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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. Clin Cancer Res; 21(12); 2753–62. ©2015 AACR.

Supplementary Methods, Figures (1-6) and Tables (1, 2 and 4). Supplementary Figure 1: Shows how RG7356 blocks binding of CD44-Fc to HA in a concentration dependent manner for two fixed CD44-Fc concentrations. Supplementary Figure 2: Shows hyaluronic acid levels in cell lysate and supernatant in 12 HEK293 clones transfected with CD44s. Clone 4 was selected for further experiments Supplementary Figure 3: Absolute signal of CD44s expression based on RNASeq data compared to CD44s levels measured by Westernblot (IM7 antibody). Supplementary Figure 4: Absolute signal of CD44v expression based on RNASeq data compared to the CD44v levels measured by Westernblot (BMSv6 antibody). Supplementary Figure 5: Western Blots of the 36 cancer cell lines used for Xenograft models using either IM7 or BMSv6 antibodies. Supplementary Figure 6: Western Blot analysis of CD44 isoform status in samples from 9 human tumor xenograft models using either IM7 or BMSv6 antibodies. Supplementary Table 1: Details for all xenograft models: cell line name, source, %TGI, CD44 isoform status, growth medium, inoculation site, treatment schedule and dose Supplementary Table 2: Cell line name, source, CD44 isoform status as well as hyaluronic acid levels in 36 human solid tumor cell lines. Supplementary Table 4: Number of genes found to be differentially regulated in BRCA, LUSC and UCEC cancer patients available in TCGA either expressing CD44s or CD44v.

Supplementary Tables 3, 5, 6 and 7. Supplementary Table 3: Contains the results of the differential gene expression analysis between CD44s HEK and native HEK cells (log ratios on the gene level and FDR corrected p-values) Supplementary Table 5: Contains the results of differential gene expression analysis between a subgroup of TCGA UECE patients expressing either CD44s or CD44v as major isoform (log ratio and FDR corrected p-values) Supplementary Table 6: Contains the results of differential gene expression analysis between a subgroup of TCGA BRCA patients expressing either CD44s or CD44v as major isoform (log ratio and FDR corrected p-values) Supplementary Table 7: Contains the results of differential gene expression analysis between a subgroup of TCGA LUSC patients expressing either CD44s or CD44v as major isoform (log ratio and FDR corrected p-values)

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 KTRANS (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.

Supplementary Table S1. Criteria for defining dose-limiting toxicities; Supplementary Table S2. Plasma pharmacokinetic parameters of vanucizumab on Cycles 1 and 4 following bi-weekly administration of ascending doses of vanucizumab; Supplementary Table S3. Plasma pharmacokinetic parameters of vanucizumab on Cycles 1 and 4 following weekly administration of ascending doses of vanucizumab.

Background RO7122290 (RO) is a potent next generation 4-1BB agonist simultaneously targeting fibroblast activation protein (FAP). FAP is highly expressed on cancer-associated fibroblasts in many solid tumors, while expression in healthy tissue is low. 4 1BB stimulation via FAP mediated cross linking augments the cytotoxicity, proliferation, and longevity of immune effector cells in FAP-positive tumors. RO was labelled with Zirconium-89 (89Zr) to visualize FAP-dependent tumor accumulation and assess the biodistribution in patients (pts) after successful proof of principle of 89Zr-based PET in preclinical pilot studies. Methods Pts with advanced and/or metastatic solid tumors were eligible for this sub-study of an ongoing Phase 1/1b trial (EUDRACT 2017-003961-83). RO was administered intravenously once at a total dose of 5, 45, 200 or 500 mg consisting of RO (cold) + 5 mg 89Zr-RO (hot, 37.0 [± 3.4] MBq).Up to three 89Zr-PET scans were performed over a period of nine days followed by a single tumor biopsy before pts could switch to Part A (single agent) and subsequently to Part B (combination with atezolizumab) of the main study to continue treatment. Tracer uptake was calculated as peak standardized uptake value (SUVPeak) of the lesion with the highest uptake. Results 14 pts were exposed to a total dose of 5, 45, 200 (all n=3) or 500 mg (n=5); median age was 60 years (range 26–74) with seven male and female pts each. Primary tumor sites included colon (n=4), lung (n=3), thymus (n=2), anus (n=1), breast (n=1), bile duct (n=1), pleura (n=1), and uvea (n=1). In healthy tissues, uptake of 89Zr-RO was predominantly observed in the liver and spleen across all doses and in non-malignant lymph nodes in 2/3 patients at 5 mg. Consistent with the target expression, tracer uptake was detected in FAP-positive scarring tissue and tissues with ongoing remodeling. Intra-tumoral accumulation of 89Zr-RO was observed at all doses. 96 hours p.i., SUVPeak values were 12.1 [± 4.1], 10.0 [± 4.9], and 7.0 [± 3.7] for the 5, 45 and 200 mg cohorts, respectively, while SUVPeak for the 500 mg cohort was even lower at 4.9 [± 0.5]. Conclusions 89Zr-PET confirmed tumor-specific uptake and expected biodistribution pattern of 89Zr-RO. The decrease in SUV with increasing doses suggest that more cold antibodies saturated FAP binding sites in the tumor. 89Zr-PET results supported together with clinical PK, PD, safety and response data the selection of the recommended phase 2 dose and schedule of RO in combination with atezolizumab.

