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Introduction: Although checkpoint inhibitors (CPIs) have improved outcomes for patients with metastatic melanoma, those progressing on CPIs have limited therapeutic options. To address this unmet need and overcome CPI resistance mechanisms, novel immunotherapies, such as T-cell engaging agents, are being developed. The use of these agents has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs), which is challenging to predict preclinically and can lead to neutralization of the drug and loss of efficacy. Methods: TYRP1-TCB (RO7293583; RG6232) is a T-cell engaging bispecific (TCB) antibody that targets tyrosinase-related protein 1 (TYRP1), which is expressed in many melanomas, thereby directing T cells to kill TYRP1-expressing tumor cells. Preclinical studies show TYRP1-TCB to have potent anti-tumor activity. This first-in-human (FIH) phase 1 dose-escalation study characterized the safety, tolerability, maximum tolerated dose/optimal biological dose, and pharmacokinetics (PK) of TYRP1-TCB in patients with metastatic melanoma (NCT04551352). Results: Twenty participants with cutaneous, uveal, or mucosal TYRP1-positive melanoma received TYRP1-TCB in escalating doses (0.045 to 0.4 mg). All participants experienced ≥1 treatment-related adverse event (TRAE); two participants experienced grade 3 TRAEs. The most common toxicities were grade 1-2 cytokine release syndrome (CRS) and rash. Fractionated dosing mitigated CRS and was associated with lower levels of interleukin-6 and tumor necrosis factor-alpha. Measurement of active drug (dual TYPR1- and CD3-binding) PK rapidly identified loss of active drug exposure in all participants treated with 0.4 mg in a flat dosing schedule for ≥3 cycles. Loss of exposure was associated with development of ADAs towards both the TYRP1 and CD3 domains. A total drug PK assay, measuring free and ADA-bound forms, demonstrated that TYRP1-TCB-ADA immune complexes were present in participant samples, but showed no drug activity in vitro. Discussion: This study provides important insights into how the use of active drug PK assays, coupled with mechanistic follow-up, can inform and enable ongoing benefit/risk assessment for individuals participating in FIH dose-escalation trials. Translational studies that lead to a better understanding of the underlying biology of cognate T- and B-cell interactions, ultimately resulting in ADA development to novel biotherapeutics, are needed. [ABSTRACT FROM AUTHOR]

Introduction: Angiopoetin-2 (Ang-2) is a key mediator of tumour angiogenesis. When upregulated it is associated with tumour progression and poor prognosis. Anti-vascular endothelial growth factor (VEGF) therapy has been widely used in the treatment of metastatic colorectal cancer (mCRC). The potential benefit of combined inhibition of Ang-2 and VEGF-A in previously untreated patients with mCRC was evaluated in the phase II McCAVE study (NCT02141295), assessing vanucizumab versus bevacizumab (VEGF-A inhibitor), both in combination with mFOLFOX-6 (modified folinic acid [leucovorin], fluorouracil and oxaliplatin) chemotherapy. To date, there are no known predictors of outcome of antiangiogenic treatment in patients with mCRC. In this exploratory analysis, we investigate potential predictive biomarkers in baseline samples from McCAVE participants. Methods: Tumour tissue samples underwent immunohistochemistry staining for different biomarkers, including Ang-2. Biomarker densities were scored on the tissue images using dedicated machine learning algorithms. Ang-2 levels were additionally assessed in plasma. Patients were stratified by KRAS mutation status determined using next generation sequencing. Median progression-free survival (PFS) for each treatment group by biomarker and KRAS mutation was estimated using Kaplan-Meier plots. PFS hazard ratios (and 95% confidence intervals) were compared using Cox regression. Results: Overall low tissue baseline levels of Ang-2 were associated with longer PFS, especially in patients with wild-type KRAS status. In addition, our analysis identified a new subgroup of patients with KRAS wild-type mCRC and high levels of Ang-2 in whom vanucizumab/mFOLFOX-6 prolonged PFS significantly (logrank p=0.01) by ~5.5 months versus bevacizumab/mFOLFOX-6. Similar findings were seen in plasma samples. Discussion: This analysis demonstrates that additional Ang-2 inhibition provided by vanucizumab shows a greater effect than single VEGF-A inhibition in this subpopulation. These data suggest that Ang-2 may be both a prognostic biomarker in mCRC and a predictive biomarker for vanucizumab in KRAS wild-type mCRC. Thus, this evidence can potentially support the establishment of more tailored treatment approaches for patients with mCRC. [ABSTRACT FROM AUTHOR]

