ASCO, Author Interviews, Biomarkers, Cancer Research, Cost of Health Care, Immunotherapy / 07.06.2016 Interview with: Neil T. Mason, MBA Personalized Medicine Strategist Personalized Cancer Medicine Division of Population Science Moffitt Cancer Center MedicalResearch: What is the background for this study? What are the main findings? Response: Immune checkpoint inhibitors targeting PD-1 (nivolumab and pembrolizumab) and CTLA-4 (ipilimumab) have revolutionized the treatment of metastatic disease in melanoma and non-small cell lung cancer with additional indications showing positive results. These drugs have elicited profound and durable responses in a significant number of patients, but have been criticized for their high cost. Though the price of the drugs themselves can reach over $100,000 per year, they can also cause severe, life threatening toxicities that are difficult and expensive manage. This model utilizes patient data from a large, NCI-designated cancer center to estimate the average cost of treatment with immune checkpoint inhibitors based on average duration of treatment and reported incidence of major toxicities. Based on the model, PD-1 inhibitor therapies are less costly than ipilimumab due to the significantly higher cost per dose of ipilimumab and average treatment duration of less than a year for PD-1 inhibitors. Managing drug-related toxicities were estimated to contribute between $8,200 and $9,600 to the cost of therapy with nivolumab adding the most cost. (more…)
ASCO, Author Interviews, Brain Cancer - Brain Tumors, Cancer Research, Immunotherapy / 04.06.2016 Interview with: Wayne L. Furman, MD Department of Oncology Jude Children's Research Hospital Memphis, TN 38105-3678 What is the background for this study? What are the main findings? Dr. Furman: Despite improvement in 2-yr EFS from 46% to 66% with the inclusion of dinutuximab, a monoclonal antibody that recognizes a glycoprotein on neuroblasts called ‘GD2’ (disialoganglioside), more than one-third of children with high-risk neuroblastoma still are not cured. Therefore novel therapeutic approaches are needed for this subset of patients. The clinical evaluation of various anti-GD 2 monoclonal antibodies in children with neuroblastoma has been exclusively focused on treatment of patients after recovery from consolidation, in a state of ‘minimal residual disease’. This is because traditionally chemotherapy has been thought to be too immunosuppressive to combine with monoclonal antibodies. However recent studies suggest, even in the setting of “bulky” solid tumors, the combination of chemotherapy with monoclonal antibodies can enhance the effectiveness of the antibodies. First, chemotherapy can increase the efficacy of antibodies by depleting cells of the immune system that suppress immune function. Also chemotherapy-induced tumor cell death can trigger tumor antigen release, uptake by antigen processing cells and an enhanced antitumor immune response. There is also data that anti-GD2 monoclonal antibodies can suppress tumor cell growth independent of immune system involvement. Furthermore anti-GD2 monoclonal antibodies and chemotherapy have non-overlapping toxicities. All of these reasons were good reasons to evaluate the addition of a novel anti-GD2 monoclonal antibody, called hu14.18K322A, to chemotherapy, outside the setting of minimal residual disease, in children with newly diagnosed children with high-risk neuroblastoma. (more…)
Author Interviews, Dermatology, Immunotherapy / 01.06.2016 Interview with: Benjamin M. Perry, DO Silver Falls Dermatology Salem, OR 97302 What is the background for this study? Dr. Perry: Our interest in this subject developed when a patient came into our clinic with concern of multiple new nevi developing on palmoplantar surfaces following initiation of treatment with Rituximab. We conducted a review of the existing literature and found that this wasn’t a known adverse effect. From that point, we wanted to know the pathogenesis, prognosis, and management for eruptive nevi that developed in the setting of medication use. A collective review had not been previously performed on this subject. In essence, we had questions that were unanswered and set out to find the answers. (more…)
