio = 1.71, 95% CI = 1.29–2.27), but not persistent hyperparathyroidism. Furthermore, 73.0% of patients with persistent hyperparathyroidism and 61.5% with tertiary hyperparathyroidism did not receive any treatment at 1-year post-kidney transplantation. Conclusion Persistent hyperparathyroidism affected 61.7% and tertiary hyperparathyroidism affected 21.5% of kidney transplantation recipients; however, the majority of patients were not treated. Pre–kidney transplantation parathyroid hormone levels ≥300pg/mL and the use of calcimimetics are associated with the development of tertiary hyperparathyroidism. These findings encourage the re-evaluation of recommended pre-kidney transplantation parathyroid hormone thresholds and reconsideration of pre-kidney transplantation secondary hyperparathyroidism treatments to avoid the adverse sequelae of tertiary hyperparathyroidism in kidney transplantation recipients.