Study Reports Hair Repigmentation During Immunotherapy For Lung Cancer

MedicalResearch.com Interview with:
Dr. Noelia Rivera MD

Dermatologist
Hospital Universitari Germans Trias i Pujol, Badalona
Universitat Autònoma de Barcelona

MedicalResearch.com: What is the background for this study?

Response: In the last few years some new therapies targeting immune checkpoints have been developed. The programmed death receptor-1 (PD-1) are immune checkpoints that prevent the immune system to act against own tissues. By blocking these mediators it is possible to prevent tumors to escape from the immune system.

About half of the patients receiving these therapies will develop mild to moderate cutaneous adverse events. In the pre-authorization studies for malignant melanoma these include rash, vitiligo, and pruritus. “Rash” has commonly been reported as an adverse event in many oncologic trials evaluating the drugs, without providing further information about the clinical or histological details. Lately, lichenoid eruptions associated to these therapies have been reported and it suggests that an important percentage of these reactions present lichenoid histological features.

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Report of Benign Moles Undergoing Immune Reaction During Nivolumab Therapy in a Patient With Melanoma

MedicalResearch.com Interview with:

Yasuhiro Nakamura, M.D., Ph.D. Associate Professor Department of Skin Oncology/Dermatology Comprehensive Cancer Center Saitama Medical University International Medical Center Hidaka, Saitama

Dr. Nakamura

Yasuhiro Nakamura, M.D., Ph.D.
Associate Professor
Department of Skin Oncology/Dermatology
Comprehensive Cancer Center
Saitama Medical University International Medical Center
Hidaka, Saitama

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Regressing nevi, which are frequently associated with halo phenomenon, occur in approximately 1% of the general population. In patients with melanoma, spontaneous or treatment-related depigmentation of the skin (vitiligo) is sometimes observed. Although humoral and cellular immune responses may play a crucial role in their development, immune reactions to benign melanocytic nevi (BMN) without a halo are extremely rare in both the general population and in patients with melanoma.

This publication reports a rare case with multiple metastatic melanomas who showed a remarkable clinical response to nivolumab with a simultaneous prominent immune reaction to multiple BMN without halo phenomenon. This rare phenomenon may be associated with dramatic efficacy of nivolumab in melanoma patients.

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Tofacitinib -XELJANZ: Potential New Treatment Option For Moderate To Severe Ulcerative Colitis

MedicalResearch.com Interview with:

William J. Sandborn, MD Professor of Medicine and Adjunct Professor of Surgery Chief, Division of Gastroenterology Vice Chair for Clinical Operations, Department of Medicine Director, UCSD IBD Center University of California San Diego and UC San Diego Health System

Dr. Sandborn

William J. Sandborn, MD
Professor of Medicine and Adjunct Professor of Surgery
Chief, Division of Gastroenterology
Vice Chair for Clinical Operations, Department of Medicine
Director, UCSD IBD Center
University of California San Diego and
UC San Diego Health System

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There is still a substantial unmet need for new treatments for patients with ulcerative colitis.

A previous Phase II study had suggested that tofacitinib might be effective for short term therapy of ulcerative colitis. The patients in that study for the most part had not failed anti-TNF therapy. Now we report the findings from 3 large Phase III trials, two short term trials and one long term trial, demonstrating that tofacitinib 10 mg twice daily is effective for short term therapy, and that both 5 mg and 10 mg twice daily is effective for long term therapy. We also demonstrated that tofacitinib is effective both in patients who have not failed anti-TNF therapy and patients who have failed anti-TNF therapy.

The study demonstrated induction of clinical remission, clinical response and mucosal healing (flexible sigmoidoscopy improvement) over the short term, and maintenance of clinical remission, clinical response, and mucosal healing over the long term.

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Granzyme B Probe Plus PET Scanning Helps Determine Response To Immunotherapy

MedicalResearch.com Interview with:

Ben Larimer, PhD research fellow in lab of Umar Mahmood, MD, PhD Massachusetts General Hospital Professor, Radiology, Harvard Medical School

Dr. Ben Larimer

Ben Larimer, PhD research fellow in lab of
Umar Mahmood, MD, PhD

Massachusetts General Hospital
Professor, Radiology, Harvard Medical School

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:
Although immunotherapies such as checkpoint inhibitors have revolutionized cancer treatment, unfortunately they only work in a minority of patients. This means that most people who are put on a checkpoint inhibitor will not benefit but still have the increased risk of side effects. They also lose time they could have spent on other therapies. The ability to differentiate early in the course of treatment patients who are likely to benefit from immunotherapy from those who will not greatly improves individual patient care and helps accelerate the development of new therapies.

