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CHRISTINE FILLMORE BRAINSON, PHD, ASSISTANT PROFESSOR AT UNIVERSITY OF KENTUCKY MARKEY CANCER CENTER, EXPLAINS THE IMPLICATIONS OF RECENT DISCOVERIES IN NON-SMALL CELL LUNG CANCER SUBTYPES.

CHRISTINE FILLMORE BRAINSON, PHD, ASSISTANT PROFESSOR AT UNIVERSITY OF KENTUCKY MARKEY CANCER CENTER, EXPLAINS THE IMPLICATIONS OF RECENT DISCOVERIES IN NON-SMALL CELL LUNG CANCER SUBTYPES.

The two major types of non-small cell lung cancer (NSCLC), adenocarcinomas and squamous cell carcinomas, have long been considered two distinct diseases. But researchers are now discovering that these tumor types may have a much more complicated, intertwined relationship.

As researchers gather for the 2018 American Society of Clinical Oncology meeting, we reviewed the implications of these discoveries for the future of lung cancer treatment with Christine Fillmore Brainson, PhD, assistant professor at the University of Kentucky Markey Cancer Center.

What are some of the unanswered questions that continue to drive research in NSCLC?

We still don’t know which cells are the culprits — the “cells of origin” for different subtypes of lung cancer. That’s something our lab is trying to parse out in mouse models. Understanding the cells of origin may help us to develop treatments that specifically target these NSCLC subtypes.

We’re also trying to personalize treatment for lung cancer patients. At the University of Kentucky, when lung cancer patients don’t respond to chemotherapy, we sequence their tumor biopsy. This lets us understand the unique genetic combinations that contribute to their lung cancer. Then we consider the approved and investigational therapies that target those mutations.

How has our understanding of different types of lung cancer evolved recently?

We’re beginning to understand that there may be more plasticity in NSCLC subtypes than we had thought. Sometimes, a patient is originally diagnosed with adenocarcinoma. Then a second biopsy after treatment may reveal that those tumors have qualities of both adenocarcinoma and squamous cell carcinomas. Having a tumor that looks like both, which we call adenosquamous lung cancer, complicates things, and it has a poor prognosis. This transformation could be a factor in resistance to therapy in NSCLC.

Non-small Cell Lung Cancer Subtypes

Do we know what drives this change in the tumor cells?

We typically only see second biopsies after a patient has been treated with epidermal growth factor receptor (EGFR) kinase inhibitors. So that treatment might be driving the transformation in patients. Or it might also happen after chemotherapy. We don’t know because we don’t take that second biopsy then to look at it.

In a previous study, we showed that we could force this transition in mice through specific genetic changes.

How might this finding affect how doctors diagnose patients?

In the future, a diagnosis of adenosquamous lung cancer, rather than just adenocarcinomas or squamous cell carcinomas, might be common. And it might justify taking a second biopsy after chemotherapy. Right now, that’s not recommended, because often the patient isn’t doing well at that point, and you don’t want to add a lung surgery unless there will be a clear benefit.

Understanding the cells of origin may help us to develop treatments that specifically target these NSCLC subtypes.

If one NSCLC subtype can change into another, how could that affect treatment?

We’ve seen that targeted immunotherapies work well in squamous cell carcinoma. My laboratory is studying whether the transition to squamous cell carcinoma can make the patient’s cancer more susceptible to immunotherapy. We’re studying this in a mouse model right now. If we can push the transition toward squamous cell carcinoma with a targeted therapy, maybe we can boost the response to immunotherapy.

What does the future of lung cancer treatment look like?

Cytotoxic therapy, such as chemotherapy, and immunotherapy combinations are potentially going to be the future of NSCLC treatment. At ASCO, researchers will present studies that show more data on chemotherapy and immunotherapy combinations to treat adenocarcinomas. Combinations are being tested in clinical trials, and the Food and Drug Administration have approved a few combinations for specific circumstances. We see that some patients do much better when treated with immunotherapy and chemotherapy. So we should continue exploring combinations of immunotherapies with our standard therapies. Combinations seem to be one clear way to go forward.

To learn more about how immunotherapies may be a new partner for chemotherapy, read “The Evolving Role of Chemotherapy in Lung Cancer.”

For decades, researchers seeking to develop new treatment options for multiple sclerosis (MS) believed that it was primarily a disease of the brain’s white matter, but recent studies have highlighted that grey matter plays an important role as well. For instance, grey matter loss, known as atrophy, may be seen in early stages of the disease and is associated with worsening symptoms.

As part of this year’s efforts to raise awareness of the disease during World MS Day on May 30, Dr. Robert Zivadinov, professor of Neurology and director of the Buffalo Neuroimaging Analysis Center and Center for Biomedical Imaging at Clinical Translational Science Institute at the University of Buffalo, explains researchers’ evolving understanding of the role of grey matter damage in MS.

