Medicine and Health Sciences Commons^™

Preliminary Results From A First-In-Human Phase 1 Study Of The Cd40 Agonist Monoclonal Antibody (Mab) Cdx-1140, Rachel Sanborn, Michael S. Gordon, Mark O'Hara, Nina Bhardwaj, Yi He, Tracey Rawls, Tibor Keler, Michael Yellin

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: Agonist CD40 mAbs can mediate antitumor immunity through multiple mechanisms, including enhancing tumor antigen presentation, activation of tumoricidal macrophages, and direct growth inhibition/killing of CD40- expressing tumor cells. To fully exploit these mechanisms may require the mAb to be dosed at levels that provide significant tumor and tissue penetration, without dose-limiting-toxicities (DLT) from systemic CD40 activation. Our agonist CD40 mAb, CDX-1140, was selected based on its unique and linear dose-dependent in vitro and in vivo activity and is postulated will achieve maximum agonist activity at dose levels associated with good systemic exposure. CDX-1140 is a fully human IgG2 agonist …

Delayed Immune-Related Events After Discontinuation Of Immunotherapy – Dire Syndrome?, Marcus Couey, R. Bryan Bell, Ashish Patel, Marka R Crittenden, Brendan Curti, Rom Leidner

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: Although the temporality of immune-related adverse events (irAE) is well-recognized during immunotherapy to be highly variable and often delayed,[1] post-immunotherapy irAE are rarely described and potentially under-recognized. In 2013, two cases were reported in abstract form in Deutschen Dermatologischen Gesellschaft.[2] In July 2018 a case of autoimmune hepatitis eight months post-immunotherapy was reported in The Oncologist[3] and a dermatologic series appeared online in JAMA Dermatology.[4] With expanding indications for IO and an increasing number of clinical trials in the curative-neoadjuvant setting, larger numbers of patients are being treated in earlier stages of disease and often for short courses. Given …

Mv-626, A Potent And Selective Inhibitor Of Enpp1 Enhances Sting Activation And Augments T-Cell Mediated Anti-Tumor Activity In Vivo, Jason Baird, Gregory Dietsch, Vincent Florio, Michael Gallatin, Clayton Knox, Joshua Odingo, Marka Crittenden, Michael J. Gough

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: STING is an endogenous sensor of cGAMP, which is synthesized by cGAS following detection of cytoplasmic DNA. STING activation leads to interferon production and activation of inflammatory pathways that facilitate cytolytic T cell priming. STING agonists administered intratumorally show potent anti-tumor efficacy in a range of preclinical models; several agonists are in clinical development. Radiation therapy also increases cytoplasmic DNA levels in cancer cells, resulting in STING activation and secretion of inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the phosphodiesterase that negatively regulates STING by hydrolyzing cGAMP. MV-626, a highly potent and selective ENPP1 inhibitor with 100% oral bioavailability …

Inducible T Cell Co-Stimulator (Icos) Is Upregulated On Lymphocytes Following Radiation Of Tumors And Icos Agonism In Combination With Radiation Results In Enhanced Tumor Control, Michael J. Gough, Shelly Bambina, Monica Gostissa, Christopher Harvey, David Friedman, Marka R Crittenden

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: Radiation and co-stimulatory ligands or checkpoint inhibitors have demonstrated improved anti-tumor immunity and overall survival in preclinical animal studies. However, the results of human trials suggest we have not yet found the optimal combination. Here we demonstrate upregulation of ICOS expression on T cells following focal tumor radiation and test the hypothesis that ICOS agonism in combination with radiation will enhance the immunologic effect of radiation resulting in increased survival.

Methods: BALB/c mice bearing CT26 tumors or C57BL/6 mice bearing Panc02 tumors were treated at d14 with 20Gy CT guided radiation therapy and anti-ICOS antibody or isotype control antibody …

Pegzilarginase In Combination With Agonist Anti-Ox40 Therapy Enhances T Cell Priming And Effector Function Leading To Improved Tumor Regression And Survival, Melissa Kasiewicz, Annah Rolig, Elizabeth Sturgill, Mark Badeaux, Scott Rowlinson, William L. Redmond

