Gutiérrez, Martín

Background Cysteine–cysteine chemokine receptors 2 (CCR2) and 5 (CCR5) contribute to immune suppression in tumor microenvironments. CCR2 and CCR5 antagonists have demonstrated antitumor activity in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), respectively. This phase 1b/2, open-label study evaluated BMS-813160, a CCR2/5 dual antagonist, in combination with chemotherapy±nivolumab in advanced PDAC or metastatic CRC. Methods Part 1 included patients with metastatic untreated (first-line (1L)) PDAC, 1L CRC, or previously treated (second or third line (2/3L)) microsatellite stable (MSS) CRC. Patients received 2 weeks of BMS-813160 monotherapy (300 mg two times a day, 600 mg once daily, 300 mg once daily, or 150 mg once daily) and then BMS-813160+chemotherapy (gemcitabine+nab-paclitaxel (gem/nabP; 1L PDAC), 5-fluorouracil+leucovorin+irinotecan (FOLFIRI; 1L CRC)), or nivolumab (2/3L MSS CRC). Part 2 included patients with metastatic 1L PDAC or 2L CRC. Patients received BMS-813160 300 mg two times a day+gem/nabP±nivolumab (1L PDAC), BMS-813160 300 mg two times a day or 150 mg once daily+FOLFIRI (2L CRC), or chemotherapy alone. Primary endpoints were safety and pharmacodynamics (Part 1) and efficacy (Part 2). Results In Part 1, 22 of 75 (29%) and 54 of 72 (72%) patients experienced a treatment-related adverse event during monotherapy lead-in and overall, respectively. Two dose-limiting toxicities (rash and pericardial effusion with pericarditis, both grade 3) occurred. In Part 2, patients with 1L PDAC who received BMS-813160 300 mg two times a day+gem/nabP+nivolumab achieved an overall response rate (ORR) of 37% (13/35); the median duration of response (DOR) was 45 weeks (95% CI 26.1 to not evaluable). ORRs with BMS-813160 300 mg two times a day+gem/nabP and gem/nabP alone were 26% (9/35) and 28% (9/32), respectively; median DORs were 121 and 31 weeks, respectively. Progression-free survival rates at 24 weeks were 56% (BMS-813160 300 mg two times a day+gem/nabP+nivolumab), 56% (BMS-813160 300 mg two times a day+gem/nabP), and 50% (gem/nabP). ORRs in 2L CRC were 19% (6/32; BMS-813160 300 mg two times a day+FOLFIRI), 13% (4/32; BMS-813160 150 mg once daily+FOLFIRI), and 27% (7/26; FOLFIRI). Conclusions In 1L PDAC, BMS-813160 300 two times a day+gem/nabP±nivolumab demonstrated durable antitumor response and was well tolerated. BMS-813160 combination regimens were tolerable in other cohorts, but clinical efficacy was not demonstrated. Trial registration number NCT03184870 .

Abstract Lung diseases, including lung cancer, are rising causes of global mortality. Despite novel imaging technologies and the development of biomarker assays, the detection of lung cancer remains a significant challenge. However, the lung communicates directly with the external environment and releases aerosolized droplets during normal tidal respiration, which can be collected, stored and analzsed as exhaled breath condensate (EBC). A few studies have suggested that EBC contains extracellular vesicles (EVs) whose microRNA (miRNA) cargos may be useful for evaluating different lung conditions, but the cellular origin of these EVs remains unknown. In this study, we used nanoparticle tracking, transmission electron microscopy, Western blot analyses and super resolution nanoimaging (ONi) to detect and validate the identity of exhaled EVs (exh‐EVs). Using our customizable antibody‐purification assay, EV‐CATCHER, we initially determined that exh‐EVs can be selectively enriched from EBC using antibodies against three tetraspanins (CD9, CD63 and CD81). Using ONi we also revealed that some exh‐EVs harbour lung‐specific proteins expressed in bronchiolar Clara cells (Clara Cell Secretory Protein [CCSP]) and Alveolar Type II cells (Surfactant protein C [SFTPC]). When conducting miRNA next generation sequencing (NGS) of airway samples collected at five different anatomic levels (i.e., mouth rinse, mouth wash, bronchial brush, bronchoalveolar lavage [BAL] and EBC) from 18 subjects, we determined that miRNA profiles of exh‐EVs clustered closely to those of BAL EVs but not to those of other airway samples. When comparing the miRNA profiles of EVs purified from matched BAL and EBC samples with our three tetraspanins EV‐CATCHER assay, we captured significant miRNA expression differences associated with smoking, asthma and lung tumor status of our subjects, which were also reproducibly detected in EVs selectively purified with our anti‐CCSP/SFTPC EV‐CATCHER assay from the same samples, but that confirmed their lung tissue origin. Our findings underscore that enriching exh‐EV subpopulations from EBC allows non‐invasive sampling of EVs produced by lung tissues.