Background: Ideally, monoclonal antibodies provide selective treatment by targeting the tumour, without affecting normal tissues. Therefore, antibody imaging is of interest, preferably in early stages of drug development. However, the imaging signal consists of specific, as well as non-specific, uptake. The aim of this study was to assess specific, target-mediated uptake in normal tissues, with immuno-PET in a phase I dose escalation study, using the anti-CD44 antibody RG7356 as example. Results: Data from thirteen patients with CD44-expressing solid tumours included in an imaging sub-study of a phase I dose escalation clinical trial using the anti-CD44 antibody RG7356 was analysed. Zirconium-labelled RG7356 (1 mg; 37 MBq) was administered after a variable dose of unlabelled RG7356 (0 to 675 mg). Tracer uptake in normal tissues (liver, spleen, kidney, lung, bone marrow, brain and blood pool) was used to calculate the area under the time antibody concentration curve (AUC) and expressed as tissue-to-blood AUC ratios. Within the dose range of 1 to 450 mg, tissue-to-blood AUC ratios decreased from 10.6 to 0.75 ± 0.16 for the spleen, 7.5 to 0.86 ± 0.18 for the liver, 3.6 to 0.48 ± 0.13 for the bone marrow, 0.69 to 0.26 ± 0.1 for the lung and 1.29 to 0.56 ± 0.14 for the kidney, indicating dose-dependent uptake. In all patients receiving ≥ 450 mg ( n = 7), tumour uptake of the antibody was observed. Conclusions: This study demonstrates how immuno-PET in a dose escalation study provides a non-invasive technique to quantify dose-dependent uptake in normal tissues, indicating specific, target-mediated uptake. [ABSTRACT FROM AUTHOR]

Double-stranded ribonucleic acid (dsRNA) serves as a danger signal associated with viral infection and leads to stimulation of innate immune cells. In contrast, the immunostimulatory potential of single-stranded RNA (ssRNA) is poorly understood and innate immune receptors for ssRNA are unknown. We report that guanosine (C)- and uridine (U)-rich ssRNA oligonucleotides derived from human immunodeficiency virus-1 (HIV-1) stimulate dendritic cells (DC) and macrophages to secrete interferon-α and proinflammatory, as well as regulatory, cytokines. By using Toll-like receptor (TLR)-deficient mice and genetic complementation, we show that murine TLR7 and human TLR8 mediate species-specific recognition of GU-rich ssRNA. These data suggest that ssRNA represents a physiological ligand for TLR7 and TLR8. [ABSTRACT FROM AUTHOR]

Loxoribine (7-allyl-7,8-dihydro-8-oxo-guanosine) acts as synthetic adjuvant in anti-tumor responses. Here we first demonstrate that loxoribine activates cells of the innate immune system selectively via the Toll-like receptor (TLR) 7/MyD88-dependent signaling pathway. TLR7- and MyD88-deficient immune cells fail to proliferate or produce cytokines in response to loxoribine, and genetic complementation of TLR7-deficient cells with murine or human TLR7 confers responsiveness. Subsequently we show that cellular activation by loxoribine and resiquimod (R-848), a stimulus for TLR7 and TLR8, depends on acidification and maturation of endosomes and targets MyD88 to vesicular structures with lysosomal characteristics. This mode of TLR7 and TLR8 action resembles CpG-DNA-driven TLR9 activation. We thus conclude that TLR7, 8 and 9 form a functional subgroup within the TLR family that recognizes pathogen-associated molecular patterns in endosomal/lysosomal compartments. [ABSTRACT FROM AUTHOR]

Reports that human toll-like receptors (TLRs) can independently mediate recognition of the same antiviral compound, imidazoquinoline resiquimod (R-848). Identification of ligands for TLRs; Sensitivity of TLR7 to R-848.