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: Tumor cells defective in enzymes required for arginine biosynthesis are dependent upon arginine uptake from the environment. Extracellular depletion of arginine directly affects tumor cells, inducing autophagy and apoptosis. Pegzilarginase (AEB1102) is a bioengineered, pegylated, human arginase 1 (Aeglea Biotherapeutics) currently in phase I clinical trials. This arginine-depleting agent has been shown to both inhibit arginine auxotrophic tumor growth and to enhance the efficacy of PD-L1 blockade in preclinical models. In the current study, we investigated the therapeutic efficacy and mechanism of action of combined pegzilarginase/anti-OX40 (aOX40) immunotherapy. We hypothesized that pegzilarginase/aOX40 treatment would synergize to enhance T cell …

Tumor Infiltrating Lymphocyte Recruitment After Peri-Lymphatic Irx-2 Cytokine Immunotherapy In Resectable Breast Cancer And Head And Neck Carcinoma, Joanna Pucilowska, Venkatesh Rajamanickam, Nikki Moxon, Monil Shah, Maritza Martel, Alison Conlin, James E. Egan, David B. Page

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: The IRX-2 biologic is a subcutaneous injectable immunotherapy composed of IL-2 and other cytokines derived from stimulated lymphocytes. Preclinically, IRX-2 activates T cells, natural killer cells, macrophages, and dendritic cells, and facilitates maturation of antigen-presenting cells.Tumor-infiltrating lymphocytes (TILs) are associated with improved outcomes in many cancers including early stage breast cancer (ESBC) and head and neck squamous cell carcinoma (HNSCC). We report data on TIL recruitment associated with pre-operative IRX-2 in a phase Ib ESBC trial, as well as phase Ib and IIa HNSCC trials.

Methods: The pre-operative IRX-2 regimen was evaluated in both ESBC and HNSCC trials for …

Open-Source Digital Image Analysis Of Whole-Slide Multiplex Immunohistochemistry, Nikhil Lonberg, Carmen Ballesteros-Merino, Shawn Jensen, Bernard A Fox

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: Successful digital image analysis (DIA) of cancer tissue is accurate and reproducible. These points of emphasis have brought procedures like the tissue microarray (TMA) and hotspot regions of interest (ROI) under scrutiny. The nature in which a pathologist selects TMAs and ROIs is conducive to bias. Whole Slide Imaging (WSI) offers a solution in its unbiased region selection and consideration of a larger tissue sample. However, options for softwares that can handle such large throughput are scarce. Additionally, while multiplex immunohistochemistry (mIHC) is becoming popular [1], documentation of its digital analysis tools remains minimal [2]. The combination of these …

Integrative Spatially-Resolved, High-Plex Digital Profiling Enables Characterization Of Complex Immune Biology In The Tumor Microenvironment Of Mesothelioma, Carmen Ballesteros-Merino, Moritz Widmaier, Sarah Church, Thomas Herz, Alexei Budco, Das Medrikova, Ivan Kanchev, Andrew White, Douglas Hinerfeld, Shawn Jensen, John Handy, Rachel Sanborn, Carlo Bifulco, Sarah Warren, Joseph Beechem, Bernard .. Fox

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: Malignant mesothelioma is an aggressive cancer with poor prognosis and few effective therapies. Since mesothelioma is derived from the mesothelium of the lung, we hypothesize that immune cells in the tumor microenvironment (TME) may behave differently than other solid tumors. In our previous studies, utilizing multi-plexed immunofluorescence, we did not find immune phenotypes associated with improved patient survival. Here we describe a novel combination of two technologies to spatially characterize the interface between mesothelioma cells, stroma and immune cells in the TME in a high-plex capacity.

Methods: Ten FFPE mesothelioma tumors were characterized by Definiens’ Immune-Oncology Profiling (IOP) and …

Single Cell Sequencing To Identify Tcrs That Recognize Autologous Tumor Cells After Vaccination With Allogeinic Dribble Vaccine, Hong-Ming Hu, Christopher C. Paustian, Zhifa Wen, Tarsem L. Moudgil, Traci L. Hilton, Sam Bookhardt, Guangjie Yu, Eric Tran, Venkatesh Rajamanickam, Walter Urba, Rachel E. Sanborn, Bernard A. Fox

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: Adoptive immunotherapy with tumor-specific TCR gene-modified T cells has the potential to eradicate bulky disease. Traditional methods of TCR identification require lengthy in vitro culture to generate clonal T-cell populations, which adds time and complexity to this promising therapy. Here we described a simplified and reliable method to identify TCRs by single cell TCR sequencing of cells sorted with antibodies against T-cell surface markers that are up-regulated only when they are stimulated with specific tumor cell antigens.