Author Interviews, Cancer Research, Dermatology, Immunotherapy, Melanoma, NYU / 21.05.2016 Interview with: Melissa A. Wilson, MD, PhD Assistant professor of Medical Oncology NYU Langone Perlmutter Cancer Center What are the most common types of skin cancer? Dr. Wilson: Basal cell carcinoma, squamous cell carcinoma and melanoma. With rare exception, all are related to sun exposure. Are some types of skin cancer more serious than others? Dr. Wilson: Melanoma is the most serious form of skin cancer, with the highest risk of developing into metastatic disease. Most basal cell and squamous cell carcinomas are superficial and not as invasive, so removal is the treatment. Rarely, these can cause invasive and metastatic disease, but this occurs infrequently. Melanoma is much more serious. Of course, the earlier melanoma is detected and the earlier stage that it is, is more predictive of a favorable outcome. Who is most prone to skin cancer? Dr. Wilson: Persons with excessive sun exposure, fair skin, light hair and blue eyes - although it can certainly occur in anyone. (more…)
Author Interviews, Cancer Research, Colon Cancer, Immunotherapy, Leukemia, Multiple Sclerosis, Neurology / 13.05.2016 Interview with: PD Dr. Mathias Buttmann Senior Consultant Neurologist and Head of the Multiple Sclerosis Outpatient Clinic University of Wuerzburg Wuerzburg, Germany What is the background for this study? What are the main findings? Dr. Buttmann: The synthetic anthracenedione mitoxantrone is approved for disease-modifying treatment of patients with aggressive forms of relapsing or secondary progressive multiple sclerosis (MS). It has been known for years that this DNA-intercalating agent increases the risk of acute myeloid leukemia. We performed a retrospective cohort study to investigate whether mitoxantrone also increases the risk for other types of malignancies. We included all 677 mitoxantrone-treated  multiple sclerosis patients who were seen at our large German academic MS centre between 1994 and 2007 and collected follow-up information on the occurrence of malignancies, death and causes of death as of 2011. Follow-up was complete in 676 patients. The median age at mitoxantrone initiation was 41 years and the median follow-up duration was 8.7 years. We identified 37 patients with a malignancy after mitoxantrone initiation, among them 4 cases of acute myeloic leukemia and 7 cases of colorectal cancer. Compared to the general population matched for sex, age and year of occurrence, we calculated an 1.5-fold increased incidence of any type of malignancy, a tenfold increased incidence of acute myeloic leukemia and a threefold increased incidence of colorectal cancer, while the incidence of other types of malignancies was not increased. Higher age at mitoxantrone initiation but neither higher cumulative mitoxantrone dose nor treatment with other immuosuppressive agents was identified as a malignancy risk factor. Fifty-five patients had died, among them 12 from a malignancy. Our study confirmed previous reports on an increased incidence of acute myeloic leukemia after mitoxantrone treatment and newly described an association between mitoxantrone therapy and an increased incidence of colorectal cancer. (more…)
Author Interviews, Immunotherapy, JAMA, Multiple Sclerosis, UCSF / 02.05.2016 Interview with: Jennifer Graves, MD, PhD, MAS Adult and Pediatric Multiple Sclerosis Centers UCSF What is the background for this study? What are the main findings? Dr. Graves: Cessation of medications with effects on immune trafficking may be more likely to cause rebound inflammatory activity in autoimmune diseases such as multiple sclerosis.  We observed 5 strikingly severe relapses consistent with rebound events following cessation of fingolimod treatment and identified several similar cases in the literature.  At our center the rebound events occurred with an approximate 10% frequency. What should clinicians and patients take away from your report? Dr. Graves: Fingolimod cessation may be complicated by rebound phenomena in some patients, similar to what has been observed with natalizumab. Both of these medications have effects on immune cell trafficking, likely explaining the association with rebound events.  Careful consideration must be taken in stopping these medications. (more…)
