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https://www.readbyqxmd.com/read/29018445/natural-killer-t-cells-in-cancer-immunotherapy
#1
REVIEW
Shiny Nair, Madhav V Dhodapkar
Natural killer T (NKT) cells are specialized CD1d-restricted T cells that recognize lipid antigens. Following stimulation, NKT cells lead to downstream activation of both innate and adaptive immune cells in the tumor microenvironment. This has impelled the development of NKT cell-targeted immunotherapies for treating cancer. In this review, we provide a brief overview of the stimulatory and regulatory functions of NKT cells in tumor immunity as well as highlight preclinical and clinical studies based on NKT cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28561703/hematologic-malignancies-plasma-cell-disorders
#2
Madhav V Dhodapkar, Ivan Borrello, Adam D Cohen, Edward A Stadtmauer
Multiple myeloma (MM) is a plasma cell malignancy characterized by the growth of tumor cells in the bone marrow. Properties of the tumor microenvironment provide both potential tumor-promoting and tumor-restricting properties. Targeting underlying immune triggers for evolution of tumors as well as direct attack of malignant plasma cells is an emerging focus of therapy for MM. The monoclonal antibodies daratumumab and elotuzumab, which target the plasma cell surface proteins CD38 and SLAMF7/CS1, respectively, particularly when used in combination with immunomodulatory agents and proteasome inhibitors, have resulted in high response rates and improved survival for patients with relapsed and refractory MM...
2017: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/28343904/clinical-and-serologic-responses-after-a-two-dose-series-of-high-dose-influenza-vaccine-in-plasma-cell-disorders-a-prospective-single-arm-trial
#3
Andrew R Branagan, Eamon Duffy, Randy A Albrecht, Dennis L Cooper, Stuart Seropian, Terri L Parker, Geliang Gan, Fangyong Li, Daniel Zelterman, Chandra Sekhar Boddupalli, Lin Zhang, Rakesh Verma, Thomas M Ferencz, Madhav V Dhodapkar
BACKGROUND: Patients with multiple myeloma (MM) and other plasma cell disorders are highly susceptible to influenza infections, which are major causes of morbidity in this population, despite the routine administration of a seasonal influenza vaccination. Existing data are limited by small and retrospective studies, which suggest poor seroprotection rates of < 20% after standard influenza vaccination in patients with MM. PATIENTS AND METHODS: Patients with plasma cell dyscrasia (n = 51) were treated with a 2-dose series of high-dose inactivated trivalent influenza vaccine during the 2014 to 2015 influenza season...
May 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28331613/systematic-evaluation-of-immune-regulation-and-modulation
#4
REVIEW
David F Stroncek, Lisa H Butterfield, Michael A Cannarile, Madhav V Dhodapkar, Tim F Greten, Jean Charles Grivel, David R Kaufman, Heidi H Kong, Firouzeh Korangy, Peter P Lee, Francesco Marincola, Sergio Rutella, Janet C Siebert, Giorgio Trinchieri, Barbara Seliger
Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28115591/type-ii-nkt-cells-and-their-emerging-role-in-health-and-disease
#5
REVIEW
Madhav V Dhodapkar, Vipin Kumar
NKT cells recognize lipid Ags presented by a class I MHC-like molecule CD1d, a member of the CD1 family. Although most initial studies on NKT cells focused on a subset with semi-invariant TCR termed invariant NKT cells, the majority of CD1d-restricted lipid-reactive human T cells express diverse TCRs and are termed type II NKT cells. These cells constitute a distinct population of circulating and tissue-resident effector T cells with immune-regulatory properties. They react to a growing list of self- as well as non-self-lipid ligands, and share some properties with both invariant NKT and conventional T cells...
February 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28018970/interlesional-diversity-of-t-cell-receptors-in-melanoma-with-immune-checkpoints-enriched-in-tissue-resident-memory-t-cells
#6
Chandra Sekhar Boddupalli, Noffar Bar, Krishna Kadaveru, Michael Krauthammer, Natopol Pornputtapong, Zifeng Mai, Stephan Ariyan, Deepak Narayan, Harriet Kluger, Yanhong Deng, Rakesh Verma, Rituparna Das, Antonella Bacchiocchi, Ruth Halaban, Mario Sznol, Madhav V Dhodapkar, Kavita M Dhodapkar
Heterogeneity of tumor cells and their microenvironment can affect outcome in cancer. Blockade of immune checkpoints (ICPs) expressed only on a subset of immune cells leads to durable responses in advanced melanoma. Tissue-resident memory T (TRM) cells have recently emerged as a distinct subset of memory T cells in nonlymphoid tissues. Here, we show that functional properties and expression of ICPs within tumor-infiltrating lymphocytes (TILs) differ from those of blood T cells. TILs secrete less IL-2, IFN-γ, and TNF-α compared with circulating counterparts, and expression of VEGF correlated with reduced TIL infiltration...