Vanucizumab is a novel bispecific antibody inhibiting vascular endothelial growth factor (VEGF-A) and angiopoietin-2 (Ang-2) that demonstrated safety and anti-tumor activity in part I of a phase I study of 42 patients with advanced solid tumors. Part II evaluated the pharmacodynamic effects of vanucizumab 30 or 15 mg/kg every 2 weeks in 32 patients. Serial plasma samples, paired tumor, and skin-wound-healing biopsies were taken over 29 days to evaluate angiogenic markers. Vanucizumab was associated with marked post-infusion reductions in circulating unbound VEGF-A and Ang-2. By day 29, tumor samples revealed mean reductions in density of microvessels (-32.2%), proliferating vessels (-47.9%) and Ang-2 positive vessels (-62.5%). Skin biopsies showed a mean reduction in density of microvessels (-49.0%) and proliferating vessels (-25.7%). Gene expression profiling of tumor samples implied recruitment and potential activation of lymphocytes. Biopsies were safely conducted. Vanucizumab demonstrated a consistent biological effect on vascular-related biomarkers, confirming proof of concept. Skin-wound-healing biopsies were a valuable surrogate for studying angiogenesis-related mechanisms., Competing Interests: Declaration of Competing Interest The following authors are employees and shareholders of Roche Diagnostics GmbH: FH, GB, OK, SVH, KL; AJL is an employee of Soladis GmbH; CHO is an employee and shareholder of F. Hoffmann-La Roche AG; PG was an employee of Roche Innovation Center at the time of manuscript preparation, now retired; SR is an employee of F. Hoffmann-La Roche; AL and NW are employees of Roche Diagnostics GmbH; MH has received honoraria for acting as a speaker, consultant or advisory board member (Celgene, Pfizer, Novartis, MSD, EMD, Ipsem, Shire, SOBI, Champions Oncology, Agenus, Erytech, Pharmacyte, Bioline, BioOncotech, Oncomatrix, VCN, Bayer, BMS, Nelum, Eng T Cells), holds stock (Champions Oncology, Pharmacyte, BioOncotech, Nelum, Eng T Cell), and has received royalties (Myriad) and financial support paid to his institution for clinical trials or research grants (Berg, Bioline, Pfizer, EMD, Celgene, ASANA, Bycicle, Oncomatrix, BioExcell, Erytech); CM has acted as principal/sub-investigator of clinical trials (AbbVie, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare AG, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech AG, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Exelixis, Forma, Gamamabs, Genentech, Inc., Gilead Sciences, Inc, GlaxoSmithKline, Glenmark Pharmaceuticals, H3 Biomedicine, Inc, F. Hoffmann-La Roche AG, Incyte Corporation, Innate Pharma, Iris Servier, Janssen Cilag, Kura Oncology, Kyowa Kirin Pharm, Eli Lilly, Loxo Oncology, Lytix Biopharma AS, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology NV, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre, Rigontec GmbH, F. Hoffmann-La Roche, Sanofi Aventis, Sierra Oncology, Taiho Pharma, Tesaro, Inc., Tioma Therapeutics, Inc., Xencor), received research grants (AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, F. Hoffmann-La Roche, Sanofi), received non-financial support (drug supplied) (AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Johnson & Johnson, Eli Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche) and received consultant/advisory fees (Amgen, Astellas, Astra Zeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Eli Lilly, MedImmune, Novartis, Pfizer, F. Hoffmann-La Roche, Sanofi, Orion); MMG has acted as consultant/advisory board member (F. Hoffmann-La Roche) and received travel expenses (F. Hoffmann-La Roche, Pfizer); ClT has participated in advisory boards (AstraZeneca, F. Hoffmann-La Roche, MSD, BMS, Merck Serono, GSK, Nanobiotix, Amgen); MK is a co-founder and shareholder of HistoGeneX N.V., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Bevacizumab, a VEGF-A inhibitor, in combination with chemotherapy, has proven to increase progression-free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angiogenic factor angiopoetin-2 (Ang-2) is associated with poor prognosis in many cancers, including mCRC. Preclinical models demonstrate improved activity when inhibiting both VEGF-A and Ang-2, suggesting that the dual VEGF-A and Ang-2 blocker vanucizumab (RO5520985 or RG-7221) may improve clinical outcomes. This phase II trial evaluated the efficacy of vanucizumab plus modified (m)FOLFOX-6 (folinic acid (leucovorin), fluorouracil (5-FU) and oxaliplatin) versus bevacizumab/mFOLFOX-6 for first-line mCRC., Patients and Methods: All patients received mFOLFOX-6 and were randomized 1:1 to also receive vanucizumab 2,000 mg or bevacizumab 5 mg/kg every other week. Oxaliplatin was given for eight cycles; other agents were continued until disease progression or unacceptable toxicity for a maximum of 24 months. The primary endpoint was investigator-assessed PFS., Results: One hundred eighty-nine patients were randomized (vanucizumab, n = 94; bevacizumab, n = 95). The number of PFS events was comparable (vanucizumab, n = 39; bevacizumab, n = 43). The hazard ratio was 1.00 (95% confidence interval, 0.64-1.58; p = .98) in a stratified analysis based on number of metastatic sites and region. Objective response rate was 52.1% and 57.9% in the vanucizumab and bevacizumab arm, respectively. Baseline plasma Ang-2 levels were prognostic in both arms but not predictive for treatment effects on PFS of vanucizumab. The incidence of adverse events of grade ≥3 was similar between treatment arms (83.9% vs. 82.1%); gastrointestinal perforations (10.8% vs. 8.4%) exceeded previously reported rates in this setting. Hypertension and peripheral edema were more frequent in the vanucizumab arm., Conclusion: Vanucizumab/mFOLFOX-6 did not improve PFS and was associated with increased rates of antiangiogenic toxicity compared with bevacizumab/mFOLFOX-6. Our results suggest that Ang-2 is not a relevant therapeutic target in first-line mCRC., Implications for Practice: This randomized phase II study demonstrates that additional angiopoietin-2 (Ang-2) inhibition does not result in superior benefit over anti-VEGF-A blockade alone when each added to standard chemotherapy. Moreover, the performed pharmacokinetic and pharmacodynamic analysis revealed that vanucizumab was bioavailable and affected its intended target, thereby strongly suggesting that Ang-2 is not a relevant therapeutic target in the clinical setting of treatment-naïve metastatic colorectal cancer. As a result, the further clinical development of the dual VEGF-A and Ang-2 inhibitor vanucizumab was discontinued., (© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Experimental Design: Patients received escalating biweekly (3-30 mg/kg) or weekly (10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in K TRANS (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation. Conclusions: Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. Clin Cancer Res; 24(7); 1536-45. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Transmembrane glycoprotein CD44 is overexpressed in various malignancies. Interactions between CD44 and hyaluronic acid are associated with poor prognosis, making CD44 an attractive therapeutic target. We report results from a first-in-human phase I trial of RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, in patients with advanced CD44-expressing solid malignancies.Sixty-five heavily pretreated patients not amenable to standard therapy were enrolled and received RG7356 intravenously biweekly (q2w) or weekly (qw) in escalating doses from 100 mg to 2,250 mg. RG7356 was well tolerated. Most frequent adverse events were fever, headache and fatigue. Dose-limiting toxicities included headache (1,500 mg q2w and 1,350 mg qw) and febrile neutropenia (2,250 mg q2w). The maximum tolerated dose with q2w dosing was 1,500 mg, but was not defined for qw dosing due to early study termination. Clinical efficacy was modest; 13/61 patients (21%) experienced disease stabilization lasting a median of 12 (range, 6-35) weeks. No apparent dose- or dose schedule-dependent changes in biological activity were reported from blood or tissue analyses. Tumor-targeting by positron emission tomography (PET) using 89Zr-labeled RG7356 was observed for doses ≥200 mg (q2w) warranting further investigation of this agent in combination regimens.

