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madhav v dhodapkar

Madhav V Dhodapkar
All cases of multiple myeloma (MM) are preceded by precursor states termed as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). Genetic analyses of MGUS cells have provided evidence that it is a genetically advanced lesion wherein tumor cells carry many of the genetic changes found in MM cells. Intraclonal heterogeneity is also established early during the MGUS phase. While the genetic features of MGUS or SMM cells at baseline may predict disease risk, transition to MM involves altered growth of pre-existing clones...
October 13, 2016: Blood
Rituparna Das, Till Strowig, Rakesh Verma, Srinivas Koduru, Anja Hafemann, Stephanie Hopf, Mehmet H Kocoglu, Chiara Borsotti, Lin Zhang, Andrew Branagan, Elizabeth Eynon, Markus G Manz, Richard A Flavell, Madhav V Dhodapkar
Most human cancers, including myeloma, are preceded by a precursor state. There is an unmet need for in vivo models to study the interaction of human preneoplastic cells in the bone marrow microenvironment with non-malignant cells. Here, we genetically humanized mice to permit the growth of primary human preneoplastic and malignant plasma cells together with non-malignant cells in vivo. Growth was largely restricted to the bone marrow, mirroring the pattern in patients with myeloma. Xenografts captured the genomic complexity of parental tumors and revealed additional somatic changes...
October 10, 2016: Nature Medicine
Chandra Sekhar Boddupalli, Shiny Nair, Simon M Gray, Heba N Nowyhed, Rakesh Verma, Joanna A Gibson, Clara Abraham, Deepak Narayan, Juan Vasquez, Catherine C Hedrick, Richard A Flavell, Kavita M Dhodapkar, Susan M Kaech, Madhav V Dhodapkar
Immune surveillance in tissues is mediated by a long-lived subset of tissue-resident memory T cells (Trm cells). A putative subset of tissue-resident long-lived stem cells is characterized by the ability to efflux Hoechst dyes and is referred to as side population (SP) cells. Here, we have characterized a subset of SP T cells (Tsp cells) that exhibit a quiescent (G0) phenotype in humans and mice. Human Trm cells in the gut and BM were enriched in Tsp cells that were predominantly in the G0 stage of the cell cycle...
October 3, 2016: Journal of Clinical Investigation
Shiny Nair, Andrew R Branagan, Jun Liu, Chandra Sekhar Boddupalli, Pramod K Mistry, Madhav V Dhodapkar
Antigen-driven selection has been implicated in the pathogenesis of monoclonal gammopathies. Patients with Gaucher's disease have an increased risk of monoclonal gammopathies. Here we show that the clonal immunoglobulin in patients with Gaucher's disease and in mouse models of Gaucher's disease-associated gammopathy is reactive against lyso-glucosylceramide (LGL1), which is markedly elevated in these patients and mice. Clonal immunoglobulin in 33% of sporadic human monoclonal gammopathies is also specific for the lysolipids LGL1 and lysophosphatidylcholine (LPC)...
February 11, 2016: New England Journal of Medicine
Madhav V Dhodapkar, Rachael Sexton, Rituparna Das, Kavita M Dhodapkar, Lin Zhang, Ranjini Sundaram, Sonal Soni, John J Crowley, Robert Z Orlowski, Bart Barlogie
Blockade of immune checkpoints (ICPs) has led to impressive responses in cancer patients. However, the impact of preexisting immunity and ICPs on the risk of malignant transformation in human preneoplasia has not been prospectively studied. We prospectively analyzed antigen-specific B/T-cell immunity, immune composition of the tumor microenvironment, and the expression of a panel of ICPs on tumor and tumor-infiltrating immune cells in 305 patients with asymptomatic monoclonal gammopathy enrolled in S0120 under the auspices of SWOG...
November 26, 2015: Blood
Noffar Bar, Terri L Parker, Madhav V Dhodapkar
No abstract text is available yet for this article.
November 10, 2015: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Madhav V Dhodapkar, Kavita M Dhodapkar
The therapeutic potential of the immune system in the context of hematologic malignancies has long been appreciated particularly due to the curative impact of allogeneic hematopoietic stem cell transplantation (SCT). The role of immune system in shaping the biology and evolution of these tumors is now well recognized. While the contribution of the immune system in anti-tumor effects of certain therapies such as immune-modulatory drugs and monoclonal antibodies active in hematologic malignancies is quite evident, the immune system has also been implicated in anti-tumor effects of other targeted therapies...
