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Supplemental Table S1

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Supplementary Figure and Table Legends

Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti–PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile, and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an IFNγ gene signature following treatment, as well as increased systemic expression of the IFN-inducible chemokine CXCL10.Significance:In this phase Ib study in patients with advanced melanoma, intratumoral TLR9 agonist vidutolimod in combination with pembrolizumab had a manageable safety profile and showed promising clinical activity, supporting the further clinical development of vidutolimod to overcome PD-1 blockade resistance through induction of an IFN response.See related commentary by Sullivan, p. 2960.This article is highlighted in the In This Issue feature, p. 2945

Supplementary figures 1-6, supplementary tables 1-4

Bortezomib pharmacokinetic parameters following a single intravenous 1.3 mg/m2 bolus dose in the presence or absence of tabalumab and dexamethasone

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Percentage Change from Baseline (PCB) for B-cells (CD19+) and Immunoglobulins (Ig)at 20-day time intervals post-baseline.

Percentage Change from Baseline (PCB) for B-cells (CD19+) and Immunoglobulins (Ig)at 20-day time intervals post-baseline.

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Table S1. Treatment emergent adverse events regardless of causality in {greater than or equal to}10% of patients; Table S2. Best Overall Response; Table S3. Reasons for Emibetuzumab Discontinuation.

Bortezomib pharmacokinetic parameters following a single intravenous 1.3 mg/m2 bolus dose and varying single intravenous doses of tabalumab

Purpose: AME-133v is a humanized monoclonal antibody engineered to have increased affinity to CD20 and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) better than rituximab. Safety, pharmacokinetics, and efficacy were assessed in a phase 1/2 trial in patients with previously treated follicular lymphoma (FL).Patients and Methods: AME-133v was characterized in vitro by ADCC and cell binding assays. A phase 1 study was conducted in which 23 previously treated patients with FL were assigned sequentially to one of five dose-escalation cohorts of AME-133v at 2, 7.5, 30, 100, or 375 mg/m2 weekly × 4 doses.Results: AME-133v showed a 13- to 20-fold greater binding affinity for CD20 and was 5- to 7-fold more potent than rituximab in ADCC assays. Cell binding assays showed AME-133v and rituximab competed for an overlapping epitope on the CD20 antigen, and AME-133v inhibited binding of biotinylated rituximab to CD20 in a concentration-dependent manner. AME-133v was well tolerated by patients and common related adverse events included chills and fatigue. One patient experienced a dose-limiting toxicity of neutropenia. AME-133v showed nonlinear pharmocokinetics with properties similar to rituximab. Selective reduction of B cells during and after AME-133v treatment was shown by flow cytometry of peripheral blood. A partial or complete response was observed in 5 of 23 (22%) patients and the median progression-free survival was 25.4 weeks.Conclusions: AME-133v was safe and well tolerated at the doses tested. AME-133v showed encouraging results as an anti-CD20 therapy in heavily pretreated FL patients with the less favorable FcγRIIIa F-carrier genotype. Clin Cancer Res; 18(5); 1395–403. ©2012 AACR.

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Treatment duration by patient and emibetuzumab dose for emibetuzumab monotherapy (A) and emibetuzumab + erlotinib (B).

Purpose: Tabalumab, a human mAb that neutralizes B-cell–activating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib.Experimental Design: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter.Results: The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia, and peripheral sensory neuropathy. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than dose-proportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months, and the median response duration (4 patients censored) was 7.2 months.Conclusions: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation. Clin Cancer Res; 22(23); 5688–95. ©2016 AACR.

Pharmacokinetic parameters of tabalumab in multiple myeloma patients

Purpose: The MET/HGF pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGF-dependent and HGF-independent MET signaling. Here, we report dose escalation results from the first-in-human phase I trial of emibetuzumab.Experimental Design: The study comprised a 3+3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered i.v. every 2 weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.Results: Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg and 14 non–small cell lung cancer (NSCLC) patients at 700, 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. No dose-limiting toxicities and related serious or ≥ grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear PK at doses >210 mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab + erlotinib (700 mg and 2,000 mg). Both of the responders to emibetuzumab + erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression.Conclusions: Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700 to 2,000 mg i.v. Q2W. Clin Cancer Res; 23(8); 1910–9. ©2016 AACR.

Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti–PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile, and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an IFNγ gene signature following treatment, as well as increased systemic expression of the IFN-inducible chemokine CXCL10. Significance: In this phase Ib study in patients with advanced melanoma, intratumoral TLR9 agonist vidutolimod in combination with pembrolizumab had a manageable safety profile and showed promising clinical activity, supporting the further clinical development of vidutolimod to overcome PD-1 blockade resistance through induction of an IFN response. See related commentary by Sullivan, p. 2960. This article is highlighted in the In This Issue feature, p. 2945

Metabolic dysregulation is a hallmark of cancer. Many tumors exhibit auxotrophy for various amino acids, such as arginine, because they are unable to meet the demand for these amino acids through endogenous production. This vulnerability can be exploited by employing therapeutic strategies that deplete systemic arginine in order to limit the growth and survival of arginine auxotrophic tumors. Pegzilarginase, a human arginase-1 enzyme engineered to have superior stability and enzymatic activity relative to the native human arginase-1 enzyme, depletes systemic arginine by converting it to ornithine and urea. Therapeutic administration of pegzilarginase in the setting of arginine auxotrophic tumors exerts direct antitumor activity by starving the tumor of exogenous arginine. We hypothesized that in addition to this direct effect, pegzilarginase treatment indirectly augments antitumor immunity through increased antigen presentation, thus making pegzilarginase a prime candidate for combination therapy with immuno-oncology (I-O) agents. Tumor-bearing mice (CT26, MC38, and MCA-205) receiving pegzilarginase in combination with anti–PD-L1 or agonist anti-OX40 experienced significantly increased survival relative to animals receiving I-O monotherapy. Combination pegzilarginase/immunotherapy induced robust antitumor immunity characterized by increased intratumoral effector CD8+ T cells and M1 polarization of tumor-associated macrophages. Our data suggest potential mechanisms of synergy between pegzilarginase and I-O agents that include increased intratumoral MHC expression on both antigen-presenting cells and tumor cells, and increased presence of M1-like antitumor macrophages. These data support the clinical evaluation of I-O agents in conjunction with pegzilarginase for the treatment of patients with cancer.

Background In the treatment-naive setting, PD-1 blockade is associated with greater response in T cell-inflamed vs non-T cell-inflamed tumors. CMP-001 is a CpG-A oligonucleotide TLR9 agonist in a virus-like particle that is hypothesized to activate tumor-associated plasmacytoid dendritic cells (pDCs) to secrete type I interferons. Through this activity, CMP-001 may convert the tumor microenvironment to a Th1-like chemokine milieu (eg, increased CXCL10) and induce an antitumor CD8+ T-cell response. We have recently reported that intratumoral injection of CMP-001 + IV pembrolizumab (pembro) had an acceptable safety profile and can reverse PD-1 blockade resistance in patients (pts) with melanoma (Milhem et al, SITC 2019). Regression was observed in injected and uninjected lesions. Herein we report pharmacodynamic and translational data. Methods This 2-part, open-label, multicenter, phase 1b study (NCT02680184) enrolled pts with metastatic/unresectable melanoma and stable disease (SD) or progressive disease (PD) on/after anti−PD-1 therapy. In part 1 (3+3 dose-escalation and dose-expansion), pts received CMP-001 + pembro. In part 2, pts received CMP-001 monotherapy. Determination of safety and clinical activity were the study's main objectives. Prespecified pharmacodynamic and translational studies evaluated serum chemokines and evaluated tumor biopsies using RNA and/or whole exome sequencing and immunohistochemistry for PD-L1 (reported as H-score), CD8, and CD303 (pDC marker). Results As of September 30, 2020, 159 pts (part 1) and 40 pts (part 2) have been treated. A greater median fold increase of serum CXCL10 (a marker of innate immunity, n=40) was observed in responders (R) to CMP-001 + pembro (18.8x) vs nonresponders (NR) after treatment (9.9x in SD; 6.15x in PD; differences were not statistically significant). Preliminary analyses showed that interferon gene expression distinguished R vs NR. Tumor biopsy analyses (part 1, n=139; part 2, n=34) showed that pts with high PD-L1, high CD8+ T cells, or inflamed transcriptional signatures at baseline were less likely to respond to CMP-001 + pembro vs pts without inflammation markers at baseline. Baseline mean PD-L1 expression (H-score) was 8.1 in R (n=10) vs 21.8 in NR (n=49). Posttreatment biopsies generally showed increased PD-L1, CD8+ T cells, and inflamed transcriptional signatures in R vs NR. Neither tumor mutational burden nor baseline pDC density distinguished R vs NR. Conclusions In pts with anti-PD-1 refractory melanoma, intratumoral CMP-001 ± pembro appears to disproportionately induce antitumor responses in noninflamed tumors. Clinical response to CMP-001 ± pembro was associated with induction of markers of both innate and adaptive antitumor immunity. Citation Format: Jason John Luke, Riyue Bao, John M. Kirkwood, Yousef Zakharia, Diwakar Davar, Elizabeth Buchbinder, Theresa Medina, Adil Daud, Antoni Ribas, Jiaxin Niu, Geoffrey Gibney, Kim Margolin, Anthony J. Olszanski, Inderjit Mehmi, Takami Sato, Montaser Shaheen, Aaron Morris, Dmitri Bobilev, Katie Campbell, George Weiner, James E. Wooldridge, Arthur M. Krieg, Mohammed Milhem. CMP-001 demonstrates improved response in noninflamed anti-PD-1 refractory melanoma and response is associated with serum CXCL10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT032.