Purpose: CD44, a cell surface glycoprotein, plays important roles in the development, progression, and metastasis of various tumor types. The aim of this study was to investigate how the expression of CD44 isoforms influences the interaction with hyaluronic acid (HA) and how differential isoform expression impacts antitumoral responses in vivo to treatment with RG7356, a humanized anti-CD44 antibody inhibiting CD44-HA interaction., Experimental Design: CD44 isoform expression on various tumor cell lines was analyzed by RNASeq while data on patients with different tumor types were obtained from the publicly available TCGA RNASeq dataset as well as a phase I clinical study (NCT01358903). We analyzed the link between HA production and CD44 isoform expression as well as the consequences of blocking the CD44-mediated cell adhesion to HA using RG7356. The correlation between CD44 isoform expression and antitumor response to RG7356 treatment was investigated in the corresponding murine xenograft in vivo models as well as in a subset of patients treated with RG7356 from a recently completed phase I clinical trial., Results: CD44 isoform expression, in particular expression of CD44s, is associated with HA production and predicts response to treatment with RG7356 in tumor xenograft models. Furthermore, patient data suggest that CD44 isoform status is a potential predictive biomarker for clinical response to treatment with RG7356., Conclusions: We provide new insights into the close interplay between CD44 and HA and a potential biomarker to enrich patient responses to RG7356 in the clinic., (©2015 American Association for Cancer Research.)