Immune Modulation with RANKL Blockade through Denosumab Treatment in Patients with Cancer.

Denosumab is a fully human mAb that binds receptor activator of NFκB ligand (RANKL). It is routinely administered to patients with cancer to reduce the incidence of new bone metastasis. RANK-RANKL interactions regulate bone turnover by controlling osteoclast recruitment, development, and activity. However, these interactions also can regulate immune cells including dendritic cells and medullary thymic epithelial cells. Inhibition of the latter results in reduced thymic negative selection of T cells and could enhance the generation of tumor-specific T cells. We examined whether administering denosumab could modify modulate circulating immune cells in patients with cancer. Blood was collected from 23 patients with prostate cancer and 3 patients with renal cell carcinoma, all of whom had advanced disease and were receiving denosumab, prior to and during denosumab treatment. Using high-dimensional mass cytometry, we found that denosumab treatment by itself induced modest effects on circulating immune cell frequency and activation. We also found minimal changes in the circulating T-cell repertoire and the frequency of new thymic emigrants with denosumab treatment. However, when we stratified patients by whether they were receiving chemotherapy and/or steroids, patients receiving these concomitant treatments showed significantly greater immune modulation, including an increase in the frequency of natural killer cells early and classical monocytes later. We also saw broad induction of CTLA-4 and TIM3 expression in circulating lymphocytes and some monocyte populations. These findings suggest that denosumab treatment by itself has modest immunomodulatory effects, but when combined with conventional cancer treatments, can lead to the induction of immunologic checkpoints. See related Spotlight by Nasrollahi and Davar, p. 383.

CD4+ CAR-T cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR-T cell therapy.

Multiple myeloma is characterized by frequent clinical relapses following conventional therapy. Recently, chimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) has been established as a treatment option for patients with relapsed or refractory disease. However, while >70% of patients initially respond to this treatment, clinical relapse and disease progression occur in most cases. Recent studies showed persistent expression of BCMA at the time of relapse, indicating that immune intrinsic mechanisms may contribute to this resistance. While there were no pre-existing T cell features associated with clinical outcomes, we found that patients with a durable response to CAR-T cell treatment had greater persistence of their CAR-T cells compared to patients with transient clinical responses. They also possessed a significantly higher proportion of CD8+ T effector memory cells. In contrast, patients with short-lived responses to treatment have increased frequencies of cytotoxic CD4+ CAR-T cells. These cells expand in vivo early after infusion but express exhaustion markers (HAVCR2 and TIGIT) and remain polyclonal. Finally, we demonstrate that non-classical monocytes are enriched in the myeloma niche and may induce CAR-T cell dysfunction through mechanisms that include TGFß. These findings shed new light on the role of cytotoxic CD4+ T cells in disease progression after CAR-T cell therapy.

Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma.

BACKGROUND: In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC. METHODS: Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality. RESULTS: In the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+ T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+ B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1-) eomesodermin (EOMES+)) CD8+ T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+ EOMES+) CD8+ T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation. CONCLUSION: Ibrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors. TRIAL REGISTRATION NUMBER: NCT02562898.

The Association Between Race and Frailty in Older Adults Presenting to a Nononcologic Urology Practice.

OBJECTIVE: To explore whether there is an association between nonwhite race and frailty among older adults presenting to an academic nononcologic urology practice. MATERIALS AND METHODS: This is a prospective study of individuals ages ≥65years presenting to a nononcologic urology practice between December 2015 and November 2016. All individuals had a Timed Up and Go Test (TUGT, where a slower TUGT time of ≥15 seconds is suggestive of frailty. TUGT times, race (white vs nonwhite), and other clinical data were extracted from the electronic medical record using direct queries. Multivariable logistic regression was used to identify the association between race and slower TUGT times while adjusting for age, gender, number of medications, body mass index, and number of urologic diagnoses. RESULTS: Among the 1715 individuals in our cohort, 33.9% were of nonwhite race and 15.3% had TUGT ≥15 seconds. A higher percentage of nonwhite individuals had TUGT times ≥15 seconds compared to white individuals (23.6% vs 11.1%, P <.01). TUGT times ≥15 seconds were significantly associated with nonwhite race after adjusting for clinical factors (adjusted odds ratio 2.5, 95% confidence interval 1.8-3.3). CONCLUSION: Among older adults presenting to an academic nononcologic urology practice, nonwhite race was associated with increased odds of frailty. A greater understanding of the relationship between race and frailty is needed to better address the needs of this vulnerable population.

Automating the Capture of Structured Pathology Data for Prostate Cancer Clinical Care and Research.

