Immunotherapy

22 Dec

Posted at 23:57h in Author Interviews, Genetic Research, Immunotherapy
MedicalResearch.com Interview with: Benjamin Greenbaum, PhD Assistant Professor and Professor Nina Bhardwaj MD PhD Hematology and Medical Oncology Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York, NY 10029 Medical Research: What is the background for this study? Response: It has recently become clear that, due to epigenetic alterations, tumors transcribe non-coding RNAs that are typically silenced. Often such RNA emanates from the “dark matter” genome. Many of these regions consist of repetitive elements and endogenous retroelements that are rarely transcribed in normal tissue. At the same time, due to immunotherapy, understanding the role of the immune system and immune activation in tumors has become critically important. The activation of specific elements of the innate immune system in a tumor may have either beneficial or detrimental effects for patients. Moreover, recent work has suggested that endogenous element activation can lead to improved immunotherapy outcomes. Therefore, it is critically important to understand the nature of innate immune activation in tumors and what triggers are responsible for these responses. We have been developing methods to detect abnormal patterns in viral RNA that may indicate activation of the innate immune system. We have found that patterns of motif usage avoided in the evolution of viruses, such as influenza, indicate RNA features that provoke an innate immune response. The innate immune system is capable of sensing motifs in viruses. We tested directly whether these avoided patterns are immunostimulatory.

11 Dec

Posted at 21:19h in Author Interviews, Immunotherapy, Lymphoma, NYU/NYMC
[caption id="attachment_20027" align="alignleft" width="200"]Dr. Catherine S. M. Diefenbach MD Assistant Professor of Medicine NYU Cancer Center New York, NY 10016 Dr. Diefenbach[/caption] MedicalResearch.com Interview with: Dr. Catherine S. M. Diefenbach MD Assistant Professor of Medicine NYU Langone Laura and Isaac Perlmutter Cancer Center New York, NY 10016  Medical Research: What is the background for this study? What are the main findings? Dr. Diefenbach: The background of the study is that through an understanding of the unique immunobiology of Hodgkin lymphoma we can derive rational treatment strategies which may heighten the efficacy of existing therapies, and improve the outcomes for patients with relapsed disease.  In E4412 which is a national study sponsored by the Eastern Cooperative Oncology Group (ECOG-ACRIN) we explore the safety and efficacy of combination of the antibody drug conjugate brentuximab vedotin which targets CD30 on the surface of the Hodgkin lymphoma tumor cells, and immune stimulation of the T cells in the tumor microenvironment using checkpoint inhibitors.  We reported the data from the first arm of the study Brentuximab Vedotin and Ipilimumab.  To date 23 patients with relapsed Hodgkin lymphoma have been treated; the combination of brentuximab and ipilimumab was safe and well tolerated with primarily grade 1 and 2 toxicities.  In 18 patients evaluable for response the ORR was 72% with a complete response rate of 50%.

09 Dec

Posted at 17:23h in Author Interviews, Breast Cancer, Chemotherapy, Immunotherapy
[caption id="attachment_19926" align="alignleft" width="160"]Director and Chairman Department of Surgery President, Austrian Breast&Colorectal Cancer Study Group Head, Breast Health Center Vienna Comprehensive Cancer Center Vienna Medical University of Vienna - Department of Surgery Austria Prof. Michael Gnant[/caption] MedicalResearch.com Interview with: Professor Michael Gnant, M.D., FASC Director and Chairman Department of Surgery President, Austrian Breast&Colorectal Cancer Study Group Head, Breast Health Center Vienna Comprehensive Cancer Center Vienna Medical University of Vienna - Department of Surgery Austria Medical Research: What is the background for this study? What are the main findings? Response: The background of this presentation is as follows: For many years, we have seen intriguing - but also sometimes conflicting - results of trials using adjuvant bone-targeted therapy. ABCSG-18 is a placebo-controlled trial of adjuvant denosumab 60mg twice yearly, and I have been able to present to you at this year’s ASCO meeting the dramatic reduction in clinical fractures which was the primary end point of the trial. We have also showed that twice yearly denosumab can be administered without added toxicity in this double-blind placebo-controlled trial. These results were as well published in the Lancet earlier this year. The obvious question remaining now is whether adjuvant treatment with the anti-RANK ligand antibody also improves outcomes in a way similar to what bisphosphonates do. Main findings of ABCSG-18: disease-free survival results of the intention-to-treat analysis: In the placebo group, we observed 203 DFS events. In the denosumab group, there were 167 DFS events, resulting in a hazard ratio of 0.816, indicating an 18% relative DFS improvement by denosumab. In terms of absolute differences, the benefit was 1.2% at 3 years, 2.1% at 5 years, and 3.1% at 7 years.