August 2015: Seminars in Oncology
Lionel Apetoh, Mark J Smyth, Charles G Drake, Jean-Pierre Abastado, Ron N Apte, Maha Ayyoub, Jean-Yves Blay, Marc Bonneville, Lisa H Butterfield, Anne Caignard, Chiara Castelli, Federica Cavallo, Esteban Celis, Lieping Chen, Mario P Colombo, Begoña Comin-Anduix, Georges Coukos, Madhav V Dhodapkar, Glenn Dranoff, Ian H Frazer, Wolf-Hervé Fridman, Dmitry I Gabrilovich, Eli Gilboa, Sacha Gnjatic, Dirk Jäger, Pawel Kalinski, Howard L Kaufman, Rolf Kiessling, John Kirkwood, Alexander Knuth, Roland Liblau, Michael T Lotze, Enrico Lugli, Francesco Marincola, Ignacio Melero, Cornelis J Melief, Thorsten R Mempel, Elizabeth A Mittendorf, Kunle Odun, Willem W Overwijk, Anna Karolina Palucka, Giorgio Parmiani, Antoni Ribas, Pedro Romero, Robert D Schreiber, Gerold Schuler, Pramod K Srivastava, Eric Tartour, Danila Valmori, Sjoerd H van der Burg, Pierre van der Bruggen, Benoît J van den Eynde, Ena Wang, Weiping Zou, Theresa L Whiteside, Daniel E Speiser, Drew M Pardoll, Nicholas P Restifo, Ana C Anderson
Whereas preclinical investigations and clinical studies have established that CD8(+) T cells can profoundly affect cancer progression, the underlying mechanisms are still elusive. Challenging the prevalent view that the beneficial effect of CD8(+) T cells in cancer is solely attributable to their cytotoxic activity, several reports have indicated that the ability of CD8(+) T cells to promote tumor regression is dependent on their cytokine secretion profile and their ability to self-renew. Evidence has also shown that the tumor microenvironment can disarm CD8(+) T cell immunity, leading to the emergence of dysfunctional CD8(+) T cells...
April 2015: Oncoimmunology
Norma Bloy, Jonathan Pol, Fernando Aranda, Alexander Eggermont, Isabelle Cremer, Wolf Hervé Fridman, Jitka Fučíková, Jérôme Galon, Eric Tartour, Radek Spisek, Madhav V Dhodapkar, Laurence Zitvogel, Guido Kroemer, Lorenzo Galluzzi
The use of patient-derived dendritic cells (DCs) as a means to elicit therapeutically relevant immune responses in cancer patients has been extensively investigated throughout the past decade. In this context, DCs are generally expanded, exposed to autologous tumor cell lysates or loaded with specific tumor-associated antigens (TAAs), and then reintroduced into patients, often in combination with one or more immunostimulatory agents. As an alternative, TAAs are targeted to DCs in vivo by means of monoclonal antibodies, carbohydrate moieties or viral vectors specific for DC receptors...
November 2014: Oncoimmunology
Kartik Sehgal, Rituparna Das, Lin Zhang, Rakesh Verma, Yanhong Deng, Mehmet Kocoglu, Juan Vasquez, Srinivas Koduru, Yan Ren, Maria Wang, Suzana Couto, Mike Breider, Donna Hansel, Stuart Seropian, Dennis Cooper, Anjan Thakurta, Xiaopan Yao, Kavita M Dhodapkar, Madhav V Dhodapkar
In preclinical studies, pomalidomide mediated both direct antitumor effects and immune activation by binding cereblon. However, the impact of drug-induced immune activation and cereblon/ikaros in antitumor effects of pomalidomide in vivo is unknown. Here we evaluated the clinical and pharmacodynamic effects of continuous or intermittent dosing strategies of pomalidomide/dexamethasone in lenalidomide-refractory myeloma in a randomized trial. Intermittent dosing led to greater tumor reduction at the cost of more frequent adverse events...
