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Abstract Background SUNRISE, a global, double-bind, Phase III trial of docetaxel (D) plus bavituximab (B) or D plus placebo (P) in previously treated non-squamous non-small cell lung cancer (NSCLC), demonstrated similar overall survival (OS) in both treatment arms. Immune correlate analyses including pre-treatment IFN-γ levels in blood and tumor tissue were used to potentially identify prognostic and/or predictive correlation with clinical outcome. Methods Serum was isolated from all randomized NSCLC patients at screening, periodically during treatment and at disease progression for evaluation of IFN-γ levels using the SimoaTM assay (Myriad RBM, Austin, TX, USA). Available archival tissue was also tested for 91- immune gene activation markers, including IFN-γ by the Fluidigm-based gene-expression platform (Sirona Dx, Lake Oswego, OR, USA). Kaplan-Meier statistical methods and Cox proportion hazards models were utilized to evaluate and contrast the correlation of peripheral and intratumoral IFN-γ levels with OS. Patients were classified paradoxically as IFN-γ "low" with a favorable disease prognosis versus "high" associated with more aggressive disease based on the median. Results Pretreatment serum results were available for 582 out of the 597 randomized patients. Each patient was classified to be pre-treatment IFN-γ high or low (< cut-off) using cut-off 0.093 pg/ml, which is the median IFN-γ value in the D+B group. Median overall survival (mOS) in all patients with IFN-γ low is 11.3 months (95% confidence interval [CI], 10.1-13.5) versus 10.4 months (95% CI, 8.4-11.3) in all IFN-γ high; p=0.047. mOS of D+B arm is 11.6 months (95% CI, 10.2-13.9) and 11.1 months (95% CI, 9.1-14.7) in the D group; p=0.982 for IFN-γ low. mOS of D+B arm is 9.0 months (95% CI, 6.7-11.2) and 10.6 months (95% CI, 8.9-13.0) in the D group; p=0.252 for IFN-γ high. With the limited intratumoral IFN-γ gene expression data (n=33), no statistically significant correlation with OS was observed. Conclusions Correlative approaches identified low peripheral low IFN-γ at pretreatment as a biomarker of interest correlating with more favorable clinical outcomes and is consistent with the hypothesis that bavituximab may demonstrate more immunomodulatory effects in patients with “immune cold” tumors. Citation Format: Nikoletta Kallinteris, Leora Horn, Min Tang, Tobias Guennel, Shen Yin, Jennifer Lai, Joseph Shan, Rachel E. Sanborn. IFN-γ analysis in blood and tissue as a potential prognostic and/or predictive biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT159. doi:10.1158/1538-7445.AM2017-CT159

11603 Background: SUNRISE, a global, double-bind, Phase III trial of docetaxel (D) plus bavituximab (B) or D plus placebo (P) in previously treated non-squamous non-small cell lung cancer, demonstrated similar overall survival (OS) in both treatment arms. Biomarkers including pre-treatment PD-L1 expression are being retrospectively assessed in on-going exploratory analyses. Methods: Archival tissue obtained at the time of diagnosis was requested but not required in the SUNRISE trial. FFPE slides were stained with a panel of lymphoid cell markers: CD3+, CD8+, FoxP3+, PD-L1+, CD163+, CK+ and DAPI using a 6-plex quantitative immunohistochemistry (IHC) assay (OPAL, PerkinElmer, Hopkinton, MA, USA). Baseline PD-L1 expression was retrospectively scored on tumor cells (TC) as a percentage of PD-L1 expressing tumor cells: TC3≥50%, TC2≥5% and < 50%, TC1≥1% and < 5%, and TC0 < 1%. Cox regression models for PD-L1 IHC subgroup populations were used for correlation with OS. Results: In the subset of patients with available diagnostic biopsies (110 out of 597 randomized patients), the prevalence of PD-L1 expression was 5% for TC3, 18% for TC2/3, 35% for TC1/2/3, 65% for TC0. Median OS (mOS) of the D+B arm is 11.5 months (TC0, < 1%) and 6.0 months (TC1/2/3, ≥1%) with HR 0.38 (95% CI, 0.19-0.76); p-value = 0.004. mOS of the D+P arm is 11.1 months (TC0, < 1%) and 10.4 months (TC1/2/3, ≥1%) with HR 0.93 (95% CI, 0.47-1.87); p value = 0.844. Conclusions: Baseline PD-L1 expression in a subset of SUNRISE patients demonstrated that PD-L1 expression (TC0) was associated with a significantly prolonged OS compared to positive PD-L1 expression (TC1/2/3) in patients receiving D+B. No difference in OS was observed in the D+P group by PD-L1 expression. These observations are consistent with the hypothesis that bavituximab may demonstrate more effect in PD-L1 negative or low expressing “immune cold” tumors. Clinical trial information: NCT01999673.