TPS6089 Background: PD-1 blockade ± chemotherapy has recently become a primary systemic therapy recommended by NCCN guidelines for patients (pts) with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, most pts still do not respond to treatment, indicating a large unmet need for pts with unresectable disease. CMP-001 is a toll-like receptor 9 (TLR9) agonist comprising a CpG-A oligodeoxynucleotide packaged in a virus-like particle that can induce type I interferon secretion from tumor-associated plasmacytoid dendritic cells, promoting a Th1-like chemokine milieu in the tumor microenvironment and inducing an antitumor CD8+ T-cell response. In a phase (ph) 1b study in pts with metastatic melanoma, intratumoral (IT) injection of CMP-001 + intravenous (IV) pembrolizumab (pembro) reversed PD-1 blockade resistance, induced responses in injected and noninjected lesions, and had an acceptable safety profile (Milhem et al, SITC 2020). This combination is therefore being tested in pts with HNSCC. Methods: CMP-001-007 (NCT04633278) is an open-label, multicenter, ph 2 study designed to investigate the efficacy and safety of CMP-001 + IV pembro in adult pts with histologically or cytologically confirmed R/M HNSCC considered incurable by local therapies. Eligible pts have undergone a pretreatment tumor biopsy, received no prior systemic therapy in the R/M setting, and have primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. In addition, pts must have PD-L1-positive tumors (combined positive score ≥1), known tumor human papillomavirus (HPV) status (for oropharyngeal cancer), and measurable disease per RECIST v1.1 with ≥1 lesion amenable to IT injection. Pts with primary tumors in the nasopharynx are excluded. Enrolled pts will receive CMP-001 10 mg once weekly for 7 doses and every 3 weeks (Q3W) thereafter. The first dose may be administered subcutaneously or via IT injection, with all subsequent doses administered IT. All pts will also receive pembro 200 mg IV Q3W after the CMP-001 injection. Treatment continues until unacceptable toxicity or disease progression. The primary endpoint is investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints include safety, duration of response (DOR), progression-free survival (PFS), overall survival, and effects of HPV infection and PD-L1 expression on ORR, DOR, and PFS. Exploratory endpoints include analyses of baseline and changes from baseline in tumor or serum biomarkers related to TLR9, immune checkpoints, and potential predictors of response, as well as serum concentrations of CXCL10 and CMP-001. Refer to clinicaltrials.gov/ct2/show/NCT04633278 for the most current information on enrolling sites. Clinical trial information: NCT04633278.

Previous research investigated concepts of tactile salience and core variables mediating effects on human perception and learning, resulting in validation of independent scaled ratings of tactile salience. This approach provides an integrated and systematic approach to assess effectiveness of tactile displays. We report an initial series of comparative tests of various multi-tactor cues, or tactions. Tactions were developed to vary in temporal sequencing and amplitude. In the first experiment 8 tactions were used; a follow-up investigation used 12. In this report we summarize results, with a focus on experiment methods association with measurement of tactile salience, ease of learning, and ease of recall.

This phase 2 study assessed the safety and efficacy of ocaratuzumab, a humanized anti-CD20 monoclonal antibody. Fifty patients with previously treated follicular lymphoma (FL) and a low-affinity genotype of FcγRIIIa received ocaratuzumab 375 mg/m(2) weekly for 4 weeks. Grade 3/4/5 adverse events (AEs) were reported in 11/1/1 patients, respectively. Serious AEs were reported by 11/50 patients, and three discontinued due to AEs. One patient died from aspiration pneumonia due to possibly drug-related nausea and vomiting. Investigator-assessed response rate was 30% (15/50), including four complete responses (CR), three CR unconfirmed (CRu) and eight partial responses (PR). Investigator-assessed median Progression-free survivial (PFS) was 38.3 weeks. Ocaratuzumab's pharmacokinetic profile was similar to that reported for rituximab. Lymphocyte subset analysis showed significant, selective reduction of B-cells during and after ocaratuzumab treatment. Ocaratuzumab at this dose and schedule is active and well tolerated in patients with previously treated FL with low affinity FcγRIIIa genotypes. ClinTrials registry number: NCT00354926.

Future U.S. Army robots are developing capabilities to better “see” (e.g., scan and recognize objects), “think” (e.g., recognize implications and decide on a best course of action), and “act” (e.g., execute actions). This report describes systematic feedback gained from active duty Soldiers with dismounted squad level experience, to identify preferences and levels of trust with regard to squad level robotic capabilities, roles, and tactics. Soldier-based feedback will inform ongoing programs of research regarding U.S. Army Autonomous Squad Member (ASM) capabilities, through validation of mission scenarios, information requirements, and tactical maneuvers.