June 25, 2015: Blood
Madhav V Dhodapkar, Kavita M Dhodapkar
Targeting antigens directly to dendritic cells (DCs) in situ has emerged as a promising strategy to potentiate immunity. A recent clinical trial of antibody-mediated targeting of tumor antigen NY-ESO1 to the DC receptor DEC-205 demonstrated an induction of strong cellular and humoral responses. Recent studies with DC-targeting via nanoparticles suggest that combinatorial targeting of multiple human DC subsets may further improve the efficacy of DC targeting.
2014: Oncoimmunology
Angara Sureshbabu, Mansoor A Syed, Chandra Sekhar Boddupalli, Madhav V Dhodapkar, Robert J Homer, Parviz Minoo, Vineet Bhandari
BACKGROUND: Earlier studies have reported that transforming growth factor beta 1(TGFβ1) is a critical mediator of hyperoxia-induced acute lung injury (HALI) in developing lungs, leading to impaired alveolarization and a pulmonary phenotype of bronchopulmonary dysplasia (BPD). However, the mechanisms responsible for the TGFβ1-induced inflammatory signals that lead to cell death and abnormal alveolarization are poorly understood. We hypothesized that TGFβ1 signaling via TGFβR2 is necessary for the pathogenesis of the BPD pulmonary phenotype resulting from HALI...
2015: Respiratory Research
Rituparna Das, Rakesh Verma, Mario Sznol, Chandra Sekhar Boddupalli, Scott N Gettinger, Harriet Kluger, Margaret Callahan, Jedd D Wolchok, Ruth Halaban, Madhav V Dhodapkar, Kavita M Dhodapkar
Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from 45 patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic and functional signatures in vivo in purified human T cells and monocytes...
February 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Lorenzo Galluzzi, Erika Vacchelli, José-Manuel Bravo-San Pedro, Aitziber Buqué, Laura Senovilla, Elisa Elena Baracco, Norma Bloy, Francesca Castoldi, Jean-Pierre Abastado, Patrizia Agostinis, Ron N Apte, Fernando Aranda, Maha Ayyoub, Philipp Beckhove, Jean-Yves Blay, Laura Bracci, Anne Caignard, Chiara Castelli, Federica Cavallo, Estaban Celis, Vincenzo Cerundolo, Aled Clayton, Mario P Colombo, Lisa Coussens, Madhav V Dhodapkar, Alexander M Eggermont, Douglas T Fearon, Wolf H Fridman, Jitka Fučíková, Dmitry I Gabrilovich, Jérôme Galon, Abhishek Garg, François Ghiringhelli, Giuseppe Giaccone, Eli Gilboa, Sacha Gnjatic, Axel Hoos, Anne Hosmalin, Dirk Jäger, Pawel Kalinski, Klas Kärre, Oliver Kepp, Rolf Kiessling, John M Kirkwood, Eva Klein, Alexander Knuth, Claire E Lewis, Roland Liblau, Michael T Lotze, Enrico Lugli, Jean-Pierre Mach, Fabrizio Mattei, Domenico Mavilio, Ignacio Melero, Cornelis J Melief, Elizabeth A Mittendorf, Lorenzo Moretta, Adekunke Odunsi, Hideho Okada, Anna Karolina Palucka, Marcus E Peter, Kenneth J Pienta, Angel Porgador, George C Prendergast, Gabriel A Rabinovich, Nicholas P Restifo, Naiyer Rizvi, Catherine Sautès-Fridman, Hans Schreiber, Barbara Seliger, Hiroshi Shiku, Bruno Silva-Santos, Mark J Smyth, Daniel E Speiser, Radek Spisek, Pramod K Srivastava, James E Talmadge, Eric Tartour, Sjoerd H Van Der Burg, Benoît J Van Den Eynde, Richard Vile, Hermann Wagner, Jeffrey S Weber, Theresa L Whiteside, Jedd D Wolchok, Laurence Zitvogel, Weiping Zou, Guido Kroemer
During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer...