Purpose:PGN650 is a F(ab′)2 antibody fragment that targets phosphatidylserine (PS), a marker normally absent that becomes exposed on tumor cells and tumor vasculature in response to oxidative stress and increases in response to therapy. PGN650 was labeled with 124I to create a positron emission tomography (PET) agent as an in vivo biomarker for tumor microenvironment and response to therapy. In this phase 0 study, we evaluated the pharmacokinetics, safety, radiation dosimetry, and tumor targeting of this tracer in a cohort of patients with cancer.Methods:Eleven patients with known solid tumors received approximately 140 MBq (3.8 mCi) 124I-PGN650 intravenously and underwent positron emission tomography–computed tomography (PET/CT) approximately 1 hour, 3 hours, and either 24 hours or 48 hours later to establish tracer kinetics for the purpose of calculating radiation dosimetry (from integration of the organ time-activity curves and OLINDA/EXM using the adult male and female models).Results:Known tumor foci demonstrated mildly increased uptake, with the highest activity at the latest imaging time. There were no unexpected adverse events. The liver was the organ receiving the highest radiation dose (0.77 mGy/MBq); the effective dose was 0.41 mSv/MBq.Conclusion:Although 124I-PGN650 is safe for human PET imaging, the tumor targeting with this agent in patients was less than previously observed in animal studies.

Ebolaviruses causes a severe and often fatal hemorrhagic fever in humans, with some species such as Ebola virus having case fatality rates approaching 90%. Currently the worst Ebola virus outbreak since the disease was discovered is occurring in West Africa. Although thought to be a zoonotic infection, a concern is that with increasing numbers of humans being infected, Ebola virus variants could be selected which are better adapted for human-to-human transmission. To investigate whether genetic changes in Ebola virus become established in response to adaptation in a different host, a guinea pig model of infection was used. In this experimental system, guinea pigs were infected with Ebola virus (EBOV), which initially did not cause disease. To simulate transmission to uninfected individuals, the virus was serially passaged five times in naive animals. As the virus was passaged, virulence increased and clinical effects were observed in the guinea pig. An RNAseq and consensus mapping approach was then used to evaluate potential nucleotide changes in the Ebola virus genome at each passage. Upon passage in the guinea pig model, EBOV become more virulent, RNA editing and also coding changes in key proteins become established. The data suggest that the initial evolutionary trajectory of EBOV in a new host can lead to a gain in virulence. Given the circumstances of the sustained transmission of EBOV in the current outbreak in West Africa, increases in virulence may be associated with prolonged and uncontrolled epidemics of EBOV.

Background: Despite recent advances in the treatment of metastatic pancreatic cancer, there remains a critical need to develop novel therapeutic strategies that are more effective and less toxic than standard chemotherapy. Targeting the tumor microenvironment in pancreatic cancer may impair tumor growth and metastases. Bavituximab is a monoclonal antibody directed against phosphatidylserine (PS), an anionic membrane phospholipid. PS is absent from normal endothelial cell surfaces. However, in the tumor microenvironment, vascular endothelial cells externalize PS on the cell surface in response to stress conditions resulting from hypoxia and reactive oxygen species. Bavituximab selectively binds to PS on pre-existing tumor blood vessels and limits tumor blood flow. Preclinical data in orthotopic pancreatic tumors in mice indicate that gemcitabine (G) increases PS exposure and the addition of bavituximab may augment the anti-tumor effect by targeting the tumor9s vascular support. Based on promising preclinical and phase I data of the combination of G plus bavituximab it is expected this combination will produce enhanced antitumor activity compared to G alone in patients with advanced pancreatic cancer. Methods: The current randomized open-label, controlled, multicenter phase 2 study is evaluating the addition of bavituximab to standard first line G compared with G alone in patients with Stage IV pancreatic carcinoma. Patients are randomized at a ratio of 1:1 and stratified by CA 19-9 level Citation Format: Shuchi Sumant Pandya, Lucas Wong, Tony R. Reid, Stephen A. Grabelsky, Merrill Kingman Shum, Kerstin B. Menander, Joseph Shan. A randomized open-label phase 2 trial of gemcitabine with or without bavituximab in patients with previously untreated stage IV pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B34.