09 Dec

Posted at 16:04h in Annals Internal Medicine, Author Interviews, Dermatology, Gastrointestinal Disease, Immunotherapy
[caption id="attachment_19875" align="alignleft" width="180"]Isabelle Cleynen PhD University of Leuven Dr. Cleynen[/caption] MedicalResearch.com Interview with: Isabelle Cleynen  PhD University of Leuven  Medical Research: What is the background for this study? What are the main findings? Dr. Cleynen : Ulcerative colitis and Crohn’s disease, together inflammatory bowel disease (IBD), are characterized by chronic inflammation of the gastrointestinal tract. Treatment for IBD usually involves drug therapy including anti-inflammatory drugs and immune system repressors, amongst which biologics as the anti-TNF antibodies used for patients with moderate to severe IBD. Although these TNF-blocking drugs are effective in many patients with immune-mediated disorders like psoriasis, rheumatoid arthritis and spondylarthropathies, and IBD, several case reports and series showed that some patients developed troubling skin problems (including psoriasis and eczema), causing them to stop the anti-TNF treatment. It is however not clear how often these skin problems develop in IBD patients treated with anti-TNF, and what could be the predisposing factors. In a retrospective cohort of 917 IBD patients initiated on anti-TNF therapy in a single center, we have studied which patients did and did not develop skin problems, what type of skin problems, how they were treated, and whether the lesions resolved upon treatment. We found that about one third of the patients developed skin problems while being treated with anti-TNF drugs. The most common type was psoriasiform eczema, often occurring in flexural regions, the scalp, and genitalia. The time between starting the TNF-blocking drug and the appearance of the skin problem varied from less than half a year to more than 4 years. Quite surprisingly, we found that the cumulative dose of the treatment, or drug serum levels were not different in skin and non-skin lesion patients. Skin lesion patients however seemed to be younger when diagnosed with IBD and when started on anti-TNF agents, more often had anti-nuclear and dsDNA antibodies (both auto-immune factors), and a higher number of skin-disease related genetic risk variants. Most patients had a good response to treatment of their skin problem. About 10% of the patients who developed skin problems, however, stopped the TNF-blocking treatment because of this issue.

09 Dec

Posted at 01:55h in Author Interviews, Cancer Research, Chemotherapy, Hematology, Immunotherapy
MedicalResearch.com Interview with: Dr. Ajai Chari MD Associate Professor Medicine, Hematology and Medical Oncology Tisch Cancer Institute Mount Sinai School of Medicine New York, NY Medical Research: What is the background for this study? Dr. Chari: This is a heavily pretreated population where the median progression free survival (PFS) of the pomalidomide dexamethasone is only 4 months and ORR is only 31%. While the anti CD38 monoclonal antibody daratumumab has single agent has activity in this setting, patients with rapidly progressive disease need combination therapy to achieve rapid and deep responses. Pomalidomide also upregulates CD38 on MM cells and like daratumumab, increases the effector cell activity against myeloma. Thus, there is a strong preclinical and clinical rationale for combining daratumumab with pomalidomide and dexamethasone.

04 Dec

Posted at 03:25h in Author Interviews, HIV, Immunotherapy, PLoS
[caption id="attachment_19703" align="alignleft" width="169"]Andreas Meyerhans, PhD ICREA Research Professor at the University Pompeu Fabra Infection Biology Group Department of Experimental and Health Sciences Universitat Pompeu Fabra Barcelona Spain Dr. Meyerhans[/caption] MedicalResearch.com Interview with: Andreas Meyerhans, PhD ICREA Research Professor at the University Pompeu Fabra Infection Biology Group Department of Experimental and Health Sciences Universitat Pompeu Fabra Barcelona Spain Medical Research: What is the background for this study? What are the main findings? Dr. Meyerhans: In brief, chronic HIV infections lead to a dampening of HIV-specific killer cells. This phenomenon is named exhaustion and is mediated by inhibitory proteins, such as PD-1, on the cell surface. A consequence of exhaustion is a reduction of the immune control over virus expansion. We have studied the effect of blocking the negative signaling from the inhibitory proteins by means of PD-1/PD-L1 pathway inhibition on effector and regulatory T cells (Treg). We found that one can augment antiviral immune control only when the virus load was well controlled in the HIV-infected individuals i.e. by antiviral drugs. In that case, PD-1/PD-L1 pathway blockage led to an expansion of anti-HIV killer cells over Treg cells. This latter are suppressive white blood cells also subject to the same inhibitory pathway regulation. In contrast, when blood cells from viremic HIV-infected individuals were analyzed, Treg cells expanded efficiently and thus reduced the effector to regulatory T cell ratio that controls HIV. Taken together, our data point to Treg cells as an important component in the outcome of PD-1/PD-L1 pathway inhibitor therapies and suggest a net gain in anti-HIV immune responses only when the HIV loads are well controlled during the administration of these novel compounds.

