Read by QxMD icon Read

robert vonderheide

Timothy Chao, Emma E Furth, Robert H Vonderheide
Tumor-associated neutrophils are increasingly recognized for their ability to promote tumor progression, mediate resistance to therapy, and regulate immunosuppression. Evidence from various murine models has shown that the chemokine receptor CXCR2 attracts neutrophil into tumors and, therefore, represents a tractable therapeutic target. Here, we report prominent expression of a neutrophil gene signature in a subset of human pancreatic adenocarcinoma (PDA). CXCL5 was the most prominently expressed CXCR2 ligand in human PDA, and its expression was higher in PDA than in any other common tumor represented in The Cancer Genome Atlas...
October 13, 2016: Cancer Immunology Research
Rebecca A Evans, Mark S Diamond, Andrew J Rech, Timothy Chao, Max W Richardson, Jeffrey H Lin, David L Bajor, Katelyn T Byrne, Ben Z Stanger, James L Riley, Nune Markosyan, Rafael Winograd, Robert H Vonderheide
In carcinogen-driven cancers, a high mutational burden results in neoepitopes that can be recognized immunologically. Such carcinogen-induced tumors may evade this immune response through "immunoediting," whereby tumors adapt to immune pressure and escape T cell-mediated killing. Many tumors lack a high neoepitope burden, and it remains unclear whether immunoediting occurs in such cases. Here, we evaluated T cell immunity in an autochthonous mouse model of pancreatic cancer and found a low mutational burden, absence of predicted neoepitopes derived from tumor mutations, and resistance to checkpoint immunotherapy...
September 8, 2016: JCI Insight
Nicole M Aiello, David L Bajor, Robert J Norgard, Amine Sahmoud, Neha Bhagwat, Minh N Pham, Toby C Cornish, Christine A Iacobuzio-Donahue, Robert H Vonderheide, Ben Z Stanger
Most cancer-associated deaths result from metastasis. However, it remains unknown whether the size, microenvironment or other features of a metastatic lesion dictate its behaviour or determine the efficacy of chemotherapy in the adjuvant (micrometastatic) setting. Here we delineate the natural history of metastasis in an autochthonous model of pancreatic ductal adenocarcinoma (PDAC), using lineage tracing to examine the evolution of disseminated cancer cells and their associated microenvironment. With increasing size, lesions shift from mesenchymal to epithelial histology, become hypovascular and accumulate a desmoplastic stroma, ultimately recapitulating the primary tumours from which they arose...
2016: Nature Communications
Vincenzo Bronte, Sven Brandau, Shu-Hsia Chen, Mario P Colombo, Alan B Frey, Tim F Greten, Susanna Mandruzzato, Peter J Murray, Augusto Ochoa, Suzanne Ostrand-Rosenberg, Paulo C Rodriguez, Antonio Sica, Viktor Umansky, Robert H Vonderheide, Dmitry I Gabrilovich
Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses...
2016: Nature Communications
Katelyn T Byrne, Robert H Vonderheide
Cancer immunotherapies are more effective in tumors with robust T cell infiltrates, but mechanisms to convert T cell-devoid tumors with active immunosuppression to those capable of recruiting T cells remain incompletely understood. Here, using genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDA), we demonstrate that a single dose of agonistic CD40 antibody with chemotherapy rendered PDA susceptible to T cell-dependent destruction and potentiated durable remissions. CD40 stimulation caused a clonal expansion of T cells in the tumor, but the addition of chemotherapy optimized myeloid activation and T cell function...
June 21, 2016: Cell Reports
Katelyn T Byrne, Nathan H Leisenring, David L Bajor, Robert H Vonderheide
Cancer immunotherapies are increasingly effective in the clinic, especially immune checkpoint blockade delivered to patients who have T cell-infiltrated tumors. Agonistic CD40 mAb promotes stromal degradation and, in combination with chemotherapy, drives T cell infiltration and de novo responses against tumors, rendering resistant tumors susceptible to current immunotherapies. Partnering anti-CD40 with different treatments is an attractive approach for the next phase of cancer immunotherapies, with a number of clinical trials using anti-CD40 combinations ongoing, but the optimal therapeutic regimens with anti-CD40 are not well understood...
July 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Ira Mellman, Vanessa M Hubbard-Lucey, Matthew J Tontonoz, Michael D Kalos, Daniel S Chen, James P Allison, Charles G Drake, Hy Levitsky, Nils Lonberg, Sjoerd H van der Burg, Douglas T Fearon, E John Wherry, Israel Lowy, Robert H Vonderheide, Patrick Hwu
With the recent FDA approvals of pembrolizumab and nivolumab, and a host of additional immunomodulatory agents entering clinical development each year, the field of cancer immunotherapy is changing rapidly. Strategies that can assist researchers in choosing the most promising drugs and drug combinations to move forward through clinical development are badly needed in order to reduce the likelihood of late-stage clinical trial failures. On October 5, 2014, the Cancer Immunotherapy Consortium of the Cancer Research Institute, a collaborative think tank composed of stakeholders from academia, industry, regulatory agencies, and patient interest groups, met to discuss strategies for de-risking immunotherapy development, with a focus on integrating preclinical and clinical studies, and conducting smarter early-phase trials, particularly for combination therapies...