The ITER-Like Antenna (ILA) for JET is a 2 toroidal by 2 poloidal array of Resonant Double Loops (RDL). It features in-vessel matching capacitors feeding RF current straps in Conjugate-T (CT) manner, a low impedance quarter-wave impedance transformer and a service stub allowing hydraulic actuator and water cooling services to reach the aforementioned capacitors. A Second Stage Matching (SSM) trombone and stub circuit allows to match the chosen CT working impedance to 30 Ω. Toroidally adjacent RDLs are fed from a 3 dB hybrid splitter. It is worth mentioning that while the in-vessel matching approach was not kept for the ICRF antenna for ITER, the other aspects of the design for ITER such as the use of short straps, the validation of the TOPICA coupling code as well as operation at >40 kV and >5 MW/m2 were confirmed by the ILA. The assessment of the ILA results (2008–9) identified that achieving routine full array operation required a better understanding of the RF circuit, tighter calibrations of RF measurements and last but not least a feedback control algorithm for the SSM. The matching and phasing of the array is controlled by 22 feedback loops actuating the 8 matching capacitors, the 4 second stage trombones and 4 stubs, the 4 Main Transmission Line (MTL) phase shifters and the 4 phases with respect to a reference of the generators feeding the upper and lower half array through 3 dB hybrid combiner-splitters. The circuit was extensively simulated allowing the development of an algorithm to drives the SSM circuit components, trombone and stub, to optimal locations with respect to the measured remaining VSWR excursions due to ELMs. The paper focusses on the new additional matching algorithms and assesses their performance.

Purpose: The MET/HGF pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGF-dependent and HGF-independent MET signaling. Here, we report dose escalation results from the first-in-human phase I trial of emibetuzumab. Experimental Design: The study comprised a 3+3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered i.v. every 2 weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Results: Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg and 14 non–small cell lung cancer (NSCLC) patients at 700, 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. No dose-limiting toxicities and related serious or ≥ grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear PK at doses >210 mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab + erlotinib (700 mg and 2,000 mg). Both of the responders to emibetuzumab + erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression. Conclusions: Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700 to 2,000 mg i.v. Q2W. Clin Cancer Res; 23(8); 1910–9. ©2016 AACR.

Summary In this double-blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N = 72), tabalumab 100 mg (N = 74), or tabalumab 300 mg (N = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m2 on a 21-day cycle. No significant intergroup differences were observed among primary (median progression-free survival [mPFS]) or secondary efficacy outcomes. The mPFS was 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR) [95% confidence interval (CI)] = 1·13 [0·80–1·59], P = 0·480; tabalumab 300 mg vs. placebo HR [95% CI] = 1·03 [0·72–1·45], P = 0·884). The most commonly-reported treatment-emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF13B) expression (n = 162) had significantly longer mPFS than those with high BAFF expression (n = 55), using the 75th percentile cut-off point (mPFS [95% CI] = 8·3 [7·0–9·3] months vs. 5·8 [3·7–6·6] months; HR [95% CI] = 1·59 [1·11–2·29], P = 0·015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma.

Background: Tumors with impaired arginine synthesis are susceptible to extracellular arginine depletion. We report results from the first-in-human phase I trial of pegzilarginase (AEB1102, Co-ArgI-PEG), a pegylated, recombinant, cobalt-substituted human arginase I (NCT02561234). Experimental design: Patients with metastatic solid tumors refractory to standard therapies were enrolled in 3+3 cohorts at increasing dose levels of weekly intravenous pegzilarginase. Primary endpoint was to determine the maximum tolerated dose (MTD). Additional endpoints included safety, pharmacokinetics, pharmacodynamics, immunogenicity, expression of arginine synthesis pathway enzymes in tumor tissue, and preliminary efficacy. Results: Forty patients were enrolled in 9 cohorts at doses from 0.01 to 0.40 mg/kg. The 3 most prevalent histologies (4 patients each) were colorectal and prostate adenocarcinoma, and uveal melanoma. Two dose limiting toxicities (DLT) were observed: G3 failure to thrive (0.33 mg/kg) and G3 maculopapular rash (0.40 mg/kg). After assessment of overall safety profile, the MTD was determined to be 0.33 mg/kg once weekly. Other related serious or ≥ grade 3 adverse events (AEs) not considered DLTs per protocol were hypophosphatemia (2 patients), and anemia, neutropenia, tremor, weakness, and transient hypertension (one occurrence each in a single patient). Pegzilarginase-related AEs in ≥10% of patients included nausea (9 patients with G1-2), stomatitis/mouth sores (8), fatigue (8), vomiting (6), pruritic, macular, or maculopapular rash (4, 1 G3), decreased appetite (4), and diarrhea (4). Pegzilarginase exposure was dose proportional on day 1 and day 29 for all doses starting at 0.02 mg/kg, and the mean half-life was constant at doses ≥ 0.04 mg/kg (33-55 hr after dose 5). On average, doses ≥0.18 mg/kg depleted arginine to ≤10% of baseline for up to 72 hrs. Analysis of the initial 27 patients revealed no anti-drug antibodies (ADAs). Median number of doses was 6.5 (range 1-20); 4 patients had stable disease after 8 weeks of treatment and continued in the trial for a total of 16-20 weeks. ASS1, ASL, and OTC expression levels varied across the different histologies. Conclusions: The MTD of pegzilarginase was 0.33 mg/kg, and the PK/PD profile supports once-weekly dosing with potential adjustable margin. The manageable safety profile, absence of ADA, and observation of stable disease supports further exploration as monotherapy and combination therapy. Expansion cohorts were initiated at MTD in specific histologies with high probability of low ASS1 expression (uveal melanoma, cutaneous melanoma and small-cell lung cancer [SCLC]). Based on pre-clinical data showing enhanced effects of PD-1 inhibition, a parallel study is investigating pegzilarginase in combination with pembrolizumab for patients with previously-treated SCLC. Citation Format: Drew W. Rasco, S. Gail Eckhardt, Diwakar Davar, Karl Lewis, Humberto Lara-Guerra, Susan E. Alters, Stephen Eckert, Scott W. Rowlinson, James E. Wooldridge, Richard D. Carvajal. Phase I dose escalation trial of pegzilarginase in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT030.