DR. ROBERT ZIVADINOV FROM THE UNIVERSITY OF BUFFALO BELIEVES UNRAVELING THE ROLE OF GREY MATTER IN MULTIPLE SCLEROSIS MAY HAVE IMPLICATIONS FOR FUTURE TREATMENTS.

DR. ROBERT ZIVADINOV FROM THE UNIVERSITY OF BUFFALO BELIEVES UNRAVELING THE ROLE OF GREY MATTER IN MULTIPLE SCLEROSIS MAY HAVE IMPLICATIONS FOR FUTURE TREATMENTS.

MS was previously considered to affect white matter primarily. How has that understanding evolved to include grey matter?

“About 15 years ago, improved imaging techniques revealed that large areas of grey matter were affected in patients. This evidence helped explain why some patients had such severe disease but relatively few damaged areas in the white matter, known as lesions.”

Are there specific regions of grey matter that are affected by MS?

“Not all parts of the grey matter are equally affected. There’s definitely significant involvement of the cortical layers of the brain’s grey matter, which is linked to symptoms such as fatigue, cognitive changes and memory loss.

“The deep grey matter is also involved in MS as well, and in particular the thalamus, which relays motor signals and regulates things like consciousness, sleep and alertness.”

“Some studies have found that grey matter atrophy correlates with disability, cognitive impairment and disease progression better than white matter.”

What do researchers know about the connection between the loss of grey matter, cognitive dysfunction, disability and MS progression?

“Many studies have found links between grey matter damage with both physical and cognitive impairment in patients with MS, including symptoms such as muscle control, sensory perception and memory. Some studies have found that grey matter atrophy correlates with disability, cognitive impairment and disease progression better than white matter lesions do.

“Studies also suggest that grey matter lesions occur rather early on, particularly in relapsing-remitting MS, even before white matter lesions appear. It could very well be a potential marker for predicting disease progression.”

What is preventing it from becoming a more useful predictor of disease progression?

“Grey matter lesions are less pronounced than white brain lesions, so doctors have difficulty seeing them on typical MRIs. Instead, we have to use advanced, highly sensitive MRI techniques to measure changes in grey matter, but those techniques aren’t available everywhere. They require specialized equipment and expertise that is typically only found in academic research centers. That is one reason why grey matter atrophy has had limited use in the clinic.”

What do we still not understand about grey matter atrophy in people with MS?

“We still don’t understand what causes the damage. Grey matter atrophy is associated with several genetic, viral and environmental risk factors, but we haven’t pinpointed the mechanisms yet.”

What can be done to reduce the risk of damage to grey matter?

“That’s the holy grail. Most MS trials weren’t necessarily designed to answer that question. We are going to have to change the design of MS trials. Instead of only using MRIs of white matter lesions as an endpoint, we’ll need more sensitive imaging techniques to monitor grey matter changes over time as well.”

To learn more about how MS affects the brain over a lifetime, read “How Multiple Sclerosis Affects the Brain and CNS.”

Dr. Robert Zivadinov is a paid consultant for Celgene.

Last week, scientists, physicians and patient advocates gathered in Chicago for the 2018 American Society of Gene & Cell Therapy (ASGCT) annual meeting to discuss results of recent trials for cellular immunotherapies, including chimeric antigen receptor (CAR) T cell therapies. These treatments have the potential to change the treatment paradigm in oncology, but obstacles remain for cancer centers seeking to take advantage of this new approach.

In this Q&A, Dr. Helen Heslop, director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston Methodist Hospital and Texas Children’s Hospital, explains what was discussed at the meeting regarding the practical challenges cancer centers are facing when offering CAR T cell therapies to patients.

DR. HELEN HESLOP FROM BAYLOR COLLEGE OF MEDICINE EXPLAINS SOME OF THE CHALLENGES OF IMPLEMENTING CHIMERIC ANTIGEN RECEPTOR T CELL THERAPIES.

DR. HELEN HESLOP FROM BAYLOR COLLEGE OF MEDICINE EXPLAINS SOME OF THE CHALLENGES OF IMPLEMENTING CHIMERIC ANTIGEN RECEPTOR T CELL THERAPIES.

What types of centers are offering CAR T cell therapy?

“A variety of centers are setting up CAR T cell programs, including public and private, large and small, pediatric and adult cancer centers.

“Everyone is doing it slightly differently, so we need to share best practices regarding the practical nuts and bolts of implementation in three broad areas: setting up a program to offer CAR T cell therapies, what it takes to get accredited and issues with access and reimbursement.”

How is the administration of cellular immunotherapies different from traditional treatments?

“Giving a patient cell therapy is different than typical small molecules or biologics. The patient’s lymphocytes are separated from the rest of the patient’s blood cells and plasma in a process called apheresis. The lymphocytes are then sent to a central manufacturing to be genetically reengineered. The modified cells are then sent to the treating center as a frozen CAR T cell product. The product is then thawed and infused back into the patient.

