Medicine and Health Sciences Commons^™

A Pilot Study Comparing The Efficacy Of Lactate Dehydrogenase Levels Versus Circulating Cell-Free Micrornas In Monitoring Responses To Checkpoint Inhibitor Immunotherapy In Metastatic Melanoma Patients., Matias A Bustos, Rebecca Gross, Negin Rahimzadeh, Hunter Cole, Linh T Tran, Kevin Tran, Ling Takeshima, Stacey L Stern, Steven O'Day, Dave Hoon

Articles, Abstracts, and Reports

Serum lactate dehydrogenase (LDH) is a standard prognostic biomarker for stage IV melanoma patients. Often, LDH levels do not provide real-time information about the metastatic melanoma patients' disease status and treatment response. Therefore, there is a need to find reliable blood biomarkers for improved monitoring of metastatic melanoma patients who are undergoing checkpoint inhibitor immunotherapy (CII). The objective in this prospective pilot study was to discover circulating cell-free microRNA (cfmiR) signatures in the plasma that could assess melanoma patients' responses during CII. The cfmiRs were evaluated by the next-generation sequencing (NGS) HTG EdgeSeq microRNA (miR) Whole Transcriptome Assay (WTA; 2083 …

The Society For Immunotherapy Of Cancer (Sitc) Clinical Practice Guideline On Immunotherapy For The Treatment Of Acute Leukemia., Michael M Boyiadzis, Ivan Aksentijevich, Daniel A Arber, John Barrett, Renier J Brentjens, Jill Brufsky, Jorge Cortes, Marcos De Lima, Stephen J Forman, Ephraim J Fuchs, Linda J Fukas, Steven D Gore, Mark R Litzow, Jeffrey S Miller, John M Pagel, Edmund K Waller, Martin S Tallman

Articles, Abstracts, and Reports

Acute leukemia is a constellation of rapidly progressing diseases that affect a wide range of patients regardless of age or gender. Traditional treatment options for patients with acute leukemia include chemotherapy and hematopoietic cell transplantation. The advent of cancer immunotherapy has had a significant impact on acute leukemia treatment. Novel immunotherapeutic agents including antibody-drug conjugates, bispecific T cell engagers, and chimeric antigen receptor T cell therapies have efficacy and have recently been approved by the US Food and Drug Administration (FDA) for the treatment of patients with acute leukemia. The Society for Immunotherapy of Cancer (SITC) convened a panel of …

The Great Debate At 'Immunotherapy Bridge', Naples, December 5, 2019., Paolo A Ascierto, Carlo Bifulco, Jerome Galon, Claus Garbe, Samir N Khleif, Jennifer Mcquade, Kunle Odunsi, Hideho Okada, Chrystal M Paulos, Sergio A Quezada, Hussein A Tawbi, John Timmerman, Giorgio Trinchieri, Lisa H Butterfield, Igor Puzanov

Articles, Abstracts, and Reports

As part of the 2019 Immunotherapy Bridge congress (December 4-5, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on six topical issues in immunotherapy today. These were the use of chimeric antigen receptor T cell therapy in solid tumors, whether the Immunoscore should be more widely used in clinical practice, whether antibody-dependent cellular cytotoxicity is important in the mode of action of anticytotoxic T-lymphocyte-associated protein 4 antibodies, whether the brain is immunologically unique or just another organ, the role of microbiome versus nutrition in affecting responses to immunotherapy, and whether chemotherapy is immunostimulatory or immunosuppressive. Discussion …

Prospective Molecular Profiling Of Circulating Tumor Cells From Patients With Melanoma Receiving Combinatorial Immunotherapy., Selena Y Lin, Shu-Ching Chang, Stella Lam, Romela Irene Ramos, Kevin Tran, Shuichi Ohe, Matthew P Salomon, Ali Asgar S Bhagat, Chwee Teck Lim, Trevan D Fischer, Leland J Foshag, Christine L Boley, Steven J O'Day, Dave Hoon

Articles, Abstracts, and Reports

BACKGROUND: Blood molecular profiling of circulating tumor cells (CTCs) can enable monitoring of patients with metastatic melanoma during checkpoint inhibitor immunotherapy (CII) and in combination with targeted therapies. We developed a microfluidics-based CTC platform to explore CTC profiling utility in CII-treated patients with melanoma using a melanoma messenger RNA (mRNA)/DNA biomarker panel.