7031Background: In vitro studies demonstrate that AML cells are arginine auxotrophs and are metabolically vulnerable to arginine depletion (PMID: 24018014 & 25896651). To test the clinical utility ...

Aims: B-cell chronic lymphocytic leukemia (CLL) is a heterogeneous malignancy that clinically ranges from indolent to rapidly progressive. CLL, like other cancers, can be affected by epigenetic alterations. Materials & methods: A microarray discovery-based study was initiated to determine DNA methylation in CLL cases with a range of CD38 expression (1–92%). Results: Many loci were either methylated or unmethylated across all CD38 levels, but differential methylation was also observed for some genes. Genomic sequencing of DLEU7 confirmed extensive cytosine methylation preferentially in patient samples with low CD38 expression, whereas NRP2, SFRP2 and ADAM12 were more commonly methylated in those with high CD38 expression. Conclusion: This study demonstrates that CLL is affected by CpG island methylation in some genes that segregate with CD38 expression levels, while most others show similar methylation patterns across all levels. The CpG island methylation in certain functional gene groups and pathway-associated genes that are known to be deregulated in CLL provides additional insights into the CLL methylome and epigenetic contribution to cellular dysfunction. It will now be useful to investigate the effectiveness of epigenetic therapeutic reversal of these alterations to develop effective treatments for the disease.

Purpose: Tabalumab, a human mAb that neutralizes B-cell–activating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib. Experimental Design: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter. Results: The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia, and peripheral sensory neuropathy. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than dose-proportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months, and the median response duration (4 patients censored) was 7.2 months. Conclusions: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation. Clin Cancer Res; 22(23); 5688–95. ©2016 AACR.

A potential complication for all new multiple myeloma (MM) patients is the clinical presentation of osteolytic lesions which increase the risk for skeletal-related events (SREs). However, the contribution of SREs to the overall economic impact of MM is unclear. The impact of SREs on healthcare resource utilization (HCRU) and costs for US patients with MM was analyzed in Truven Health Marketscan Commercial Claims and Medicare Supplemental Databases.Adults diagnosed with MM between January 1, 2005 and December 31, 2010 with ≥2 claims ≥30 days apart (first claim = index date) were included. SREs included: hypercalcemia, pathologic fracture, surgery for the prevention and treatment of pathologic fractures or spinal cord compression, and radiation for bone pain. Rates of HCRU (outpatient [OP], inpatient [IP], emergency room [ER], orthopedic consultation [OC], and ancillary) and healthcare costs were compared between MM patients with and without SREs. Inverse propensity weighting was applied to adjust for potential bias.Of 1028 MM patients (mean age = 67, standard deviation = 13.2), 596 patients with ≥1 SRE and 432 without SREs were assessed. HCRU rates in IP, ER, and ancillary (p 0.01) and mean total costs of OP, IP, and ER were significantly higher (p 0.05) for patients with vs without SREs during follow-up. HCRU rates also increased with SRE frequency (p 0.05 in OP, IP, ER, OC, and ancillary), as did mean total healthcare costs, except for OC (p 0.001).A broad assessment of pharmacotherapy for the treatment of MM was not an objective of the current study. Bisphosphonate use was evaluated; however, results were descriptively focused on frequency of utilization only and were not included in the broader cost and HCRU analysis.Among US patients with MM, higher SRE frequency was associated with a significant trend of higher HCRU and total healthcare costs in several settings.