Abstract Tumors contain both microscopic and macroscopic areas of necrotic cells. These have abnormal cell membrane permeability, which allows passage of large macromolecules such as antibodies into the cell. 131I-chTNT-1/B antibody (Cotara) is a novel, single administration agent designed to target tumor necrosis that has completed a Phase II clinical trial for recurrent glioblastoma multiforme (GBM), showing 9.3 month median overall survival for patients. Since 131I-chTNT-1/B antibody is a high-molecular-mass protein, it cannot easily pass from the systemic circulation through the blood-brain barrier (BBB) and thus can only be delivered locally by an intratumoral catheter. We have developed a human ME-180 cervical carcinoma xenograft tumor model in nude mice to characterize the targeting of chTNT-1/B to necrotic areas using near infrared (NIR) optical imaging. The use of NIR optical imaging is a powerful translational tool to monitor in vivo antibody targeting. chTNT-1/B was labeled with a NIR fluorescent dye and kinetics of antibody retention in tumors was measured by NIR optical imaging following intratumoral injection of the NIR-chTNT-1/B. NIR-chTNT-1/B was retained in ME180 tumors for a longer duration compared to NIR dye alone. Labeling of chTNT-1/B with a low dye/protein ratio was necessary to demonstrate maximum specific targeting to tumor necrosis. Evaluation of in vivo antibody targeting to tumors using NIR imaging may facilitate improvements for treatment of patients with malignant glioma with Cotara. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2454. doi:1538-7445.AM2012-2454

Abstract Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane that becomes exposed on tumor vascular endothelial cells and tumor cells in response to chemotherapy, irradiation and oxidative stresses in the tumor microenvironment. Binding of antibodies targeting PS on the tumor endothelial cells and tumors leads to recruitment of immune cells and engagement of the immune system to destroy tumor vasculature. The antibodies also enhance anti-tumor immunity by blocking the immunosuppressive action of PS. In Phase II trials a chimeric anti-PS antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors. In the present study, we demonstrate imaging of primary tumor and metastases using real-time, near infrared fluorescence imaging of antibodies that specifically target PS. Tumor formation, proliferation rate and location of metastases were monitored by bioluminescence imaging (BLI) and near-infrared optical imaging of PS exposure using a near infrared dye-labeled (NIR) PGN635 F(ab')2 antibody fragment. PGN635 binds PS through the interaction of beta-2-glycoprotein 1 (2GP1) in the same manner as bavituximab binding to 2GP1 in humans. Specific co-localization of BLI and NIR-labeled PGN635 F(ab')2 was observed in tumors compared to a NIR-labeled isotype control antibody. Chemotherapy was shown to enhance the binding of PS-targeting antibodies to both primary and metastatic tumors. These data provide a rationale to image PS expression as a way to localize primary tumors or metastases and to monitor induced PS expression during the course of chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B116.

The primary aim of this study was to evaluate the biodistribution and toxicity of 131I-chimeric(ch) TNT-1/B monoclonal antibody (MAB), which binds to intracellular antigens of necrotic regions within tumors, in patients with advanced colon or colorectal cancer. The rationale for targeting areas of tumor necrosis is the observation that necrotic lesions are more abundant in cancer lesions than in surrounding tissues. Cohorts of patients with advanced colon or colorectal cancer were administered a one-time 30-60-minute intravenous (i.v.) infusion of 131I-chTNT-1/B at doses ranging from 12.95 to 66.23 MBq/kg (0.35-1.79 mCi/kg). The dose-limiting toxicity, experienced at 66.23 MBq/kg (1.79 mCi/kg) 131I-chTNT-1/B MAB, was myelosuppression. Two (2) patients at the 66.23-MBq/kg (1.79 mCi/kg) dose level had both grade 3 thrombocytopenia and grade 3 neutropenia that persisted for at least 2 weeks but were reversible. The maximum tolerated dose was 58.09 MBq/kg (1.57 mCi/kg) 131I-chTNT-1/B MAB. Of the 21 patients, one developed a moderate human antichimeric antibody (HACA) response and 6 developed low HACA responses. The infusion of 131I-chTNT-1/B MAB was well tolerated, without significant nonhematological toxicity. No patient obtained a complete or partial response, based on tumor cross-product response criteria. Tumor localization was seen in patients with dose levels at, and exceeding, 50.23 MBq/kg (1.36 mCi/kg) 131I-chTNT-1/B MAB.