December 22, 2016: JCI Insight
https://www.readbyqxmd.com/read/28018601/the-society-for-immunotherapy-of-cancer-consensus-statement-on-immunotherapy-for-the-treatment-of-hematologic-malignancies-multiple-myeloma-lymphoma-and-acute-leukemia
#7
Michael Boyiadzis, Michael R Bishop, Rafat Abonour, Kenneth C Anderson, Stephen M Ansell, David Avigan, Lisa Barbarotta, Austin John Barrett, Koen Van Besien, P Leif Bergsagel, Ivan Borrello, Joshua Brody, Jill Brufsky, Mitchell Cairo, Ajai Chari, Adam Cohen, Jorge Cortes, Stephen J Forman, Jonathan W Friedberg, Ephraim J Fuchs, Steven D Gore, Sundar Jagannath, Brad S Kahl, Justin Kline, James N Kochenderfer, Larry W Kwak, Ronald Levy, Marcos de Lima, Mark R Litzow, Anuj Mahindra, Jeffrey Miller, Nikhil C Munshi, Robert Z Orlowski, John M Pagel, David L Porter, Stephen J Russell, Karl Schwartz, Margaret A Shipp, David Siegel, Richard M Stone, Martin S Tallman, John M Timmerman, Frits Van Rhee, Edmund K Waller, Ann Welsh, Michael Werner, Peter H Wiernik, Madhav V Dhodapkar
Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia...
2016: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/27737890/mgus-to-myeloma-a-mysterious-gammopathy-of-underexplored-significance
#8
REVIEW
Madhav V Dhodapkar
All cases of multiple myeloma (MM) are preceded by precursor states termed 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. Although the genetic features of MGUS or SMM cells at baseline may predict disease risk, transition to MM involves altered growth of preexisting clones...
December 8, 2016: Blood
https://www.readbyqxmd.com/read/27723723/microenvironment-dependent-growth-of-preneoplastic-and-malignant-plasma-cells-in-humanized-mice
#9
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...
November 2016: Nature Medicine
https://www.readbyqxmd.com/read/27617863/abc-transporters-and-nr4a1-identify-a-quiescent-subset-of-tissue-resident-memory-t-cells
#10
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
https://www.readbyqxmd.com/read/26863356/clonal-immunoglobulin-against-lysolipids-in-the-origin-of-myeloma
#11
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
https://www.readbyqxmd.com/read/26468228/prospective-analysis-of-antigen-specific-immunity-stem-cell-antigens-and-immune-checkpoints-in-monoclonal-gammopathy
#12
MULTICENTER STUDY
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
https://www.readbyqxmd.com/read/26371139/stem-cell-transplantation-for-amyloidosis-improving-outcomes-but-not-for-the-faint-of-heart
#13
EDITORIAL
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
https://www.readbyqxmd.com/read/26320065/immune-modulation-in-hematologic-malignancies
#14
REVIEW
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
https://www.readbyqxmd.com/read/26137416/consensus-nomenclature-for-cd8-t-cell-phenotypes-in-cancer
#15
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
https://www.readbyqxmd.com/read/25941593/trial-watch-dendritic-cell-based-anticancer-therapy
#16
REVIEW
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
https://www.readbyqxmd.com/read/25869284/clinical-and-pharmacodynamic-analysis-of-pomalidomide-dosing-strategies-in-myeloma-impact-of-immune-activation-and-cereblon-targets
#17
RANDOMIZED CONTROLLED TRIAL
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
https://www.readbyqxmd.com/read/25610750/recent-advances-and-new-opportunities-for-targeting-human-dendritic-cells-in-situ
#18
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
https://www.readbyqxmd.com/read/25591994/conditional-overexpression-of-tgf%C3%AE-1-promotes-pulmonary-inflammation-apoptosis-and-mortality-via-tgf%C3%AE-r2-in-the-developing-mouse-lung
#19
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...
January 16, 2015: Respiratory Research
https://www.readbyqxmd.com/read/25539810/combination-therapy-with-anti-ctla-4-and-anti-pd-1-leads-to-distinct-immunologic-changes-in-vivo
#20
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
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