Non-Hodgkin's lymphoma (NHL) is a group of malignancies with heterogeneous genetic and epigenetic alterations. Discovery of molecular markers that better define NHL should improve diagnosis, prognosis and understanding of the biology. We developed a CpG island DNA microarray for discovery of aberrant methylation targets in cancer, and now apply this method to examine NHL cell lines and primary tumors. This methylation profiling revealed differential patterns in six cell lines originating from different subtypes of NHL. We identified 30 hypermethylated genes in these cell lines and independently confirmed 10 of them. Methylation of 6 of these genes was then further examined in 75 primary NHL specimens composed of four subtypes representing different stages of maturation. Each gene (DLC-1, PCDHGB7, CYP27B1, EFNA5, CCND1 and RARbeta2) was frequently hypermethylated in these NHLs (87, 78, 61, 53, 40 and 38%, respectively), but not in benign follicular hyperplasia. Although some genes such as DLC-1 and PCDHGB7 were methylated in the vast majority of NHLs, others were differentially methylated in specific subtypes. The methylation of the candidate tumor suppressor gene DLC-1 was detected in a high proportion of primary tumor and plasma DNA samples by using quantitative methylation-specific PCR analysis. This promoter hypermethylation inversely correlated with DLC-1 gene expression in primary NHL samples. Thus, this CpG island microarray is a powerful discovery tool to identify novel methylated genes for further studies of their relevant molecular pathways in NHLs and identification of potential epigenetic biomarkers of disease.

Salience has generally been regarded as a property of a stimulus that allows it to stand out and be noticed. Typically, tactile stimuli are defined by dimensions such as the frequency, intensity, force, location, and duration of the signal. However, these definitions and their associated thresholds, in isolation, are of little value if one does not consider interaction characteristics of the user or situational context. In this report we describe a preliminary model for tactile salience composed of 3 core constructs (individual differences, technology, and context) and their interactions. This definition provides an integrated approach to assess effectiveness of tactile displays. We report an initial series of comparative tests using paired comparisons with forced-choice and independent scaled ratings of various multitactor patterns. Results showed significant differences due to tactor design characteristics, patterns of tactile cue arrays, and some differences due to measurement approach. Implications for future research are discussed.

Growing evidence indicates that the affinity of monoclonal antibodies (mAbs) for CD16 (FcγRIII) plays a central role in the ability of the mAb to mediate antitumor activity. We evaluated how CD16 polymorphisms, and mAb with modified affinity for target antigen and CD16, affect natural killer (NK) cell phenotype when CD20+ malignant B cells were also present. The mAb consisted of rituximab (R), anti-CD20 with enhanced affinity for CD20 (AME-B), and anti-CD20 with enhanced affinity for both CD20 and CD16 (AME-D). Higher concentrations of mAb were needed to induce CD16 modulation, CD54 up-regulation, and antibody-dependent cellular cytotoxicity (ADCC) on NK cells from subjects with the lower affinity CD16 polymorphism. The dose of mAb needed to induce NK activation was lower with AME-D irrespective of CD16 polymorphism. At saturating mAb concentrations, peak NK activation was greater for AME-D. Similar results were found with measurement of CD16 modulation, CD54 up-regulation, and ADCC. These data demonstrate that cells coated with mAb with enhanced affinity for CD16 are more effective at activating NK cells at both low and saturating mAb concentrations irrespective of CD16 polymorphism, and they provide further evidence for the clinical development of such mAbs with the goal of improving clinical response to mAb.

Oligodeoxynucleotides containing CpG motifs (CpG ODN) can alter various immune cell subsets important in antibody therapy of malignancy. We undertook a phase I trial of CPG 7909 (also known as PF-3512676) in patients with previously treated lymphoma with the primary objective of evaluating safety across a range of doses, and secondary objectives of evaluating immunomodulatory effects and clinical effects. Twenty-three patients with previously treated non-Hodgkin lymphoma received up to 3 weekly 2-hour intravenous (IV) infusions of CPG ODN 7909 at dose levels 0.01 to 0.64 mg/kg. Evaluation of immunologic parameters and clinical endpoints occurred for 6 weeks. Infusion-related toxicity included grade 1 nausea, hypotension, and IV catheter discomfort. Serious adverse hematologic events observed more than once included anemia (2=Gr3, 2=Gr4), thrombocytopenia (4=Gr3), and neutropenia (2=Gr3), and were largely judged owing to progressive disease. Immunologic observations included: (1) The mean ratio of NK-cell concentrations compared with pretreatment at day 2 was 1.44 (95% CI=0.94-1.94) and at day 42 was 1.53 (95% CI=1.14-1.91); (2) NK activity generally increased in subjects; and (3) Antibody-dependent cellular cytotoxicity activity increased in select cohorts. No clinical responses were documented radiographically at day 42. Two subjects demonstrated late response. We conclude CpG 7909 can be safely given as a 2-hour IV infusion to patients with previously treated non-Hodgkin lymphoma at doses that have immunomodulatory effects.