Author Interviews, Cancer Research, Immunotherapy, NEJM / 02.05.2016 Interview with: Paul Nghiem, MD, PhD Professor & Head, University of Washington Dermatology George F. Odland Endowed Chair Affiliate Investigator, Fred Hutchinson Cancer Research Center Professor, Adjunct, of Pathology and Oral Health Sciences Clinical Director, Skin Oncology, Seattle Cancer Care Alliance UW Medical Center at Lake Union Seattle WA 98109 What is the background for this study? What are the main findings? Dr. Nghiem: Merkel cell carcinoma (MCC) is about 30 times less common than malignant melanoma, but about 3 times more likely to kill a patient than a melanoma. There is no FDA-approved therapy for this cancer & chemotherapy typically only provides about 90 days prior to the cancer progressing. Because of the strong links between MCC and the immune system, including the fact that most MCCs are caused by a virus, there was interest in trying to use immune checkpoint therapy to treat advanced Merkel cell carcinoma. The response to immune stimulation with anti-PD1 therapy was about as frequent as to chemotherapy (56% of patients responded) but importantly, among the responders, 86% remained in ongoing responses at a median of 7.6 months.  While still early, this appears to be strikingly more durable than responses to chemotherapy. (more…)
Author Interviews, Immunotherapy / 19.03.2016 Interview with: Dr. Emerson C. Perin MD, PhD Texas Heart Institute Medical Director, BSLMC Catheterization Laboratory Director, Research in Cardiovascular Medicine Medical Director, Stem Cell Center What is the background for this study? Dr. Perin: Critical limb ischemia (CLI) is a devastating and debilitating disease characterized by reduced blood flow to the legs, frequently as a consequence of atherosclerosis. Patients with CLI have a poor prognosis and live with chronic pain and disability. The disease manifests clinically as pain during rest and compromised wound healing, often resulting in ulcers that don’t heal, which can lead to amputation. Moreover, Critical limb ischemia is a deadly disease, with an annual mortality rate of about 20%. The only effective treatment option is revascularization, but not all CLI patients are good candidates for this approach, and even for those who are, procedures can fail. These patients face a dismal prospect as no other effective treatment options are available. Clearly, new therapeutic strategies are desperately needed for this group of patients. One of the most exciting new approaches for Critical limb ischemia patients who have no options is the concept of therapeutic angiogenesis—improving regional blood flow by facilitating the growth of blood vessels. This can be accomplished by delivering angiogenic factors to the area in need of improved blood supply. Hepatocyte growth factor (HGF) is a promising novel biologic for use in this way because it’s a powerful angiogenic agent that stimulates cell proliferation and migration. Delivering HGF into the ischemic limbs of patients with CLI may result in beneficial effects that help restore compromised blood flow to the area and encourage better healing of wounds. VM202 is a plasmid DNA that simultaneously expresses two isoforms of HGF, mimicking the way the body produces HGF. On the basis of favorable results from phase 1 clinical trials showing that gene therapy with VM202 was safe, well-tolerated, and potentially beneficial in patients with ischemic diseases, we conducted a phase 2, dose-escalation clinical trial in patients with Critical limb ischemia. (more…)
Allergies, Author Interviews, Immunotherapy / 14.03.2016 Interview with: Stacy L. Rosenberg, MD UPMC Montefiore Allergy and Immunology Fellow What is the background for this study? Dr. Rosenberg: Allergy shots or allergen immunotherapy (AIT) is an effective therapy for allergic rhinoconjunctivitis (hay fever).  Low adherence has been a significant barrier, whereas rush immunotherapy to environmental allergens provides rapid build-up and offers quicker efficacy, which may improve adherence.  However, there have been concerns for increased risk of systemic reactions with rush protocols.  We describe a new protocol for modified rush AIT that offers quicker build-up towards a maintenance dose with improved safety and lower risk of systemic reactions.  We also hypothesize that there are specific characteristics that distinguish patients who develop systemic reactions in the setting of modified environmental rush immunotherapy (MERIT). What are the main findings? Dr. Rosenberg: Overall, MERIT has a good safety profile.  A subset of patients did develop systemic reactions, which were mild.  Lower BMI was associated with systemic reactions and there was a trend between history of urticaria (hives) and younger age with development of systemic reactions.  Significantly more patients with systemic reactions had allergen extracts containing cat, dust mite, and weed pollen.  Neither gender, asthma, nor anaphylaxis history were associated with an increased risk of systemic reactions. (more…)