METHODS: Blood samples (n = 213) were collected prospectively from 75 American Joint Committee on Cancer-staged III/IV melanoma patients during CII treatment and those enriched for CTCs. CTC profiling was performed using 5 known melanoma mRNA biomarkers and BRAF V600E DNA mutation. CTC biomarker status associations with clinical …

Toward A Comprehensive View Of Cancer Immune Responsiveness: A Synopsis From The Sitc Workshop., Davide Bedognetti, Michele Ceccarelli, Lorenzo Galluzzi, Rongze Lu, Karolina Palucka, Josue Samayoa, Stefani Spranger, Sarah Warren, Kwok-Kin Wong, Elad Ziv, Diego Chowell, Lisa M Coussens, Daniel D De Carvalho, David G Denardo, Jérôme Galon, Howard L Kaufman, Tomas Kirchhoff, Michael T Lotze, Jason J Luke, Andy J Minn, Katerina Politi, Leonard D Shultz, Richard Simon, Vésteinn Thórsson, Joanne B Weidhaas, Maria Libera Ascierto, Paolo Antonio Ascierto, James M Barnes, Valentin Barsan, Praveen K Bommareddy, Adrian Bot, Sarah E Church, Gennaro Ciliberto, Andrea De Maria, Dobrin Draganov, Winson S Ho, Heather M Mcgee, Anne Monette, Joseph F Murphy, Paola Nisticò, Wungki Park, Maulik Patel, Michael Quigley, Laszlo Radvanyi, Harry Raftopoulos, Nils-Petter Rudqvist, Alexandra Snyder, Randy F Sweis, Sara Valpione, Lisa H Butterfield, Mary L Disis, Bernard A Fox, Alessandra Cesano, Francesco M Marincola

Articles, Abstracts, and Reports

Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes …

Reverting Immune Suppression To Enhance Cancer Immunotherapy., Bella S Guerrouahen, Cristina Maccalli, Chiara Cugno, Sergio Rutella, Emmanuel T Akporiaye

Articles, Abstracts, and Reports

Tumors employ strategies to escape immune control. The principle aim of most cancer immunotherapies is to restore effective immune surveillance. Among the different processes regulating immune escape, tumor microenvironment-associated soluble factors, and/or cell surface-bound molecules are mostly responsible for dysfunctional activity of tumor-specific CD8

Implantable Biomaterials To Provide Local Immunotherapy Following Surgical Resection., Michael J Gough, Jason R Baird, R Bryan Bell

Articles, Abstracts, and Reports

No abstract provided.

Perilymphatic Irx-2 Cytokine Therapy To Enhance Tumor Infiltrating Lymphocytes And Pd-L1 Expression Preceding Curative-Intent Therapy In Early Stage Breast Cancer, Joanna Pucilowska, Venkatesh Rajamanickam, Katherine Sanchez, Valerie Conrad, Alison Conlin, Shagheyegh Aliabadi-Wahle, Shu-Ching Chang, Gary Grunkemeier, Nikki Moxon, Staci Mellinger, Maritza Martel, James Egan, Monil Shah, David B Page

Books, Presentations, Posters, Etc.

Background: Cytokines are being explored as a therapeutic strategy to modulate the tumor microenvironment and facilitate immunotherapy benefit in breast cancer. Here, we investigate a locoregional therapeutic approach whereby cytokines (IRX-2) are administered into the subcutaneous peri-areolar tissue (in an anatomic distribution similar to sentinel lymph node mapping) to facilitate immune cell recruitment/activation within the draining lymph nodes and tumor in ESBC. IRX-2 is derived from ex vivo phytohemagglutinin-stimulated lymphocytes and contains multiple cytokines including IL-1β, IL-2, TNF-α, IFN-γ, IL-6, IL-8, and GM-CSF, with stable concentrations from lot to lot. Preclinically, IRX-2 activates T-cells and natural killer (NK) cells, facilitates …

Updated Efficacy Of First Or Second-Line Pembrolizumab Plus In Metastatic Triple Negative Breast Cancer And Correlations With Baseline Lymphocyte And Naïve Cd4+ T-Cell Count, David Page, Joanna Pucilowska, Laura Bennetts, I Kim, Katherine Sanchez, Maritza Martel, Alison Conlin, Nikki Moxon, Staci Mellinger, Anupama Acheson, K Kemmer, Z Mitri, J Vuky, J Ahn, C Abaya, T Manigault, R Basho, Walter Urba, Hl Mcarthur

Books, Presentations, Posters, Etc.