When uncomplicated neutropenia during doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy for the treatment of Hodgkin's lymphoma is encountered, it is unclear whether or not treatment should be modified. In the present study, we determined the incidence of neutropenia, febrile neutropenia, and the relationship of febrile neutropenia to grade III/IV neutropenia and dose modification, in a large university patient population. We reviewed the charts of patients diagnosed with Hodgkin's lymphoma between 1 January 1990 and 31 December 2002 who were treated with ABVD chemotherapy, and seen at the University of Iowa with complete diagnosis, staging, and treatment dosing records. Adequate data was available on 894 treatments in 81 patients with Hodgkin's lymphoma treated with ABVD chemotherapy. Grade III/IV neutropenia was present on the scheduled day of treatment in 187 (20.9%) treatments in 64 (79%) patients. Grade III/IV neutropenia was most common at cycle 1 day 15. Febrile neutropenia developed nine times in eight patients, and eight episodes of febrile neutropenia developed when the treatment-day absolute neutrophil count (ANC) > or =1000. Dose delay of >4 days and/or dose reduction to

Immunostimulatory oligodeoxynucleotides (IS ODN) can mediate a number of immunologic effects. We previously demonstrated that treatment of B cell chronic lymphocytic leukemia (B-CLL) cells with one class of IS ODN, CpG ODN, alters their phenotype and increases their immunogenicity. Here, we demonstrate that in contrast to the classic understanding of CpG ODN as inhibitors of B cell apoptosis, IS ODN including CpG ODN induce apoptosis in B-CLL cells. It is important that these changes are seen not only with CpG ODN but with ODN that lack the classical CpG motif. B-CLL cells from 20 subjects were treated in vitro with IS ODN for up to 7 days. IS ODN treatment resulted in increased numbers of apoptotic cells in 13 out of 20 B-CLL samples. IS ODN enhanced apoptosis in samples with 13q deletion as a single aberration and had a heterogeneous effect on apoptosis in samples with other aberrations including 17p deletion, 11q deletion, or trisomy 12. Induction of apoptosis did not correlate with expression of the CpG ODN receptor Toll-like receptor 9. Apoptosis was dependent on the activation of caspases and was accompanied by up-regulation of CD95/Fas and its ligand. We conclude that IS ODN including CpG ODN can induce apoptosis of most B-CLL samples. The ability of IS ODN to induce apoptosis differs based on cytogenetic status. Up-regulation of CD95/Fas may play a role in IS ODN-induced apoptosis of B-CLL.

To report a case of anaplastic large cell lymphoma (ALCL) of the central nervous system (CNS) producing an optic neuropathy.Observational case report.A 29-year-old male presented with new onset headaches. Magnetic resonance imaging (MRI) of the brain revealed a large enhancing parietal lobe mass. Ocular exam at that time was normal. Initial diagnoses included possible bacterial cerebritis and fungal abscess. Serial lumbar punctures showed increased white blood cells but cytology was negative. A brain biopsy was non-diagnostic. The patient then presented with a left optic neuropathy. Repeat MRI of the brain and orbits revealed infiltration of the clivus and left orbital apex including the optic nerve. The patient had elevated liver function studies and an abdominal ultrasound disclosed two hypoechoic lesions. Liver biopsy confirmed the diagnosis of ALK-1 positive ALCL. The patient was treated with chemotherapy but expired seven months after the initial presentation.ALCL should be considered to be a very rare but potential cause of optic neuropathy. To our knowledge, this is the first reported case of ALCL causing an optic neuropathy.

The calibrations and verifications that are performed in preparation of the ITER-Like antenna (ILA) reinstatement at JET are reviewed. A brief reminder of the ILA system layout is given. The different calibration methods and results are then discussed. They encompass the calibrations of the directional couplers present in the system, the determination of the relation between the capacitor position readings and the capacitance value, the voltage probes calibration inside the antenna housing, the RF cables characterization and the acquisition electronics circuit calibration. Earlier experience with the ILA has shown that accurate calibrations are essential for the control of the full ILA close-packed antenna array, its protection through the S-Matrix Arc Detection and the new second stage matching algorithm to be implemented. Finally the voltage stand-off of the capacitors is checked and the phase range achievable with the system is verified. The system layout is modified as to allow dipole operation over the whole operating frequency range when operating with the 3dB combiner-splitters.

A city tax model based on the analytic hierarchy process is developed. This model allows city officials to explicitly take into account the existence of multiple decision criteria in selecting new tax options. Opinions from tax experts are used to relate tax plans to decision criteria. The paper explores the feasibility of applying commonly available decision tools to facilitate and improve decision making in local government.