The main purpose of our study was to find a way to separate immunotherapy responders from non-responders at the earliest time point possible, and develop an imaging probe that would allow us to distinguish this non-invasively.

Granzyme B is a protein that immune cells use to actually kill their target. They keep it locked up in special compartments until they get the right signal to kill, after which they release it along with another protein called perforin that allows it to go inside of tumor cells and kill them. We designed a probe that only binds to granzyme B after it is released from immune cells, so that we could directly measure immune cell killing. We then attached it to a radioactive atom that quickly decays, so we could use PET scanning to noninvasively image the entire body to see where immune cells were actively releasing tumor-killing granzyme B.

We took genetically identical mice and gave them identical cancer and then treated every mouse with checkpoint inhibitors, which we knew would result in roughly half of the mice responding, but we wouldn’t know which ones until their tumors began to shrink. A little over a week after giving therapy to the mice, and before any of the tumors started to shrink, we injected our imaging probe and performed PET scans. When we looked at the mice by PET imaging, they fell into two groups. One group had high PET uptake, meaning high levels of granzyme B in the tumors, the other group had low levels of PET signal in the tumors. When we then followed out the two groups, all of the mice with high granzyme B PET uptake ended up responding to the therapy and their tumors subsequently disappeared, whereas those with low uptake had their tumors continue to grow.

We were very excited about this and so we expanded our collaboration with co-authors Keith Flaherty and Genevieve Boland to get patient samples from patients who were on checkpoint inhibitor therapy to see if the same pattern held true in humans. When we looked at the human melanoma tumor samples we saw the same pattern, high secreted granzyme levels in responders and much lower levels in non-responders.

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First Patients Enrolled in Study of Nintedanib For Progressive Fibrosing Lung Conditions

MedicalResearch.com Interview with:

Thomas Leonard, Ph.D. Executive director, Clinical Development and Medical Affairs, Specialty Care Boehringer Ingelheim Pharmaceuticals, Inc.

Dr. Thomas Leonard

Thomas Leonard, Ph.D.
Executive director, Clinical Development and Medical Affairs, Specialty Care
Boehringer Ingelheim Pharmaceuticals, Inc.

MedicalResearch.com: What is the background for this study? Would you tell us a little more about IPF?

Response: Boehringer Ingelheim’s Phase III PF-ILD (progressive fibrosing interstitial lung disease) trial will investigate the safety and efficacy of nintedanib, in a range of progressive fibrosing lung conditions other than idiopathic pulmonary fibrosis, or IPF. The PF-ILD trial is the first time that patients with different fibrosing lung diseases will be included in one single clinical trial assessing the efficacy of nintedanib as a potential treatment, and the trial is the first in the field of fibrosing lung diseases to group patients based on the clinical characteristics of their disease, rather than the diagnosis.

There are more than 200 conditions that affect the tissue and space around the air sacs of the lungs, or interstitium, and, collectively, these conditions are called interstitial lung diseases — or ILDs. Based on clinical observations, there is a group of patients with ILD who, independent from the classification of the ILD, exhibit progressive fibrosis. The proposed terminology for describing this group of patients is PF-ILD. In these patients, the disease appears to follow a course similar to IPF with worsening of respiratory symptoms, lung function, quality of life and ability to perform daily activities, as well as early mortality despite treatment.

There is currently no efficacious treatment available for PF-ILD. This trial is exploring how fibrosis in the lungs is treated and whether nintedanib is a potential treatment, based on the efficacy and safety of nintedanib in IPF, a rare and serious lung disease that causes permanent scarring of the lungs, making it difficult to breathe. IPF affects as many as 132,000 Americans, typically men over the age of 65. On average, people with IPF live only three to five years after diagnosis, and approximately 40,000 people die from this disease every year.

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Immunotherapy Ruxolitinib Cream Improves Facial Vitiligo

MedicalResearch.com Interview with:

David Rosmarin, MD Dermatologist; Assistant Professor Tufts University School of Medicine

Dr. Rosmarin

David Rosmarin, MD
Dermatologist; Assistant Professor
Tufts University School of Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Vitiligo is a disease where the immune system causes depigmentation of the skin. We performed a pilot study to evaluate the use of a new class of medication for the treatment of vitiligo.