Background: In mTNBC, anti-PD-1/L1 monotherapy is most effective when administered early in the course of disease, with recent trials demonstrating overall response rates (ORR) of 23-26% in the first-line setting and 5-6% in later lines. This may reflect iatrogenic lymphopenia from preceding cytotoxic chemotherapy. Furthermore, curative-intent chemotherapy is associated with prolonged suppression of naïve CD4+ cells, a T-cell subset that may play a critical role in the generation of de novo anti-tumor immune responses. We present the final clinical results of a pilot study evaluating the safety and efficacy of combining pembrolizumab plus standard-of-care capecitabine in the first/second-line mTNBC …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

Unleashing Endogenous Tnf-Alpha As A Cancer Immunotherapeutic., Steven F Josephs, Thomas E Ichim, Stephen M Prince, Santosh Kesari, Francesco M Marincola, Anton Rolando Escobedo, Amir Jafri

Articles, Abstracts, and Reports

Tumor necrosis factor (TNF)-alpha was originally identified in the 1970s as the serum mediator of innate immunity capable of inducing hemorrhagic necrosis in tumors. Today, a wide spectrum of biological activities have been attributed to this molecule, and clinical translation has mainly occurred not in using it to treat cancer, but rather to inhibit its effects to treat autoimmunity. Clinical trials utilizing systemic TNF-alpha administration have resulted in an unacceptable level of toxicities, which blocked its development. In contrast, localized administration of TNF-alpha in the form of isolated limb perfusion have yielded excellent results in soft tissue sarcomas. Here we …

Perspectives In Melanoma: Meeting Report From The Melanoma Bridge (30 November-2 December, 2017, Naples, Italy)., Paolo A Ascierto, Igor Puzanov, Sanjiv S Agarwala, Carlo Bifulco, Gerardo Botti, Corrado Caracò, Gennaro Ciliberto, Michael A Davies, Reinhard Dummer, Soldano Ferrone, Thomas F Gajewski, Claus Garbe, Jason J Luke, Francesco M Marincola, Giuseppe Masucci, Janice M Mehnert, Nicola Mozzillo, Giuseppe Palmieri, Michael A Postow, Stephen P Schoenberger, Ena Wang, Magdalena Thurin

Articles, Abstracts, and Reports

Metastatic melanoma represents a challenging clinical situation and, until relatively recently, there was an absence of effective treatment options. However, in 2011, the advanced melanoma treatment landscape was revolutionised with the approval of the anti-cytotoxic T-lymphocyte-associated protein-4 checkpoint inhibitor ipilimumab and the selective BRAF kinase inhibitor vemurafenib, both of which significantly improved overall survival. Since then, availability of new immunotherapies, especially the anti-programmed death-1 checkpoint inhibitors, as well as other targeted therapies, have further improved outcomes for patients with advanced melanoma. Seven years on from the first approval of these novel therapies, evidence for the use of various immune-based and …

Perspectives In Immunotherapy: Meeting Report From The Immunotherapy Bridge (29-30 November, 2017, Naples, Italy)., Paolo A Ascierto, James Brugarolas, Luigi Buonaguro, Lisa H Butterfield, David Carbone, Bruno Daniele, Robert Ferris, Bernard A Fox, Jérôme Galon, Cesare Gridelli, Howard L Kaufman, Christopher A Klebanoff, Ignacio Melero, Paul Nathan, Chrystal M Paulos, Marco Ruella, Ryan Sullivan, Hassane Zarour, Igor Puzanov

Articles, Abstracts, and Reports

Immunotherapy represents the third important wave in the history of the systemic treatment of cancer after chemotherapy and targeted therapy and is now established as a potent and effective treatment option across several cancer types. The clinical success of anti-cytotoxic T-lymphocyte-associated antigen (CTLA)-4, first, and anti-programmed death (PD)-1/PD-ligand (L)1 agents in melanoma and other cancers a few years later, has encouraged increasing focus on the development of other immunotherapies (e.g. monoclonal antibodies with other immune targets, adoptive cell transfer, and vaccines), with over 3000 immuno-oncology trials ongoing, involving hundreds of research institutes across the globe. The potential use of these …

The Need For A Network To Establish And Validate Predictive Biomarkers In Cancer Immunotherapy., Giuseppe V Masucci, Alessandra Cesano, Alexander Eggermont, Bernard A Fox, Ena Wang, Francesco M Marincola, Gennaro Ciliberto, Kevin Dobbin, Igor Puzanov, Janis Taube, Jennifer Wargo, Lisa H Butterfield, Lisa Villabona, Magdalena Thurin, Michael A Postow, Paul M Sondel, Sandra Demaria, Sanjiv Agarwala, Paolo A Ascierto