The technology implications of potential FWCD systems have been assessed at two frequencies of relevance to DEMO as part of a wider study of heating and current drive systems for the EFDA Power Plant Physics and Technology (PPP&T), based upon two reference DEMO designs. Using the results of Van Eester et al [1], systems studies carried out for a 62MHz mid-harmonic system mounted on a 23MA 5.74T 8.5m major radius DEMO suggested that antenna voltages close to 50kV, and the handling of the resultant sheath power loadings, are likely to be required if all of the 12.9MA non-bootstrap current drive is to be provided by FWCD. The "wall plug" electrical efficiency of the midharmonic option of 0.18A/W.m2, potentially rising to 0.23A/W.m2 with the future development of solid state generators, however, looks very attractive, and the coupling is less sensitive to plasma edge parameters than for existing antennas, due to the low k// of 2.8m−1. The design could be based upon that presently under consideration for ITER, except for the replacement of insulating vacuum windows located relatively close to the plasma with all-metal designs [2]. A 352MHz high-harmonic option also looks technologically feasible, using a waveguide-based design and a port plug layout has been provided. This option might bring sheath effect and voltage hold-off benefits, but this is far from proven. In this case, systems studies were not feasible due to a lack of firm results from the physics studies. For both options: (a) the RF generators, power supplies and transmission line components required are either already available, or are under development for ITER, and (b) mechanical and material issues associated with the proposed FWCD antenna structures appear challenging, but will need solving on a wider basis across DEMO.

JET ICRH plant faults from 2008 - 2012 have been catalogued and a new assessment of the reliability of the plant by sub-system is given. Data from pulses where ICRH was used, excluding the ITER-Like Antenna (ILA) and its generators, has been collated. This is compared to fault data in order to investigate any correlation between faults and operations. The number of faults is shown to have decreased between 2011-2012 in comparison to 2008-2009 as the time between faults is shown to have increased. Future electronic fault logging requirements to enable easier analysis are discussed. Due to the changing configuration of the ICRH plant; the introduction of ELM tolerant systems, generator upgrade, changes to the settings of the VSWR protection et cetera, a method to expand the fault database to include more historical data [1] in a consistent way are discussed.

T cells play a key role in the control of abnormal B cell proliferation. Factors that play a role in inadequate T cell responses include absence of expression of costimulatory and adhesion molecules by the malignant B cells and lack of cytotoxic T cells specific for tumor-associated antigens. A number of approaches have been used to enhance T cell response against malignant B cells. Agents such as soluble CD40 ligand can enhance expression of costimulatory molecules by the malignant B cells and improve their ability to activate T cells. Anti-CD3-based bispecific antibodies can retarget T cells toward the tumor cells irrespective of T cell specificity. We used the V 38C13 murine lymphoma model to assess whether the combination of soluble CD40 ligand and anti-CD3-based bispecific antibody can enhance T cell activation induced by malignant B cells more effectively than either approach alone. Expression of CD80, CD86, and ICAM-1 on lymphoma cells was up-regulated by soluble CD40 ligand. Syngeneic T cells were activated more extensively by lymphoma cells when the lymphoma cells were pre-treated with soluble CD40 ligand. Bispecific-antibody induced T cell activation was more extensive when lymphoma cells pretreated with soluble CD40 ligand were present. The combination of soluble CD40 ligand plus bispecific antibody enhanced the median survival of mice compared to mice treated with bispecific antibody alone. We conclude that pretreatment of tumor cells with agents capable of inducing costimulatory molecule expression, such as soluble CD40 ligand can enhance the ability of malignant B cells to activate T cells. This effect is enhanced by the addition of bispecific antibody. The combination of enhanced expression of costimulatory molecules and retargeting of T cells by bispecific antibody may allow for a more effective T-cell-based immunotherapy.

Recent advances in our understanding of the immune response are allowing for the logical design of new approaches to cancer immunization. One area of interest is the development of new immune adjuvants. Immunostimulatory oligodeoxynucleotides containing the CpG motif (CpG ODN) can induce production of a wide variety of cytokines and activate B cells, monocytes, dendritic cells, and NK cells. Using the 38C13 B cell lymphoma model, we assessed whether CpG ODN can function as immune adjuvants in tumor antigen immunization. The idiotype served as the tumor antigen. Select CpG ODN were as effective as complete Freund’s adjuvant at inducing an antigen-specific antibody response but were associated with less toxicity. These CpG ODN induced a higher titer of antigen-specific IgG2a than did complete Freund’s adjuvant, suggesting an enhanced TH1 response. Mice immunized with CpG ODN as an adjuvant were protected from tumor challenge to a degree similar to that seen in mice immunized with complete Freund’s adjuvant. We conclude that CpG ODN are effective as immune adjuvants and are attractive as part of a tumor immunization strategy.