December 30, 2014: Oncotarget
Shiny Nair, Chandra Sekhar Boddupalli, Rakesh Verma, Jun Liu, Ruhua Yang, Gregory M Pastores, Pramod K Mistry, Madhav V Dhodapkar
Chronic inflammation including B-cell activation is commonly observed in both inherited (Gaucher disease [GD]) and acquired disorders of lipid metabolism. However, the cellular mechanisms underlying B-cell activation in these settings remain to be elucidated. Here, we report that β-glucosylceramide 22:0 (βGL1-22) and glucosylsphingosine (LGL1), 2 major sphingolipids accumulated in GD, can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Human βGL1-22- and LGL1-reactive CD1d tetramer-positive T cells have a distinct T-cell receptor usage and genomic and cytokine profiles compared with the classical type I NKT cells...
February 19, 2015: Blood
Kartik Sehgal, Ragy Ragheb, Tarek M Fahmy, Madhav V Dhodapkar, Kavita M Dhodapkar
Most vaccines depend on coadministration of Ags and adjuvants that activate APCs. Nanoparticles (NPs) have emerged as an attractive vehicle for synchronized delivery of Ags and adjuvants to APCs and can be targeted to specific cell types, such as dendritic cells (DCs), which are potent APCs. Which subset of human DCs should be targeted for optimal activation of T cell immunity, however, remains unknown. In this article, we describe a poly-lactic-coglycolic acid-based NP platform, wherein avidin-decorated NPs can be targeted to multiple human DC subsets via biotinylated Abs...
September 1, 2014: Journal of Immunology: Official Journal of the American Association of Immunologists
Kartik Sehgal, Kavita M Dhodapkar, Madhav V Dhodapkar
Dendritic cells (DCs) provide a critical link between innate and adaptive immunity. The potent antigen presenting properties of DCs makes them a valuable target for the delivery of immunogenic cargo. Recent clinical studies describing in situ DC targeting with antibody-mediated targeting of DC receptor through DEC-205 provide new opportunities for the clinical application of DC-targeted vaccines. Further advances with nanoparticle vectors which can encapsulate antigens and adjuvants within the same compartment and be targeted against diverse DC subsets also represent an attractive strategy for targeting DCs...
November 2014: Immunology Letters
Madhav V Dhodapkar, Mario Sznol, Biwei Zhao, Ding Wang, Richard D Carvajal, Mary L Keohan, Ellen Chuang, Rachel E Sanborn, Jose Lutzky, John Powderly, Harriet Kluger, Sheela Tejwani, Jennifer Green, Venky Ramakrishna, Andrea Crocker, Laura Vitale, Michael Yellin, Thomas Davis, Tibor Keler
Immune-based therapies for cancer are generating substantial interest because of the success of immune checkpoint inhibitors. This study aimed to enhance anticancer immunity by exploiting the capacity of dendritic cells (DCs) to initiate T cell immunity by efficient uptake and presentation of endocytosed material. Delivery of tumor-associated antigens to DCs using receptor-specific monoclonal antibodies (mAbs) in the presence of DC-activating agents elicits robust antigen-specific immune responses in preclinical models...
April 16, 2014: Science Translational Medicine
Madhav V Dhodapkar, Rachael Sexton, Sarah Waheed, Saad Usmani, Xenofon Papanikolaou, Bijay Nair, Nathan Petty, John D Shaughnessy, Antje Hoering, John Crowley, Robert Z Orlowski, Bart Barlogie
All cases of clinical myeloma (CMM) are preceded by an asymptomatic monoclonal gammopathy (AMG), classified as either monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic multiple myeloma (AMM). We analyzed data from AMG patients (n = 331) enrolled in a prospective, observational clinical trial (S0120). Baseline data from clinical variables, gene expression profiles (GEP) of purified tumor cells, and findings of magnetic resonance imaging (MRI) were correlated with the risk of progression to CMM requiring therapy...
January 2, 2014: Blood
Kavita M Dhodapkar, Scott N Gettinger, Rituparna Das, Henry Zebroski, Madhav V Dhodapkar
Immunotherapeutic strategies including the blockade of programmed death 1 (PD-1) receptors hold promise for the treatment of various cancers including non-small cell lung carcinoma (NSCLC). Preclinical data suggest that pre-existing tumor immunity is important for disease regression upon checkpoint blockade-based therapies. However, the nature of antigen-specific T-cell responses that correlate with the clinical response to immunotherapy in NSCLC patients is not known. The embryonic stem cell gene SRY (sex determining region Y)-box 2 (SOX2) has recently emerged as a major oncogenic driver in NSCLC...
July 1, 2013: Oncoimmunology
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