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Checkpoint inhibitors targeting PD-1/PD-L1, such as pembrolizumab, can be effective in a small population of biomarker-selected patients with metastatic prostate cancer (mPC), as has been demonstrated by small case series. The objective of this study is to help identify which biomarker-selected patients are most likely to benefit from pembrolizumab and estimate their likelihood of response. This is a single-center study in which we analyzed clinical data of 18 patients with mPC who were treated with pembrolizumab for a biomarker-driven indication. We found that 38.9% of patients showed a 50% or greater decline in PSA, all of whom had high microsatellite instability (MSI-H). One patient with MSI-H and high tumor mutation burden (TMB-H) had 100% decline in PSA and remained on pembrolizumab after 47 months. Neither MSI-H nor TMB-H, however, was sufficient for response. These results support biomarker testing for all patients with mPC and use of immunotherapy in select populations.

A wide variety of therapeutic approaches and technologies for delivering therapeutic agents have been investigated for treating cancer. Recently, immunotherapy has achieved success in cancer treatment. Successful clinical results of immunotherapeutic approaches for cancer treatment were led by antibodies targeting immune checkpoints, and many have advanced through clinical trials and obtained FDA approval. A major opportunity remains for the development of nucleic acid technology for cancer immunotherapy in the form of cancer vaccines, adoptive T-cell therapies, and gene regulation. However, these therapeutic approaches face many challenges related to their delivery to target cells, including their in vivo decay, the limited uptake by target cells, the requirements for nuclear penetration (in some cases), and the damage caused to healthy cells. These barriers can be avoided and resolved by utilizing advanced smart nanocarriers (e.g., lipids, polymers, spherical nucleic acids, metallic nanoparticles) that enable the efficient and selective delivery of nucleic acids to the target cells and/or tissues. Here, we review studies that have developed nanoparticle-mediated cancer immunotherapy as a technology for cancer patients. Moreover, we also investigate the crosstalk between the function of nucleic acid therapeutics in cancer immunotherapy, and we discuss how nanoparticles can be functionalized and designed to target the delivery and thus improve the efficacy, toxicity, and stability of these therapeutics.

Background Genetic analysis of advanced cancer is limited by availability of representative tissue. Biopsies of prostate cancer metastasized to bone are invasive with low quantity of tumor tissue. The prostate cancer genome is dynamic, however, with temporal heterogeneity requiring repeated evaluation as the disease evolves. Circulating tumor cells (CTCs) offer an alternative, “liquid biopsy”, though single CTC sequencing efforts are laborious with high failure rates. Methods We performed exome sequencing of matched treatment-naïve tumor tissue, castrate resistant tumor tissue, and pooled CTC samples, and compared mutations identified in each. Results Thirty-seven percent of CTC mutations were private to CTCs, one mutation was shared with treatment-naïve disease alone, and 62% of mutations were shared with castrate-resistant disease, either alone or with treatment-naïve disease. An acquired nonsense mutation in the Retinoblastoma gene, which is associated with progression to small cell cancer, was identified in castrate resistant and CTC samples, but not treatment-naïve disease. This timecourse correlated with the tumor acquiring neuroendocrine features and a change to neuroendocrine-specific therapy. Conclusions These data support the use of pooled CTCs to facilitate the genetic analysis of late stage prostate cancer.

Neuroendocrine prostate cancer is complex, comprising a wide spectrum of phenotypes, which has led to very different entities being inappropriately lumped together or assumed to behave like more common entities. Elucidating subtle differences is critical for treatment decision making, as this commentary describes.

Localized prostate cancers are genetically variable and frequently multifocal, comprising spatially distinct regions with multiple independently-evolving clones. To date there is no understanding of whether this variability can influence management decisions for patients with prostate tumors. Here, we present a single case from a clinical trial of neoadjuvant intense androgen deprivation therapy. A patient was diagnosed with a large semi-contiguous tumor by imaging, histologically composed of a large Gleason score 9 tumor with an adjacent Gleason score 7 nodule. DNA sequencing demonstrates these are two independent tumors, as only the Gleason 9 tumor harbors single-copy losses of PTEN and TP53 . The PTEN / TP53 -deficient tumor demonstrates treatment resistance, selecting for subclones with mutations to the remaining copies of PTEN and TP53 , while the Gleason 7 PTEN -intact tumor is almost entirely ablated. These findings indicate that spatiogenetic variability is a major confounder for personalized treatment of patients with prostate cancer. Prostate cancer is often a multifocal disease but how best to manage this clinically remains unclear. Here, the authors report a single case study of a patient with two genetically diverse tumours which showed differential response to therapy.

Understanding the developmental relationship between indolent and aggressive tumors is central to understanding disease progression and making treatment decisions. For example, most men diagnosed with prostate cancer have clinically indolent disease and die from other causes. Overtreatment of prostate cancer remains a concern. Here we use laser microdissection followed by exome sequencing of low‐ and high‐grade prostate cancer foci from four subjects, and metastatic disease from two of those subjects, to evaluate the molecular relationship of coincident cancer foci. Seventy of 79 (87%) high‐confidence somatic mutations in low‐grade disease were private to low‐grade foci. In contrast, high‐grade foci and metastases harbored many of the same mutations. In cases in which there was a metastatic focus, 15 of 80 (19%) high‐confidence somatic mutations in high‐grade foci were private. Seven of the 80 (9%) were shared with low‐grade foci and 65 (82%) were shared with metastatic foci. Notably, mutations in cancer‐associated genes and the p53 signaling pathway were found exclusively in high‐grade foci and metastases. The pattern of mutations is consistent with early divergence between low‐ and high‐grade foci and late divergence between high‐grade foci and metastases. These data provide insights into the development of high‐grade and metastatic prostate cancer. The overwhelming majority of somatic mutations in coincident low and high grade prostate cancer foci are private, suggesting these foci diverge early from a common progenitor. In contrast, synchronous metastatic disease contains few mutations not already present in high grade prostate cancer foci.

