Citations

11008 Background: SARC028 is the first multicenter Phase II study of P monotherapy in patients (pts) with STS and BS. Designed to detect clinical efficacy signals in multiple histologies, the study collected blood & tissue samples on all pts. We report extended clinical follow-up and in-depth biomarker correlates of response. Methods: The primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints were safety, 12 wk progression-free survival (PFS), and overall survival (OS). The STS arm had 10 pts in each of 4 cohorts: undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), synovial sarcoma (SS) and leiomyosarcoma (LMS). The BS arm included 40 pts with osteosarcoma (OS), Ewing sarcoma (ES) or dedifferentiated chondrosarcoma (CS). Pre- and on-P biopsies were required as well as blood at multiple time points. Tumor was assessed for PD-L1 expression (clone 22C3) and immune infiltrates by multi-color IHC (Vectra). Ongoing analyses include circulating cytokine and checkpoint levels and exome (DNA), transcriptome (RNA), and T-cell receptor (TCR) sequencing. Results: 86 pts were enrolled, 80 were evaluable for response. For STS, median follow-up was 14.5 months. The ORR in the overall STS cohort was 18% and the 12-wk PFS 55% [95% CI, 42-71]). Clinical activity was variable by histologic subtype with 40% ORR in UPS (1 CR and 3PR out of 10 evaluable pts), 2 PR/10 were seen in DDLPS, 1PR/10 in SS and 0/10 in LMS. For BS, median follow-up was 12.3 months (ORR 5%; 12-wk PFS 28% [95% CI, 14-41]), with 1PR/22 OS, 1PR/5 CS and 0/13 ES. 70 pre-P tissues were analyzed (11 excluded for insufficiency), with PD-L1+ in 3/70 (4%); all 3 were UPS. Of the 2 evaluable pts, 1 had CR and 1 PR. 2 OS were PD-L1+ on multi-color IHC, 1 had PR. All PD-L1+ samples had CD8+ T-cell infiltration. There were no post-P PD-L1+ samples. Conclusions: P has clinical activity in UPS and LPS, and expansion cohorts in those subtypes are planned. Pre-treatment PD-L1 expression was infrequent, but correlated with T-cell infiltration and response in UPS & OS. Ongoing biomarker analyses that may guide combination strategies are ongoing and will be presented at the meeting. Clinical trial information: NCT02301039.

Abstract In patients with metastatic melanoma, high blood levels of galectin‐9 are correlated with worse overall survival and a bias towards a Th2 inflammatory state supportive of tumor growth. Although galectin‐9 signaling through TIM3 on T cells has been described, less is known about the interaction of galectin‐9 with macrophages. We aimed to determine whether galectin‐9 is a binding partner of CD206 on macrophages and whether the result of this interaction is tumor‐supportive. It was determined that incubation of CD68 + macrophages with galectin‐9 or anti‐CD206 blocked target binding and that both CD206 and galectin‐9 were detected by immunoprecipitation of cell lysates. CD206 and galectin‐9 had a binding affinity of 2.8 × 10 −7 m . Galectin‐9 causes CD206 + macrophages to make significantly more FGF2 and monocyte chemoattractant protein (MCP‐1), but less macrophage‐derived chemokine (MDC). Galectin‐9 had no effect on classical monocyte subsets, but caused expansion of the non‐classical populations. Lastly, there was a positive correlation between increasing numbers of CD206 macrophages and galectin‐9 expression in tumors, and high levels of CD206 macrophages correlated negatively with melanoma survival. These results indicate that galectin‐9 binds to CD206 on M2 macrophages, which appear to drive angiogenesis and the production of chemokines that support tumor growth and poor patient prognoses. Targeting this interaction systemically through circulating monocytes may therefore be a novel way to improve local anti‐tumor effects by macrophages. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Objective: A growing number of cancer antineoplastic agents can cause life-threatening acute infusion reactions. Because previous studies have not studied these reactions from the perspective of patients, this study was undertaken with that objective in mind. Methods: Patients who had an acute infusion reaction were interviewed based on the Leventhal model. Once saturation of content was achieved, interviews were transcribed and analyzed with qualitative methodology. Results: Twenty-one patients were enrolled. Most were women (n = 15); the median age was 58 years, and paclitaxel was the most common inciting agent. Three themes emerged. First, these reactions are frightening; patients made remarks such as “I was just thinking oh my God, I am dying.” Second, prior education about these reactions seemed to mitigate this fear, “Basically everything the nurses told me potentially could happen, like happened. So, I was prepared.” Third, when health-care providers were prompt and attentive during the reaction, patients described less fear with future chemotherapy, “So no, I’m really not fearful about going in tomorrow because I know they’ll be there and they’ll be watching me.” Conclusion: These reactions evoke fear which can be mitigated with education prior to and with prompt responsiveness during the acute infusion reaction.

Abstract The neutral protease tryptase has been isolated from a human mast cell line, HMC-1. The HMC-1 line was established from the peripheral blood of a patient with mast cell leukemia and maintained as continuously proliferating clones in vitro and as solid mast cell tumors in nude mice. HMC-1-derived tryptase was purified by sequential chromatography on Dowex 1, DEAE 5 PW, and heparin-agarose. Purified tryptase has an apparent molecular weight of 150,000, as determined by molecular sieve HPLC, but migrates as a doublet of bands of 32/35,000 on SDS-PAGE gels. Maximal enzymatic activity was observed at pH 8.5. Cleavage of tosyl-L-arginine methyl ester by purified tryptase was inhibited by dansyl-L-glutamyl-glycyl-L-arginine chloromethyl ketone 2 HCI, HgCI2, tosyl-L-lysine chloromethyl ketone, leupeptin, and PMSF but not by benzamidine, aprotinin, tosyl-L-phenylalanine chloromethyl ketone, soybean trypsin inhibitor, human plasma, ovomucoid inhibitor, or lima bean trypsin inhibitor. Microsequencing of purified tryptase yielded an amino terminal sequence that was identical to that previously reported for human pituitary-derived tryptase.

The development and utilization of monoclonal antibodies (mAbs) have been of great interest in all fields of medicine. A substantial increase in the production and development of mAbs has occurred because these biologic agents are proving to be effective and less toxic given their targeted mechanism of action. However, data are limited on coadministration of two or more mAbs. With the increasing availability of mAbs and the comorbidities of some patients, assessment is needed of the ability to safely use multiple mAbs for an individual patient. Although the efficacy of coadministered mAbs may be inferred from their specific targets, we could find no literature reporting such a finding. Herein, we report our experience using two different classes of mAbs to treat hypereosinophilic syndrome and ulcerative colitis in a single patient.