Background RO7122290 (RO) is a bispecific antibody-like fusion protein that simultaneously targets FAP, abundantly expressed by cancer-associated fibroblasts in most solid tumors, and 4-1BB, transiently expressed on activated T cells. Pre-clinical experiments revealed strong intra-tumoral CD8+ T cells infiltration in FAP-positive tumors, cytokines induction and significant anti-tumor activity mediated by RO (signal 2 of T cell activation), upon TCR/CD3 engagement (signal 1) or in combination with atezolizumab (ATZ). In this first-in-human study, the pharmacodynamic (PD) effects of RO were assessed, both as single agent (SA) (Part A) and in combination with ATZ (Part B). Methods Pts with advanced and/or metastatic solid tumors were eligible for this ongoing Phase 1/1b trial (EUDRACT 2017-003961-83). RO was administered intravenously, weekly (QW) at escalating dose levels (DLs). In Part A, 62 pts were treated at 13 DLs of RO, dose range 5–2000 mg. In Part B, 39 pts were treated at 8 DLs of RO, dose range 45–2000 mg, with ATZ 1200 mg Q3W. Secondary biomarker objective was characterization of PD effects in tumor tissue and blood. The endpoints were change from baseline in intra-tumoral density (cell/mm2) and proliferation (Ki67) of CD8+ T cells measured by immunohistochemistry (IHC), and change in activation (4-1BB) and proliferation (Ki67) of peripheral CD8+ T cells measured by flow cytometry. Exploratory objectives were characterization of PD effects in plasma/serum and measurement of intra-tumoral immune activation. The endpoints were change in peripheral cytokines (TNF-alfa, IFN-gamma, IL-6) and soluble(s) factors (sCD25, s4-1BB) concentration measured by ELISA, and intra-tumoral changes in gene expression measured by RNAseq. Results In the periphery, we observed transient expression of 4-1BB on CD4+ and CD8+ T cells, along with secretion of s4-1BB and inflammatory cytokines, suggesting 4-1BB targeting and potent T cell activation. The concomitant induction of proliferating T cells indicated the potential association to priming and formation of tumor-reactive T cells. In the tumor, we detected increased CD8+ T cells infiltration and proliferation, in both Parts. Proliferating CD8+ T cells increased in both tumor nests and surrounding stroma, with a preferential accumulation in the latter. RNAseq analysis revealed induction of 4-1BB, PD-1 and IFN-gamma, indicating intra-tumoral T cells activation in Part B. Conclusions PD activity was consistent with the postulated MoA, confirming RO to be a potent tumor-targeted 4-1BB agonist in the clinical setting. Our observations suggest that RO can synergize with endogenous T cell receptor stimulation, both as SA and in combination with ATZ.

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 KTRANS (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.

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. 89Zirconium-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. Electronic supplementary material The online version of this article (10.1186/s13550-018-0358-8) contains supplementary material, which is available to authorized users.

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. Clin Cancer Res; 21(12); 2753–62. ©2015 AACR.

// C. Willemien Menke-van der Houven van Oordt 1 , Carlos Gomez-Roca 2 , Carla van Herpen 3 , Andrew L. Coveler 4 , Devalingam Mahalingam 5 , Henk M. W. Verheul 1 , Winette T. A. van der Graaf 3 , Randolph Christen 6 , Dominik Ruttinger 7 , Stefan Weigand 7 , Michael A. Cannarile 7 , Florian Heil 7 , Michael Brewster 8 , Antje-Christine Walz 9 , Tapan K. Nayak 9 , Ernesto Guarin 9 , Valerie Meresse 9 and Christophe Le Tourneau 10 1 Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands 2 Clinical Research Unit, Department of Medical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse – Oncopole, Toulouse, France 3 Radboud University Medical Center, Nijmegen, The Netherlands 4 Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA 5 Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA 6 Product Development, Safety Risk Management, Roche, Basel, Switzerland 7 Pharma Research & Early Development, Roche Innovation Center, Penzberg, Germany 8 Pharma Research & Early Development, Roche Innovation Centre, Welwyn, UK 9 Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland 10 Department of Medical Oncology, Institut Curie, Saint-Cloud & Paris, France, and Versailles-Saint-Quentin-en-Yvelines University, Versailles, France Correspondence to: C. Willemien Menke-van der Houven van Oordt, email: // Keywords : RG7356, anti-CD44 humanized antibody, advanced solid tumors, advanced CD44-expressing solid malignancies, phase I trial Received : March 28, 2016 Accepted : July 10, 2016 Published : August 05, 2016 Abstract 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 89 Zr-labeled RG7356 was observed for doses ≥200 mg (q2w) warranting further investigation of this agent in combination regimens.