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 .

Background Desmoplastic small round cell tumor is a rare sarcoma type with poor prognosis for which there is no standard of care. It primarily affects adolescents and young adults and treatment is both multimodal and challenging due to the aggressive nature of the disease. Case Presentation we describe a case of a 27-year-old male who presented with hematuria and a five-centimeter mass on his bladder wall. His case details an especially challenging diagnosis as the pathology and IHC raised the suspicion for a poorly differentiated urothelial carcinoma until next-generation sequencing revealed the ESWR1::WT1 fusion gene rearrangement pathognomonic for desmoplastic small round cell tumor. After failing multiple lines of chemotherapy and also pembrolizumab, the patient was started on enfortumab-vedotin (EV), an antibody-drug conjugate targeting Nectin-4. Patient sustained partial response and documented disease control with clinical benefit for 23 months. Later, IHC staining of the tumor for nectin-4 was found to be moderately positive. Conclusion This case report is the first documented usage of EV in the management of a desmoplastic small round cell tumor case and gives light to a new potential therapeutic strategy for this rare and aggressive tumor.

Background Many current therapies for metastatic castration-resistant prostate cancer (mCRPC) are aimed at AR signaling; however, resistance to these therapies is inevitable. To personalize CRPC therapy in an individual with clinical progression despite maximal AR signaling blockade, it is important to characterize the status of AR activity within their cancer. Biopsies of bone metastases are invasive and frequently fail to yield sufficient tissue for further study. Evaluation of circulating tumor cells (CTCs) offers an alternative, minimally invasive mechanism to characterize and study late-stage disease. The goal of this study was to evaluate the utility of CTC interrogation with respect to the AR as a potential novel therapeutic biomarker in patients with mCRPC. Methods Fifteen mL of whole blood was collected from patients with progressive, metastatic mCRPC, the mononuclear cell portion was isolated, and fluorescence-activated cell sorting (FACS) was used to isolate and evaluate CTCs. A novel protocol was optimized to use ImageStreamX to quantitatively analyze AR expression and subcellular localization within CTCs. Co-expression of AR and the proliferation marker Ki67 was also determined using ImageStreamX. Results We found inter-patient and intra-patient heterogeneity in expression and localization of AR. Increased AR expression and nuclear localization are associated with elevated co-expression of Ki-67, consistent with the continued role for AR in castration-resistant disease. Despite intra-patient heterogeneity, CTCs from patients with prior exposure to abiraterone had increased AR expression compared to CTCs from patients who were abiraterone-naïve. Conclusions As our toolbox for targeting AR function expands, our ability to evaluate AR expression and function within tumor samples from patients with late-stage disease will likely be a critical component of the personalized management of advanced prostate cancer. AR expression and nuclear localization varies within patients and between patients; however it remains associated with markers of proliferation. This supports a molecularly diverse AR-centric pathobiology imparting castration-resistance.

Abstract Background Despite advances in the treatment of metastatic ccRCC, few patients are cured. Therapies exploiting novel targets are needed. Antigen screening identified ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase family member 3) as having consistent high expression in ccRCC and low expression in normal tissue. ENPP3 is a transmembrane ectoenzyme involved in hydrolysis of extracellular nucleotides. XmAb819 is a 2 + 1 bispecific antibody with high-avidity bivalent ENPP3 binding and mid-affinity monovalent CD3 binding. XmAb819 is engineered for preferential engagement and T cell-mediated cytolysis of high ENPP3-expressing cancer cells. Methods This is a multicenter, open-label, dose-escalation/expansion study enrolling up to 190 participants with advanced ccRCC. The primary objective is safety and tolerability; the secondary objective is preliminary anti-tumor activity. Part A, dose escalation, establishes a priming dose, step-up dose(s), a cohort-limit dose, and the dosing schedule for both intravenous (IV) and subcutaneous (SC) administration. Part B, dose expansion, evaluates the safety and efficacy of the recommended dose established in Part A. All subjects will have disease progression on standard-of-care therapies. XmAb819 will be administered weekly; cohort-limit doses will be administered in 21-day cycles until disease progression or unacceptable toxicity. Adverse events are graded using CTCAE v5.0; CRS using ASTCT Consensus Grading (Lee, 2019). Efficacy is assessed per investigator using RECIST v1.1. Enrollment and dose escalation continues in both the IV and SC cohorts. Significance & Vision XmAb819 is an investigational, novel bispecific T-cell engager engineered to bind and kill high ENPP3-expressing cells. The XmAb819-01 study is a trial designed to enroll patients with ccRCC, a solid tumor that overexpresses ENPP3. Initial evidence of anti-tumor activity in ccRCC has been observed, and tolerability supports continued dose escalation. Trial Schema The dosing period consists of priming, step-up, and target doses.