MedicalResearch.com: What should readers take away from your report?

Response: After applying topical ruxolitinib cream twice a day, patients had significant repigmentation, particularly those with facial vitiligo.

This treatment holds promise as a potential new treatment for vitiligo. Because it is a topical, it spares many side effects of taking a medication orally.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Secukinumab Provides Sustained Improvements in Dermatology-Specific Quality of Life in Moderate to Severe Psoriasis Patients Through 3 Years of Treatment

MedicalResearch.com
Eric Hughes
Global Development Franchise Head Immunology & Dermatology
Novartis

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Psoriasis is a chronic immune-mediated inflammatory disease that negatively impacts patients’ quality of life (QOL); therefore QOL outcomes are increasingly recognized as an important measure of efficacy in psoriasis, complementing traditional measures of severity such as the Psoriasis Area and Severity Index (PASI).

Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-17A), exhibits significant efficacy in the treatment of moderate-to-severe psoriasis, ankylosing spondylitis and psoriatic arthritis, demonstrating a rapid onset of action and a favorable safety profile.

Biologic therapies for psoriasis have previously been associated with a fall-off in efficacy over time; accordingly, extended follow-up is required to adequately evaluate novel therapeutic strategies like IL-17A inhibition. Recently, results from the extension of the SCULPTURE secukinumab trial showed that high responses initially achieved with secukinumab at year 1 in the SCULPTURE study were sustained over time up to 3 years with no new or unexpected safety concerns. In this analysis, we examined whether the sustained efficacy observed in SCULPTURE up to 3 years was translated into sustained effect of secukinumab on patient’s QOL measured by the Dermatology Life Quality Index (DLQI) questionnaire.

SCULPTURE, a multi-center extension study, was conducted with subjects who completed 52 weeks of treatment. Subjects were randomized into two maintenance dosing regimens; a fixed-interval schedule of secukinumab 300 mg every 4 weeks (Fixed interval dosing regimen (FI) cohort), and secukinumab retreatment-as-needed (Retreatment as needed (RAN) cohort), in which subjects received placebo until start of relapse, at which time secukinumab 300 mg every 4 weeks was re-initiated.

The analysis using as-observed data showed that at Year 3, improvements in the total score on DLQI was well sustained in both FI and RAN cohorts. Approximately two-thirds of the subjects in the FI cohort reported no impact of skin disease on QOL (corresponding to a score of 0 or 1 on DLQI). The proportion of patients in the RAN cohort reporting no impact of the disease on their QOL was well sustained through 3 years but remained consistently lower than those observed in the FI cohort. The results for each subscale of the DLQI questionnaire were consistent with those with DLQI total score i.e. showing high and sustained proportions of patients reporting no impact of the disease on different domains of health-related QOL in the two secukinumab cohorts with greater effect in the FI cohort compared to the RAN cohort.

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Safer Immunotherapy Dupilumab (Dupixent) FDA Approved For Atopic Dermatitis

MedicalResearch.com Interview with:

Emma Guttman, MD, PhD Professor, Dermatology, Medicine and Clinical Immunology Vice Chair of Research in the Dermatology Department Director of the center for Excellence  Eczema in the Occupational/Contact Dermatitis clinic  Director of the Laboratory of Inflammatory Skin Diseases Icahn School of Medicine at Mount Sinai Medical Center New York

Dr. Guttman

Emma Guttman, MD, PhD
Professor, Dermatology, Medicine and Clinical Immunology
Vice Chair of Research in the Dermatology Department
Director of the center for Excellence
Eczema in the Occupational/Contact Dermatitis clinic
Director of the Laboratory of Inflammatory Skin Diseases
Icahn School of Medicine at Mount Sinai Medical Center
New York

MedicalResearch.com: Would you briefly explain what is meant by atopic dermatitis? How many people are affected by this disorder?

Response: Atopic dermatitis or eczema as most people know it is an itchy red scaly skin disorder characterized by a very severe itch, that disrupts daily activities, and sleep and severely impairs the quality of life of patients. In the US 30 million people are affected by it, and 1/3 of these we expect to be moderate to severe.

MedicalResearch.com: What is the background for Dupilumab therapy? How does it differ from emollients, steroids or topical immunomodulator treatments for eczema ie Protopic?