02 Dec

Posted at 21:18h in ASCO, Author Interviews, Immunotherapy, Ovarian Cancer
[caption id="attachment_19783" align="alignleft" width="192"]Junzo Hamanishi M.D., Ph.D. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine Assistant Professor Kyoto Japan Dr. Hamanishi[/caption] MedicalResearch.com Interview with: Junzo Hamanishi  M.D., Ph.D. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine Assistant Professor Kyoto Japan Medical Research: What is the background for this study? Dr. Hamanishi: More than 70% of patients with advanced ovarian cancer who achieve remission ultimately relapse and there are few effective treatments for these patients. Because the development of new treatment strategies for these patients is urgently required, we have focused on and studied the potential of cancer cells to escape from host immunity with PD-1/PD-L1 immunosuppressive signal in the tumor microenvironment to find new treatment strategies to overcome this phenomenon, collaborating with Professor Honjo who discovered PD-1 since 2006. Therefore, we conducted a phase II clinical trial in 20 platinum-resistant, recurrent ovarian cancer patients to evaluate the safety and anti-tumor efficacy of anti-PD-1 antibody (nivolumab) with 2 cohort at a dose of 1 or 3 mg/kg (constituting two 10-patient cohorts). Medical Research: What are the main findings? Dr. Hamanishi: This study is the first investigator-initiated phase II clinical trial testing the safety and efficacy of nivolumab against platinum-resistant ovarian cancer. In the 20 patients in whom responses could be evaluated, the best overall response was 15%, including two patients with a durable complete response (3mg/kg cohort). The disease control rate in all 20 patients was 45%. The median progression-free survival was 3.5 months, with a median overall survival of 20.0 months. Especially in the 3 mg/kg cohort, two patients achieved a complete response, and disease stabilized in another two patients. The objective response rate in 3mg/kg cohort cohort was 20% and disease was controlled in 40% of the higher-dose group. In the four patients who demonstrated an antitumor response, responses were durable and evident. Grade 3 or 4 treatment-related adverse events (AE) occurred in eight out of 20 patients or 40% overall. However, the frequency of AEs were not different in 2 cohorts.

19 Nov

Posted at 23:31h in Author Interviews, Cancer Research, Immunotherapy

[caption id="attachment_19503" align="alignleft" width="200"] Mr. Wildgust[/caption] MedicalResearch.com Interview with: Mark Wildgust Global Medical Affairs Head for Hematology The Janssen Pharmaceutical Companies of Johnson & Johnson This week, the U.S. Food and Drug Administration (FDA) approved first-in-class immunotherapy DARZALEX™ (daratumumab) injection for intravenous infusion for the treatment of patients with multiple myeloma (MM) who have received...

14 Nov

Posted at 21:18h in AACR, Author Interviews, Duke, Immunotherapy
[caption id="attachment_19174" align="alignleft" width="160"]Jiayuh Lin, Ph.D. Associate Professor, College of Medicine, The Ohio State University Dr. Lin[/caption] MedicalResearch.com Interview with: Jiayuh Lin, Ph.D. Associate Professor, College of Medicine, The Ohio State University Medical Research: What is the background for this study? What are the main findings? Dr. Jiayuh Lin: Pancreatic cancer is one of the most serious forms of cancer.  Because of the poor response to chemotherapy as conventionally used, patients with any stage of pancreatic cancer may appropriately be considered candidates for clinical trials using novel agents. IL-6 signaling plays an important role in oncogenesis and high serum IL-6 levels is a poor prognostic factor for overall survival in pancreatic cancer. Therefore, IL-6 is considered as a viable target for pancreatic cancer therapy.  We utilized a drug discovery method with Multiple Ligand Simultaneous Docking and drug repositioning to identify an existing FDA-approved drug Bazedoxifene with previously unknown biological function as an IL-6/GP130 inhibitor.  Bazedoxifene can inhibit cell viability of pancreatic cancer cells expressing IL-6 and suppressed pancreatic tumor growth in vivo.