Author Interviews, Dermatology, Immunotherapy / 08.03.2016 Interview with: Dr. Andrew Blauvelt MD MPH President of Oregon Medical Research Center What is the background for this study? Dr. Blauvelt: Secukinumab (brand name Cosentyx)is a monoclonal antibody directed against interleukin 17A, a key cytokine involved in psoriasis pathogenesis. Efficacy and safety of secukinumab treatment for moderate-to severe psoriasis has been previously published. There are relatively few head-to-head comparison studies between biologic therapies for psoriasis, making direct comparison of these drugs difficult. (more…)
Author Interviews, Immunotherapy / 29.01.2016 Interview with: Dr. Mark Heffernan PhD Dr. Mark Heffernan is a Nexvet co-founder, and has served as Chief Executive Officer and a member of the Nexvet board of directors since April 2011. In 2003, Dr. Heffernan co-founded Opsona Therapeutics Ltd., an Irish biotechnology company focused on human mAbs for inflammatory and oncology diseases. He also worked in R&D and business development roles for two Australia biotechnology companies, Antisense Therapeutics Limited and Metabolic Pharmaceuticals Pty Ltd., for a number of years. Dr. Heffernan has a BSc in Biochemistry and Pharmacology and a Ph.D. in Biochemistry from Monash University (Australia). Tell me about Nexvet and its background? What is the company’s mission statement or goal? Dr. Heffernan:   Nexvet is a public (NASDAQ: NVET) clinical-stage biopharmaceutical company focused on developing and commercializing novel, species-specific biologics for companion animals (pets). We were founded five years ago and our mission has been to transform animal medicine by leading the introduction of biologic therapies (monoclonal antibodies and therapeutic proteins) into everyday veterinary practice. Many chronic conditions stand to benefit from biologic options, just as they have in human medicine, such as inflammation and cancer. Taking products with validation in human medicine is part of Nexvet’s development strategy, which leverages human data from these innovative therapies and rapidly advances the veterinary equivalents. Can you tell us about the PETization™ platform? What is it designed to do? Dr. Heffernan:   PETization™ is Nexvet’s proprietary approach to monoclonal antibody (mAb) candidate design. It uses an algorithmic approach, ‘crunching’ libraries of natural antibody sequence data to rapidly design mAbs that are “100% species-specific” to a target species. This significantly reduces the risk of an immunogenic reaction, while preserving the parent (or ‘starting’) mAb’s affinity for its target. PETization has demonstrated a reduction in the time and cost typically associated with the development of monoclonal antibodies using conventional methods, such as CDR grafting and its affinity maturation. Thus far Nexvet has used PETization to successfully convert human and rodent mAbs into canine, feline and equine mAbs. These candidates have demonstrated safety and efficacy across the clinical development spectrum including proof-of-concept (every species) right through to late-stage pivotal studies (in dogs). (more…)
Author Interviews, Immunotherapy, NEJM, Transplantation, UCSF / 29.01.2016 Interview with: Dr. Flavio Vincenti, M.D Clinical Professor of Medicine and Surgery Departments of Medicine and Surgery Endowed Chair in Kidney Transplantation University of California, San Francisco San Francisco, CA 94143 Medical Research: What is the background for this study? What are the main findings? Dr. Vincenti: This is a phase 3 study of belacept immunosuppression as compared to cyclosporine based immunosuppression in renal transplant recipients randomly assigned to 2 treatments arms of belatacept and a controlled arm consisting of cyclosporine. The main finding of this study is that Belatacept, a fusion receptor protein that blocks co-stimulation and is administered intravenously on the maintenance of a 4 weekly maintenance therapy, had superior outcomes at 5 and 7 years as compared to patients on a CsA-based regimen. The 7 year data show that patients on either arm of belatacept had a 43 percent risk reduction of deaths or grafts loss as compared to patients treated with cyclosporine. In addition, belatcept patients had significantly better preservation of renal function throughout the 7 years of follow up and had lower incidence of donor specific antibodies. Nephrotoxicity from cyclosporine and donor specific antibodies are important causes of late graft loss. (more…)