Response: The background is that we currently do not have good treatments for long term use for our moderate to severe patients. The only approved drug by the FDA for atopic dermatitis in the US is oral prednisone, that has many long term side effects and causes disease rebound upon discontinuation. Other treatments with many side effects

are broad immune suppressants–Cyclopsorin A, Mycophenolate mofetyl and phototherapy that is not feasible for most patients.

Thus there is a large unmet need for safer and better treatments for moderate to severe atopic dermatitis patients.

Dupilumab is different since it only targets one immune axis–Th2 axis, providing a safer alternative, with high efficacy, that is equal or even better than cyclosporin A, that is the current gold standard immune suppressant, and harbors many side effects including permanent effects on the kidneys after long term use. Topical treatments, while useful for mild patients, are often not adequate or sufficient to control moderate to severe patients that usually have more than 10% body surface area involved and need a systemic treatment.

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Secukinumab (Cosentyx) Provides Greater Improvement in Quality of Life, Work Productivity, and Daily Activity Than Ustekinumab (Stelara) in Moderate To Severe Psoriasis

MedicalResearch.com Interview with:
Eric Hughes, Global Head of Development, Immunology & Dermatology

Novartis Pharma AG
Basel, Switzerland

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: It is well established that psoriasis negatively affects quality of life and work productivity. However, how the treatments affect psoriasis severity (based on skin clearance, itch, pain and scaling symptoms), health-related quality of life (HRQOL), work productivity, and daily activity directly or indirectly (via other factors) are still largely unknown.

Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-17A), exhibits significant efficacy in the treatment of moderate-to-severe psoriasis, ankylosing spondylitis, and psoriatic arthritis, demonstrating a rapid onset of action and a favorable safety profile.

In CLEAR, a Phase 3b head-to-head study versus ustekinumab, secukinumab demonstrated sustained superior efficacy in clearing skin through Week 52, greater improvement in symptoms and HRQOL, greater relief of work and activity limitations, and a comparable safety profile. In this sub-analysis of the CLEAR study, Novartis was interested in examining the relationships among multiple variables that are thought to be important to patients with psoriasis. The direct and indirect (i.e. mediated) effects of treatment (secukinumab or ustekinumab) on psoriasis severity and patients’ HRQOL, work productivity, and daily activity were examined. The evaluation was conducted using structural equation modeling (or path analysis) and compared these relationships for secukinumab versus ustekinumab at 16 and 52 weeks. Structural equation modeling or path analysis is a statistical method that models the direct and indirect relationship between multiple patient-relevant outcomes simultaneously.

Goodness-of-fit statistics for all models were excellent confirming the robustness of the results. Results at Week 16 and at Week 52 for different Psoriasis Area and Severity Index (PASI) response categories (e.g. PASI 75, PASI 90, PASI 100) indicated that psoriasis treatment indirectly affected HRQOL and work productivity and daily activity, measured with the Dermatology Life Quality Index (DLQI) and the Work Productivity and Activity Impairment (WPAI) questionnaires, respectively.

Actually, greater effect of secukinumab over ustekinumab on DLQI was mediated by greater improvement of secukinumab in PASI response as well as by greater improvement in psoriasis-related symptoms (itch, pain and scaling). Greater effect of secukinumab over ustekinumab on work productivity and daily activity was mediated by greater improvement of secukinumab in psoriasis-related symptoms.

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Newly Recognized Connection Between Immune System and Sperm Opens Window to Some Male Infertility and Cancer Vaccine Failures

MedicalResearch.com Interview with:
Kenneth S. K. Tung, M.D.
Professor of Pathology and Microbiology
Director of UVA Research Histology Core
Beirne B. Carter Center for Immunology Research
University of Virginia

MedicalResearch.com: What is the background for this study?

Response: The immune system needs to see tissue antigens to avoid responding to them in order to prevent autoimmune disease development. The current dogma, stated in all Immunology and Reproductive Biology textbooks, considers the sperm antigens in the testis to be exempted from this process. They are considered totally hidden behind a tissue barrier, and are invisible to the immune system.

Because sperm antigens are treated as foreign molecules, they should stimulate strong immune response when employed in cancer vaccines against antigens common to sperm and cancers. It is also believed that sperm molecules are protected by local factors that inhibit inflammation, whereas systemic mechanisms such as regulatory T cells would not exist.

The paradigm has restrained ongoing research on systemic tolerance to sperm, and the need to understanding systemic regulation in infertility research

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