We report a proof-of-mechanism study of RG7112, a small-molecule MDM2 antagonist, in patients with chemotherapy-naive primary or relapsed well-differentiated or dedifferentiated MDM2-amplified liposarcoma who were eligible for resection.Patients with well-differentiated or dedifferentiated liposarcoma were enrolled at four centres in France. Patients received up to three 28-day neoadjuvant treatment cycles of RG7112 1440 mg/m(2) per day for 10 days. If a patient progressed at any point after the first cycle, the lesion was resected or, if unresectable, an end-of-study biopsy was done. The primary endpoint was to assess markers of RG7112-dependent MDM2 inhibition and P53 pathway activation (P53, P21, MDM2, Ki-67, macrophage inhibitory cytokine-1 [MIC-1], and apoptosis). All analyses were per protocol. This trial is registered with EudraCT, number 2009-015522-10.Between June 3, and Dec 14, 2010, 20 patients were enrolled and completed pretreatment and day 8 biopsies. 18 of 20 patients had TP53 wild-type tumours and two carried missense TP53 mutations. 14 of 17 assessed patients had MDM2 gene amplification. Compared with baseline, P53 and P21 concentrations, assessed by immunohistochemistry, had increased by a median of 4·86 times (IQR 4·38-7·97; p=0·0001) and 3·48 times (2·05-4·09; p=0·0001), respectively, at day 8 (give or take 2 days). At the same timepoint, relative MDM2 mRNA expression had increased by a median of 3·03 times (1·23-4·93; p=0·003) that at baseline. The median change from baseline for Ki-67-positive tumour cells was -5·05% (IQR -12·55 to 0·05; p=0·01). Drug exposure correlated with blood concentrations of MIC-1 (p0·0001) and haematological toxicity. One patient had a confirmed partial response and 14 had stable disease. All patients experienced at least one adverse event, mostly nausea (14 patients), vomiting (11 patients), asthenia (nine patients), diarrhoea (nine patients), and thrombocytopenia (eight patients). There were 12 serious adverse events in eight patients, the most common of which were neutropenia (six patients) and thrombocytopenia (three patients).MDM2 inhibition activates the P53 pathway and decreases cell proliferation in MDM2-amplified liposarcoma. This study suggests that it is feasible to undertake neoadjuvant biopsy-driven biomarker studies in liposarcoma.F Hoffmann-La Roche.

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 (G)- 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.

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.

Early Phase I clinical development of RG7155, a humanized anti-CSF-1R monoclonal antibody binding to dimerization interface of CSF-1 receptor and inducing apoptosis in CSF-1R expressing macrophages is accompanied by an extensive biomarker program. Phase I biosampling aims to enable monitoring of mode of action, drug efficacy and potential tumor escape mechanisms by identifying response prediction and mechanistic efficacy markers and therefore to support optimal biological dose (OBD) definition and patient stratification for subsequent clinical testing. One biomarker hypothesis to support potential patient stratification assumes that response to treatment with RG7155 is enhanced in tumors with high CSF-1R positive macrophage infiltration and with high CSF-1 levels in the peripheral blood as the basis for tumor promoting macrophage recruitment and differentiation. The Phase I biomarker program comprises extensive biosampling including mandatory fresh baseline and on treatment tumor, skin biopsies as well as peripheral blood sampling to identify and monitor pharmacodynamic as well as mechanistic efficacy markers. Pre- and on-treatment tumor tissue analysis involves tumor infiltrating macrophage subtype characterization via CD68/CD163/CSF-1R/MHC II, CD4 and CD8 T cell assessment by multiplex IHC assays. In order to detect early tissue response prediction markers in surrogate tissue, wound associated macrophages (WAMs) are assessed in wounded skin tissue samples. Further, systematic collection of peripheral blood samples before and during RG7155 administration aims at identifying CSF-1R expressing target populations, other potential RG7155 susceptible immune cell populations by flow cytometry using CD8/CD4/CD3/CD45/MHC II/CD14/CD16/CD56/CD19 markers and an extended cytokine profiling by Luminex 17-plex panel. These markers will be correlated to direct anti-tumor effects assessed using KI67 IHC, FDG-PET, DC-Ultrasound and clinical response. Here we describe the development of the clinical biomarker strategy based on preclinical data and the specific assay developments, to enable the selection of the OBD, the correlation of TAM elimination with anti-tumor effects and the optimization of the biomarker sampling to minimize the burden of diagnostic procedures for patients in future clinical trials. Citation Format: Michael A. Cannarile, Kai Habben, Florian Heil, Ann-Marie Broeske, Dominik Ruettinger, Lisa Culton, Friedrich Feuerhake, Carola H. Ries. Exploratory biomarker program in Phase I clinical development of RG7155, a novel humanized anti-CSF-1R Mab, targeting Tumor Associated Macrophages (TAMs). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4719. doi:10.1158/1538-7445.AM2013-4719