PURPOSE: Cancer pathology findings are critical for many aspects of care but are often locked away as unstructured free text. Our objective was to develop a natural language processing (NLP) system to extract prostate pathology details from postoperative pathology reports and a parallel structured data entry process for use by urologists during routine documentation care and compare accuracy when compared with manual abstraction and concordance between NLP and clinician-entered approaches. MATERIALS AND METHODS: From February 2016, clinicians used note templates with custom structured data elements (SDEs) during routine clinical care for men with prostate cancer. We also developed an NLP algorithm to parse radical prostatectomy pathology reports and extract structured data. We compared accuracy of clinician-entered SDEs and NLP-parsed data to manual abstraction as a gold standard and compared concordance (Cohen's κ) between approaches assuming no gold standard. RESULTS: There were 523 patients with NLP-extracted data, 319 with SDE data, and 555 with manually abstracted data. For Gleason scores, NLP and clinician SDE accuracy was 95.6% and 95.8%, respectively, compared with manual abstraction, with concordance of 0.93 (95% CI, 0.89 to 0.98). For margin status, extracapsular extension, and seminal vesicle invasion, stage, and lymph node status, NLP accuracy was 94.8% to 100%, SDE accuracy was 87.7% to 100%, and concordance between NLP and SDE ranged from 0.92 to 1.0. CONCLUSION: We show that a real-world deployment of an NLP algorithm to extract pathology data and structured data entry by clinicians during routine clinical care in a busy clinical practice can generate accurate data when compared with manual abstraction for some, but not all, components of a prostate pathology report.

The Timed Up and Go Test as a Measure of Frailty in Urologic Practice.

OBJECTIVE: To evaluate the prevalence of frailty, a known predictor of poor outcomes, among patients presenting to an academic nononcologic urology practice and to examine whether frailty differs among patients who did and did not undergo urologic surgery. METHODS: The Timed Up and Go Test (TUGT), a parsimonious measure of frailty, was administered to patients ages ≥65. The TUGT, demographic data, urologic diagnoses, and procedural history were abstracted from the medical record into a prospective database. TUGT times were categorized as nonfrail (≤10 seconds), prefrail (11-14 seconds), and frail (≥15 seconds). These times were evaluated across age and urologic diagnoses and compared between patients who did and did not undergo urologic surgery using chi-square and t tests. RESULTS: The TUGT was recorded for 78.9% of patient visits from December 2015 to May 2016. For 1089 patients, average age was 73.3 ± 6.3 years; average TUGT time was 11.6 ± 6.0 seconds; 30.0% were categorized as prefrail and 15.2% as frail. TUGT times increased with age, with 56.9% of patients age 86 and over categorized as frail. Times varied across diagnoses (highest average TUGT was 14.3 ± 11.9 seconds for patients with urinary tract infections); however, no difference existed between patients who did and did not undergo surgery (P = .94). CONCLUSION: Among our population, prefrailty and frailty were common, TUGT times increased with age and varied by urologic diagnosis, but did not differ between patients who did and did not undergo urologic surgery, presenting an opportunity to consider frailty in preoperative surgical decision making.

Overactive Bladder Is Strongly Associated With Frailty in Older Individuals.

OBJECTIVE: To understand the relationship between age, frailty, and overactive bladder (OAB). MATERIALS AND METHODS: This is a prospective study of individuals age ≥65 years presenting to an academic urology practice between December 2015 and July 2016. All patients had a Timed Up and Go Test (TUGT), a parsimonious measure of frailty, on intake, and were thereby categorized as fast (≤10 seconds), intermediate (11-14 seconds), and slow (≥15 seconds). The TUGT and other clinical data were abstracted from the electronic medical record using direct queries. Logistic regression was used to examine the relationship between frailty and the diagnosis of OAB, adjusting for age, gender, and race. RESULTS: Our cohort included 201 individuals with and 1162 individuals without OAB. Individuals with OAB had slower TUGTs (13.7 ± 7.9 seconds) than their non-OAB counterparts (10.9 ± 5.2 seconds), P <.0001, with 32.3% and 11.0% of OAB and non-OAB individuals being categorized as slow, or frail. In multivariable analysis, slower TUGT was a significant predictor of OAB (adjusted odds ratio: 3.0; 95% confidence interval: 2.0-4.8). Age was not independently associated with this diagnosis (P values >.05 for each age group). CONCLUSION: Patients with OAB are statistically significantly frailer than individuals seeking care for other non-oncologic urologic diagnoses. Frailty, when adjusted for age, race, and gender, is a statistically significant predictor of OAB. Furthermore, frailty should be considered when caring for older patients with OAB, and OAB should be assessed when caring for frail older patients.