April 2016: Cancer Immunology Research
Elizabeth O Hexner, Selina M Luger, Ran Reshef, Grace R Jeschke, James K Mangan, Noelle V Frey, Dale M Frank, Lee P Richman, Robert H Vonderheide, Nicole A Aqui, Misha Rosenbach, Yi Zhang, Anne Chew, Alison W Loren, Edward A Stadtmauer, Bruce L Levine, Carl H June, Stephen G Emerson, David L Porter
Limited cell numbers in umbilical cord blood (UCB) grafts present a major impediment to favorable outcomes in adult transplantation, largely related to delayed or failed engraftment. The advent of UCB transplantation (UCBT) using two grafts successfully circumvents this obstacle, despite the engraftment of only one unit. Preclinical models suggested that the addition of UCB T cells at the time of transplant can enhance engraftment. We tested whether ex vivo activation by CD3/CD28 costimulation and expansion of T cells from a single UCB graft would be safe and feasible in adults with advanced hematologic malignancies, with an overall objective of optimizing engraftment in single unit UCBT...
May 2016: American Journal of Hematology
Kyoung Eun Lee, Michelle Spata, Lauren J Bayne, Elizabeth L Buza, Amy C Durham, David Allman, Robert H Vonderheide, M Celeste Simon
UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths worldwide, with an exceedingly low 5-year survival rate. PDAC tumors are characterized by an extensive desmoplastic stromal response and hypovascularity, suggesting that tumor hypoxia could regulate PDAC initiation and/or progression. Using a well-defined, autochthonous Kras(G12D)-driven murine model, as well as human tumors, we demonstrate that hypoxia and stabilization of hypoxia-inducible factor 1α (HIF1α), a principal mediator of hypoxic adaptation, emerge early during preinvasive stages of PDAC...
March 2016: Cancer Discovery
Robert H Vonderheide
No abstract text is available yet for this article.
October 2015: Nature Medicine
Jaehyuk Choi, Gerald Goh, Trent Walradt, Bok S Hong, Christopher G Bunick, Kan Chen, Robert D Bjornson, Yaakov Maman, Tiffany Wang, Jesse Tordoff, Kacie Carlson, John D Overton, Kristina J Liu, Julia M Lewis, Lesley Devine, Lisa Barbarotta, Francine M Foss, Antonio Subtil, Eric C Vonderheid, Richard L Edelson, David G Schatz, Titus J Boggon, Michael Girardi, Richard P Lifton
Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma of skin-homing T lymphocytes. We performed exome and whole-genome DNA sequencing and RNA sequencing on purified CTCL and matched normal cells. The results implicate mutations in 17 genes in CTCL pathogenesis, including genes involved in T cell activation and apoptosis, NF-κB signaling, chromatin remodeling and DNA damage response. CTCL is distinctive in that somatic copy number variants (SCNVs) comprise 92% of all driver mutations (mean of 11.8 pathogenic SCNVs versus 1...
September 2015: Nature Genetics
Ran Reshef, Austin P Huffman, Amy Gao, Marlise R Luskin, Noelle V Frey, Saar I Gill, Elizabeth O Hexner, Taku Kambayashi, Alison W Loren, Selina M Luger, James K Mangan, Sunita D Nasta, Lee P Richman, Mary Sell, Edward A Stadtmauer, Robert H Vonderheide, Rosemarie Mick, David L Porter
PURPOSE: To characterize the impact of graft T-cell composition on outcomes of reduced-intensity conditioned (RIC) allogeneic hematopoietic stem-cell transplantation (alloHSCT) in adults with hematologic malignancies. PATIENTS AND METHODS: We evaluated associations between graft T-cell doses and outcomes in 200 patients who underwent RIC alloHSCT with a peripheral blood stem-cell graft. We then studied 21 alloHSCT donors to identify predictors of optimal graft T-cell content...
July 20, 2015: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Albert Lo, Liang-Chuan S Wang, John Scholler, James Monslow, Diana Avery, Kheng Newick, Shaun O'Brien, Rebecca A Evans, David J Bajor, Cynthia Clendenin, Amy C Durham, Elizabeth L Buza, Robert H Vonderheide, Carl H June, Steven M Albelda, Ellen Puré
Malignant cells drive the generation of a desmoplastic and immunosuppressive tumor microenvironment. Cancer-associated stromal cells (CASC) are a heterogeneous population that provides both negative and positive signals for tumor cell growth and metastasis. Fibroblast activation protein (FAP) is a marker of a major subset of CASCs in virtually all carcinomas. Clinically, FAP expression serves as an independent negative prognostic factor for multiple types of human malignancies. Prior studies established that depletion of FAP(+) cells inhibits tumor growth by augmenting antitumor immunity...