Methods: A tumor-infiltrating lymphocyte (TIL) culture with T cells reactive against autologous tumor was generated from a brain metastasis of a patients …

Combined Anti-Pd-1 And Anti-Lag-3 Checkpoint Blockade Enhances Cd8+ Til Effector Function While Reducing Tregs Leading To Reduced Immune Suppression And Improved Overall Survival, Elizabeth Sturgill, Courtney Mick, David Jenkins, Johanna Kaufmann, William L. Redmond

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: Checkpoint inhibition is a potent strategy to reinvigorate T cells. However, aCTLA-4 or aPD-1 monotherapy has not been effective for the majority of patients, resulting in the exploration of combinatorial approaches to improve treatment efficacy. One such target is LAG-3, which is upregulated on T cells that have experienced repeated antigen exposure, such as in the tumor microenvironment (TME), and is associated with reduced T cell effector function. In addition, high LAG-3 expression on regulatory T cells (Tregs) has been reported for patients with varying cancer types, providing an additional rationale for targeting LAG-3 with the aim of reducing …

Preliminary Evaluation Of A Novel Whole Slide Multispectral Assessment Of Seven Markers: Potential To Minimize Bias In The Characterization Of The Tumor Immune Environment, Carmen Ballesteros Merino, Shawn Jensen, Carla Coltharp, Kristin Roman, Chichung Wang, Nikhil Lonberg, Sebastian Marwitz, Tarsem Moudgil, William Miller, William Redmond, Yoshinobu Koguchi, Carlo Bifulco, Clifford Hoyt, Bernard A. Fox

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: PD-L1 expression and tumor-mutational burden enrich for patients that respond to checkpoint blockade, but these evaluations are only a component of the entire story. Recently, our lab reported that evaluation of specific cell-cell relationships provided a powerful biomarker for overall survival in patients with HPV- head and neck cancer (HNSCC). However, the areas selected for analysis were operator selected “hot spots”. This approach introduces the potential for unconscious bias in the selection process. To address this, we have sought to perform whole slide evaluations of sections to compare with hot spot analysis. This study is a preliminary report applying …

Nktr-214 (Cd122-Biased Agonist) And Nktr-262 (Tlr7/8 Agonist) Combination Treatment Pairs Local Innate Immune Activation With Systemic Cd8+ T Cell Expansion To Enhance Anti-Tumor Immunity, Annah S. Rolig, Daniel Rose, Saul Kivimäe, Deborah Charych, Werner Rubas, Jonathan Zalevsky, William L. Redmond

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: Radiation therapy (RT) remains the standard of care for many human cancers. Combining NKTR-214, a CD122-biased cytokine agonist conjugated with releasable polyethylene-glycol (PEG) chains, with local RT significantly enhanced therapeutic efficacy in preclinical models. Mechanistically, NKTR-214 provides sustained signaling through the IL-2 receptor pathway (IL-2Rβγ) to preferentially activate and expand effector CD8+ T and NK cells and RT modulates the tumor microenvironment (TME) to induce antigen-release. Together, NKTR-214/RT treatment resulted in improved therapeutic responses compared to either treatment alone. However, abscopal responses in murine tumors were modest, leading us to explore alternative approaches with the potential to elicit more …

Mertk Is A Therapeutic Target In Combination With Radiation To Promote Adaptive Immune Tumor Responses, Garth Tormoen, Jason R Baird, Gwen Kramer, Shelly Bambina, Marka R Crittenden, Michael J. Gough

Society for Immunotherapy of Cancer 2018 Annual Meeting Posters

Background: Mertk is a member of the Tyro3-Axl-Mertk (TAM) family of receptors and regulates phagocytosis of dying cells by macrophages. Cancer cells killed by radiation therapy direct repolarization of macrophages into immune suppressive phenotypes. Mertk-/- mice grafted with immunogenic tumors have enhanced tumor control following ionizing radiation compared to Mertkwt mice. Gas6 is the endogenous ligand for Mertk and its ability to signal through Mertk requires a post-translational vitamin k-dependent modification that is inhibited by warfarin.

Methods: Mertk-/- and WT mice were injected subcutaneously in the flank with 5E4 CT26 cells (BALB/c) or 5E6 Panc02-SIY cells (C57BL/6) and allowed to …