Articles, Abstracts, and Reports

Immunotherapies have emerged as one of the most promising approaches to treat patients with cancer. Recently, the entire medical oncology field has been revolutionized by the introduction of immune checkpoints inhibitors. Despite success in a variety of malignancies, responses typically only occur in a small percentage of patients for any given histology or treatment regimen. There are also concerns that immunotherapies are associated with immune-related toxicity as well as high costs. As such, identifying biomarkers to determine which patients are likely to derive clinical benefit from which immunotherapy and/or be susceptible to adverse side effects is a compelling clinical and …

Tumor And Microenvironment Evolution During Immunotherapy With Nivolumab., Nadeem Riaz, Jonathan J Havel, Vladimir Makarov, Alexis Desrichard, Walter Urba, Jennifer S Sims, F Stephen Hodi, Salvador Martín-Algarra, Rajarsi Mandal, William H Sharfman, Shailender Bhatia, Wen-Jen Hwu, Thomas F Gajewski, Craig L Slingluff, Diego Chowell, Sviatoslav M Kendall, Han Chang, Rachna Shah, Fengshen Kuo, Luc G T Morris, John-William Sidhom, Jonathan P Schneck, Christine E Horak, Nils Weinhold, Timothy A Chan

Articles, Abstracts, and Reports

The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific …

Timing Of Pd-1 Blockade Is Critical To Effective Combination Immunotherapy With Anti-Ox40., David J Messenheimer, Shawn M. Jensen, Michael E Afentoulis, Keith W Wegman, Zipei Feng, David J Friedman, Michael J. Gough, Walter Urba, Bernard A Fox

Articles, Abstracts, and Reports

Purpose: Antibodies specific for inhibitory checkpoints PD-1 and CTLA-4 have shown impressive results against solid tumors. This has fueled interest in novel immunotherapy combinations to affect patients who remain refractory to checkpoint blockade monotherapy. However, how to optimally combine checkpoint blockade with agents targeting T-cell costimulatory receptors, such as OX40, remains a critical question.Experimental Design: We utilized an anti-PD-1-refractory, orthotopically transplanted MMTV-PyMT mammary cancer model to investigate the antitumor effect of an agonist anti-OX40 antibody combined with anti-PD-1. As PD-1 naturally aids in immune contraction after T-cell activation, we treated mice with concurrent combination treatment versus sequentially administering anti-OX40 …

Induction And Characterization Of Anti-Tumor Endothelium Immunity Elicited By Vallovax Therapeutic Cancer Vaccine., Samuel C Wagner, Thomas E Ichim, Vladimir Bogin, Wei-Ping Min, Francisco Silva, Amit N Patel, Santosh Kesari

Articles, Abstracts, and Reports

ValloVax is a placental endothelium derived vaccine which induces tissue-nonspecific antitumor immunity by blocking tumor angiogesis. To elucidate mechanisms of action, we showed that production of ValloVax, which involves treating placental endothelial cells with IFN-gamma, results in upregulation of HLA and costimulatory molecules. It was shown that in mixed lymphocyte reaction, ValloVax induces Type I cytokines and allo-proliferative responses. Plasma from ValloVax immunized mice was capable of killing in vitro tumor-like endothelium but not control endothelium. Using defined antigens associated with tumor endothelial cells, specific molecular entities were identified as being targeted by ValloVax induced antibodies. Binding of predominantly IgG …

Immunotherapy Of Head And Neck Cancer: Emerging Clinical Trials From A National Cancer Institute Head And Neck Cancer Steering Committee Planning Meeting., Julie E Bauman, Ezra Cohen, Robert L Ferris, David J Adelstein, David M Brizel, John A Ridge, Brian O'Sullivan, Barbara A Burtness, Lisa H Butterfield, William E Carson, Mary L Disis, Bernard A Fox, Thomas F Gajewski, Maura L Gillison, James W Hodge, Quynh-Thu Le, David Raben, Scott E Strome, Jean Lynn, Shakun Malik

Articles, Abstracts, and Reports

Recent advances have permitted successful therapeutic targeting of the immune system in head and neck squamous cell carcinoma (HNSCC). These new immunotherapeutic targets and agents are being rapidly adopted by the oncologic community and hold considerable promise. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issue of how to further investigate the use of immunotherapy in patients with HNSCC. The goals of the meeting were to consider phase 2 or 3 trial designs primarily in 3 different patient populations: those with previously untreated, human papillomavirus-initiated oropharyngeal cancers; those with previously untreated, human papillomavirus-negative HNSCC; and …