05 Nov

Posted at 20:23h in Author Interviews, Brigham & Women's - Harvard, Cancer Research, Immunotherapy, NEJM
[caption id="attachment_18967" align="alignleft" width="175"]Toni Choueiri, MD Clinical Director, Lank Center for Genitourinary Oncology Director, Kidney Cancer Center Senior Physician Dana Farber Cancer Institute Associate Professor of Medicine, Harvard Medical School Dr. Toni Choueiri[/caption] MedicalResearch.com Interview with: Toni Choueiri, MD Clinical Director, Lank Center for Genitourinary Oncology Director, Kidney Cancer Center Senior Physician Dana Farber Cancer Institute Associate Professor of Medicine Harvard Medical School Medical Research: What is the background for this study? What are the main findings? Dr. Choueiri: In the METEOR trial, we aimed to compare cabozantinib, a novel VEGFR, MET, AXL inhibitor to everolimus, a standard 2nd line option in advanced RCC. There is an unmet in this setting. Cabozantinib resulted in a median PFS of 7.4 months compared to 3.8 months with everolimus. Responses also were 4-times higher with cabozantinib-treated patients. At the interim OS analysis, there was a strong trend favoring cabozantinib. 

31 Oct

Posted at 21:53h in Asthma, Author Interviews, Immunotherapy, Pediatrics
[caption id="attachment_18959" align="alignleft" width="135"]Stephen J. Teach, MD, MPH Chair, Department of Pediatrics Children's National Health System Washington, DC Dr. Stephen Teach[/caption] MedicalResearch.com Interview with: Stephen J. Teach, MD, MPH Chair, Department of Pediatrics Children's National Health System Washington, DC  Medical Research: What is the background for this study? What are the main findings? Dr. Teach: Inner-city children aged 6 to 17 years with moderate to severe asthma continue to experience exacerbations at high rates during the fall season despite therapy which follows the guidelines of the National Institutes of Health. These exacerbations are most common among children with a history of prior exacerbations and sensitivities to common indoor allergens who develop an upper respiratory infection with the common cold virus (rhinovirus). The PROSE study found that treatment with omalizumab begun 4 to 6 weeks before the children return to school, significantly reduced exacerbations of asthma in the first 90 days of the school year. This effect was most dramatic among those children who had experienced an exacerbation in the months preceding the beginning of the school year. Omalizumab is an antibody which binds and deactivates the IgE antibody. The IgE antibody serves as the basis for allergic sensitivity.

24 Oct

Posted at 11:44h in Author Interviews, FDA, Immunotherapy, Lung Cancer
MedicalResearch.com Interview with: Dickran Kazandjian, MD Office of Hematology and Oncology Products Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring, Maryland Medical Research: What is the background for this study? What are the main findings? Dr. Kazandjian: Nivolumab is the first approved immunotherapy, for the treatment of metastatic squamous non–small-cell lung cancer (NSCLC) after platinum-based chemotherapy.  FDA initiated an expedited review after obtaining the data monitoring committee report of a planned interim analysis of a second-line squamous NSCLC trial demonstrating a large overall survival benefit (CheckMate 017). Nivolumab efficacy in metastatic Squamous (SQ) NSCLC has been previously reported in two studies.  CheckMate 063 was a single-arm trial in 117 patients with metastatic SQ NSCLC who had progressed after previous treatment with 2 systemic regimens including platinum-based doublet chemotherapy (Rizvi et al)  CheckMate 017 was a randomized study of nivolumab compared to docetaxel in 272 patients with metastatic SQ NSCLC who had progressed after prior platinum-based doublet chemotherapy (Brahmer et al).  The median survival of patients randomized to nivolumab was 9.2 months vs 6.0 months for docetaxel (hazard ratio, 0.59; 95%CI, 0.44-0.79; P < .001) a 41% improvement in the risk of death. Approval was supported by the single-arm study which demonstrated an objective response rate of 15% and at the time of analysis, 10 of the 17 responding patients (59%) had response  durations of 6 months or longer. The FDA approved nivolumab on March 4, 2015, saving 6 months by not waiting for formal preparation of data by the sponsor and 2.5 months by expediting review.

19 Jun

Posted at 10:39h in Author Interviews, Immunotherapy, Melanoma, Nature
MedicalResearch.com Interview with: Chiara Martinoli, PhD Medical Oncology of Melanoma European Institute of Oncology Milan, Italy MedicalResearch: What is the background for this study? What are the main findings? Dr. Martinoli: The recent advent of new immunomodulatory drugs and targeted therapies is changing the therapeutic algorithm for metastatic melanoma patients. Immunomodulation with the anti-CTLA-4 antibody ipilimumab improves survival but is not devoid of potential risks. There is an urgent need for biomarkers to identify patients best suited to receive this therapy, in order to maximize treatment benefit and spare toxicities. In this study, by analyzing pre-therapy hematological parameters of a large group of metastatic melanoma patients treated with ipilimumab, we showed that neutrophil-to-lymphocyte ratio is strongly and independently associated to patient outcome. Patients with a low baseline neutrophil-to-lymphocyte ratio had a double-reduced risk of disease progression and a two-to-four-fold reduced risk of death, regardless of age, sex and LDH.