Author Interviews, Breast Cancer, Immunotherapy, PLoS / 02.01.2016 Interview with: David Gallego Ortega, PhD Group Leader, Tumour Development Group Cancer Division Garvan Institute of Medical Research Conjoint Lecturer, St Vincent’s Clinical School, Faculty of Medicine, UNSW, Australia National Breast Cancer Foundation and Cure Cancer Foundation Australia Fellow  Medical Research: What is the background for this study? What are the main findings? Dr. Ortega: We have identified a protein that 'goes rogue’ in breast cancer. The protein, called Elf5, ‘tricks' the immune system producing inflammation so that the immune cells now help the breast cancer cells to spread throughout the body. Cancer spread, or metastasis, is the ultimate cause of death of breast cancer patients, so we are very excited about our discovery because it opens the door to explore anti-inflammatory drugs that can be combined with existing therapies. We have found that luminal breast cancer patients that present high levels of Elf5 progress earlier in their disease. The Luminal subtype is the most common type of breast cancer, so these therapies will potentially benefit to 2/3 of all breast cancer patients. (more…)
Author Interviews, Immunotherapy, NEJM, Rheumatology / 24.12.2015 Interview with: Prof. dr. D.L.P. Baeten MD Clinical Immunology and Rheumatology Academic Medical Center University of Amsterdam Amsterdam, The Netherlands Medical Research: What is the background for this study? What are the main findings? Prof. Baeten: Ankylosing spondylitis is a debilitating rheumatic condition which affects young adults and with NSAIDS and TNF inhibitors as only therapeutic option. Over the last years, we generated evidence that IL-17 is an important inflammatory mediator in this condition. In the two studies reported here in the NEJM, we demonstrate that IL-17 inhibition with secukinumab has a very profound and long-lasting effect on signs and symptoms as well as inflammation in ankylosing spondylitis patients, even in those patients that failed a TNF blocker before. (more…)
Author Interviews, Genetic Research, Immunotherapy / 22.12.2015 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. (more…)
Author Interviews, Immunotherapy, Lymphoma, NYU / 11.12.2015 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%. (more…)
Author Interviews, Breast Cancer, Chemotherapy, Immunotherapy / 09.12.2015 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. (more…)
Annals Internal Medicine, Author Interviews, Dermatology, Gastrointestinal Disease, Immunotherapy / 09.12.2015 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. (more…)
Author Interviews, Cancer Research, Chemotherapy, Hematology, Immunotherapy / 09.12.2015 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. (more…)
Author Interviews, HIV, Immunotherapy, PLoS / 04.12.2015 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. (more…)
ASCO, Author Interviews, Immunotherapy, Ovarian Cancer / 02.12.2015 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. (more…)
AACR, Author Interviews, Duke, Immunotherapy / 14.11.2015 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. (more…)
Author Interviews, Brigham & Women's - Harvard, Cancer Research, Immunotherapy, NEJM / 05.11.2015 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.  (more…)
Asthma, Author Interviews, Immunotherapy, Pediatrics / 31.10.2015 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. (more…)
Author Interviews, FDA, Immunotherapy, Lung Cancer / 24.10.2015 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. (more…)
Author Interviews, Immunotherapy, Melanoma, Nature / 19.06.2015 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. (more…)
Author Interviews, Diabetes, Immunotherapy, Kidney Disease, University of Michigan / 13.06.2015 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. (more…)
Author Interviews, BMJ, Gastrointestinal Disease, Immunotherapy / 11.06.2015 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. (more…)
Author Interviews, Immunotherapy, Melanoma / 02.06.2015

Prof. Ze'ev Ronai Ph.D Scientific Director Sanford-Burnham's La 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.  (more…)