July 15, 2015: Cancer Research
Katelyn T Byrne, Robert H Vonderheide, Elizabeth M Jaffee, Todd D Armstrong
The overall objective of the fifth American Association for Cancer Research Special Conference, "Tumor Immunology and Immunotherapy: A New Chapter," organized by the Cancer Immunology Working Group, was to highlight multidisciplinary approaches of immunotherapy and mechanisms related to the ability of immunotherapy to fight established tumors. With the FDA approval of sipuleucel-T, ipilimumab (anti-CTLA-4; Bristol-Myers Squibb), and the two anti-PD-1 antibodies, pembrolizumab (formerly MK-3475 or lambrolizumab; Merck) and nivolumab (Bristol-Myers Squibb), immunotherapy has become a mainstream treatment option for some cancers...
May 12, 2015: Cancer Immunology Research
Gregory L Beatty, Rafael Winograd, Rebecca A Evans, Kristen B Long, Santiago L Luque, Jae W Lee, Cynthia Clendenin, Whitney L Gladney, Dawson M Knoblock, Patrick D Guirnalda, Robert H Vonderheide
BACKGROUND & AIMS: Immunotherapies that induce T-cell responses have shown efficacy against some solid malignancies in patients and mice, but these have little effect on pancreatic ductal adenocarcinoma (PDAC). We investigated whether the ability of PDAC to evade T-cell responses induced by immunotherapies results from the low level of immunogenicity of tumor cells, the tumor's immunosuppressive mechanisms, or both. METHODS: Kras(G12D/+);Trp53(R172H/+);Pdx-1-Cre (KPC) mice, which develop spontaneous PDAC, or their littermates (controls) were given subcutaneous injections of a syngeneic KPC-derived PDAC cell line...
July 2015: Gastroenterology
Alex Ganetsky, Todd A Miano, Mitchell E Hughes, Robert H Vonderheide, David L Porter, Ran Reshef
OBJECTIVES: Emerging data suggest that the combination of tacrolimus and the CCR5 antagonist maraviroc, both cytochrome P450-3A4 substrates, may be effective in preventing graft-versus-host disease in patients undergoing allogeneic HSCT. This study evaluated whether a pharmacokinetic interaction exists between these agents. METHODS: The study included 36 allogeneic HSCT recipients who received maraviroc + tacrolimus and 43 recipients of tacrolimus alone. We used a difference-in-differences analysis to examine the change in the concentration/dose ratios of tacrolimus after the discontinuation of maraviroc...
July 2015: Journal of Antimicrobial Chemotherapy
Saumil J Gandhi, Andy J Minn, Robert H Vonderheide, E John Wherry, Stephen M Hahn, Amit Maity
The importance of ionizing radiation has historically been limited to achieving local control of tumor cells. However, emerging evidence over the last decade suggests an increasingly important role for radiation in amplifying the antitumor immune response elicited by immunomodulatory agents. Combination of radiation with immunotherapy has been shown to elicit powerful systemic responses in several pre-clinical tumor models. Additionally, recent clinical observations support the use of radiation therapy for augmenting antitumor immunity in the metastatic setting...
November 28, 2015: Cancer Letters
Mobin A Karimi, Jerrod L Bryson, Lee P Richman, Andrew D Fesnak, Theresa M Leichner, Atsushi Satake, Robert H Vonderheide, David H Raulet, Ran Reshef, Taku Kambayashi
In allogeneic hematopoietic stem cell transplantation (HSCT), controlling graft-versus-host disease (GVHD) while maintaining graft-versus-tumor (GVT) responses is of critical importance. Using a mouse model of allogeneic HSCT, we hereby demonstrate that NKG2D expression by CD8(+) T cells plays a major role in mediating GVHD and GVT effects by promoting the survival and cytotoxic function of CD8(+) T cells. The expression of NKG2D ligands was not induced persistently on normal tissues of allogeneic HSCT-recipient mice treated with anti-NKG2D antibody, suggesting that transient NKG2D blockade might be sufficient to attenuate GVHD and allow CD8(+) T cells to regain their GVT function...
June 4, 2015: Blood
Christina Twyman-Saint Victor, Andrew J Rech, Amit Maity, Ramesh Rengan, Kristen E Pauken, Erietta Stelekati, Joseph L Benci, Bihui Xu, Hannah Dada, Pamela M Odorizzi, Ramin S Herati, Kathleen D Mansfield, Dana Patsch, Ravi K Amaravadi, Lynn M Schuchter, Hemant Ishwaran, Rosemarie Mick, Daniel A Pryma, Xiaowei Xu, Michael D Feldman, Tara C Gangadhar, Stephen M Hahn, E John Wherry, Robert H Vonderheide, Andy J Minn
Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common...
April 16, 2015: Nature
Rafael Winograd, Katelyn T Byrne, Rebecca A Evans, Pamela M Odorizzi, Anders R L Meyer, David L Bajor, Cynthia Clendenin, Ben Z Stanger, Emma E Furth, E John Wherry, Robert H Vonderheide
Disabling the function of immune checkpoint molecules can unlock T-cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4, resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFNγ in this model...
April 2015: Cancer Immunology Research
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"