13 Jun

Posted at 12:35h in Author Interviews, Diabetes, Immunotherapy, Kidney Disease, University of Michigan
MedicalResearch.com Interview with: Frank C. Brosius, MD Professor, Internal Medicine and Physiology Chief, Division of Nephrology University of Michigan Ann Arbor, MI Dr. Matthias Kretzler MD Professor, Internal Medicine Research Professor, Computational Medicine and Biology University of Michigan Ann Arbor, MI Katherine R. Tuttle MD Clinical Professor of Medicine, Division of Nephrology Medical & Scientific Director, Providence Medical Research Center/Sacred Heart Center Professor of Basic Medical Sciences, WWAMI Program Washington State University Medical Research: What is the background for this study? Response: Our University of Michigan team had found that JAK-STAT gene expression was increased in kidneys in patients with diabetic kidney disease and that these changes correlated with progression of kidney disease.  We subsequently substantiated these changes in other studies and have found that by increasing expression of just one of these genes, JAK2, in a single kidney cell type (podocytes) in mice that we can make their diabetic kidney disease much worse. At around the same time, investigators at Eli Lilly and Co. had FDA approval to test a JAK1-2 inhibitor, baricitinib, in patients with rheumatoid arthritis.  The Lilly scientists saw our human results and thought about using baricitinib in patients with diabetic kidney disease.  After initial discussions with Dr. Kretzler and myself they concluded that there was good reason to move ahead with this study and just 14 months after the initial meeting the phase 2 clinical trial of baricitinib in the treatment of patients with diabetic kidney disease was initiated.

11 Jun

Posted at 00:37h in Author Interviews, BMJ, Gastrointestinal Disease, Immunotherapy
MedicalResearch.com Interview with: Nynne Nyboe Andersen, MD, PhD student Department of Epidemiology Research Statens Serum Institut Copenhagen, Denmark Medical Research: What is the background for this study? What are the main findings? Dr. Andersen: The use of TNF-α inhibitors, including infliximab, adalimumab and certolizumab pegol to treat people with inflammatory bowel disease is increasing worldwide and has upgraded the medical treatment modalities. However, concerns about their safety, including an increased risk of serious infections have persisted because they suppress the immune system. Previous meta-analyses based on randomized controlled trials did not suggest an increased risk of serious infections in people with inflammatory bowel disease treated with TNF-α inhibitors compared to placebo. However, the trials included in the meta-analyses were designed to investigate efficacy, and not to analyze risk of rare adverse events such as serious infections and often represent selected populations. Therefore, observational studies are essential to evaluate safety in a real world setting; however, results from these studies have been conflicting. Thus, as the risk of infections associated with TNF-α inhibitor treatment in people with inflammatory bowel disease is unclear we aimed at investigating this potential risk in a population-based setting based on the entire Danish inflammatory bowel disease population. In a propensity score matched cohort we found a significant 63% increased risk of serious infections within 90 days after treatment initiation. When we prolonged follow-up to 356 days the risk was attenuated and no longer significant.  For site-specific serious infections, we found increased point estimates for sepsis, urological/gynecological infections, and skin and soft tissue infections; but these results should be interpreted cautiously because of limited power.

02 Jun

Posted at 11:46h in Author Interviews, Immunotherapy, Melanoma
Prof. Ze'ev Ronai Ph.D Scientific Director Sanford-Burnham's La JollaMedicalResearch.com Interview with: Prof. Ze'ev Ronai Ph.D Scientific Director Sanford-Burnham's La Jolla Medical Research: What is the background for this study? What are the main findings? Prof. Ronai: There is an urgent need to find new approaches to treat melanoma in patients that are resistant to current therapeutic regimes—and this represents a significant percent of melanoma patients.  We used  samples from patients with drug resistant tumors  to study the molecular basis of resistance and screened for genes involved in the process. We have identified a new player in melanoma resistance to therapy—a molecular target, which provides the basis for clinical trials with drugs currently available to these targets. We found that JAK1 kinase is one target that  is upregulated in the resistant tumors. Inhibiting JAK1 kinase can effectively overcome such resistance.