“The cell collection process is more akin to a stem cell transplant, so centers that are currently performing stem cell transplants have most of the processes in place to offer CAR T cell therapies.”

And those processes would include?

“With cellular therapies, there is the risk of developing complications that require specialized management, such as cytokine release syndrome and neurotoxicity.”

About 40 centers in the United States are offering cellular immunotherapies. But that number could rise quickly.

How many centers are currently offering CAR T cell therapy?

“Right now, about 40 centers in the United States are offering cellular immunotherapies approved by the U.S. Food and Drug Administration to patients. But there are close to 200 transplant programs across the country, so that number could rise quickly if more centers attain Risk Evaluation and Mitigation Strategy certification per the individual product labels.”

What is the most significant challenge for centers in implementing these therapies?

“Aside from the clinical issues, the financial and administrative aspects and access to these new therapies for patients are also significant challenges. Hospitals have to create new processes for this new treatment paradigm and codes for the procedures involved with CAR T cell therapy administration are not yet available.”

What’s next for cellular immunotherapies?

“So far, CAR T cells have only been approved for specific relapsed or refractory diseases. One obvious question requiring careful investigation of risks and benefits is whether you can give CAR T cell therapy earlier in the course of therapy.”

To learn more about how CAR T cells may help immune cells identify cancer cells, read “Revealing Cancer Cells to the Immune System.”

More than 32,000 oncology professionals will soon gather in Chicago for the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. This year’s meeting, with a theme of “Delivering Discoveries: Expanding the Reach of Precision Medicine,” promises to be the most exciting yet because researchers are further unraveling the different mechanisms by which cancer starts, grows and metastasizes, as well as how the immune system responds to it.

This progress is ushering in a new era of precision medicine, according to Wim Souverijns, Corporate Vice President of Global Marketing for Hematology & Oncology at Celgene. Much of the research Celgene will present at this year’s meeting includes updates on its chimeric antigen receptor (CAR) T cell therapy platforms, as well new data related its investigational pipeline across hematologic malignancies and solid tumors.

CAR T Cell Data Continue to Roll In

One area of personalized medicine with incredible potential in cancer is CAR T cell technology. This process involves a patient’s immune cells being collected, modified in a laboratory to recognize cancer cells and reinfused to attack the cancer.

At this year’s ASCO meeting, Souverijns is looking forward to seeing longer-term safety and outcome data for several clinical trials involving investigational CAR T cell therapies in relapsed or refractory patients with difficult to treat blood cancers like multiple myeloma and diffuse large B-cell lymphoma.

While these therapies come with great promise, their safety profile needs to be properly characterized to ensure appropriate use of these therapies, Souverijns explains. At ASCO he expects further insights about particular side effects such as cytokine release syndrome (CRS) and neurotoxicity.

“These longer-term data will help us to better understand these effects and how to manage them,” he said. “This will be crucial to realize the promise of these investigational treatments for patients.”

Three years ago, most patients were getting doublets, and people were questioning the need for triplets. Today, people are talking about quadruplets.

CAR T beyond Blood Cancers

The big hope is that CAR T cell therapies will be able to go beyond hematological malignancies and effectively target solid tumors as well. Preclinical data of CAR T cell therapies in solid tumors are emerging. The challenge, though, is that solid tumors often aren’t responsive to treatment simply because therapies physically can’t reach the tumor.

“CAR T also holds promise in solid tumors, but it’s going to be a much harder nut to crack from a technological and scientific perspective than with blood cancers,” Souverijns said. “The integration of Juno’s recently acquired CAR T cell science powerhouse with Celgene’s deep disease and cellular therapy expertise provides a great opportunity with these new investigational technologies for cancer patients.”

AT THIS YEAR’S AMERICAN SOCIETY OF CLINICAL ONCOLOGY MEETING, ATTENDEES WILL DISCUSS ADVANCES IN CANCER RESEARCH, INCLUDING ADVANCES IN CAR T CELL THERAPY AND COMBINATION THERAPIES BUILT ON THE FOUNDATION OF IMMUNOMODULATORS.

AT THIS YEAR’S AMERICAN SOCIETY OF CLINICAL ONCOLOGY MEETING, ATTENDEES WILL DISCUSS ADVANCES IN CANCER RESEARCH, INCLUDING ADVANCES IN CAR T CELL THERAPY AND COMBINATION THERAPIES BUILT ON THE FOUNDATION OF IMMUNOMODULATORS.

Triplets Becoming More Common in Multiple Myeloma

At last year’s ASCO conference, clinicians saw data combining immunomodulators with other therapies to treat diseases like multiple myeloma. Souverijns expects to see even more data from trials this year testing combination therapies. While these combinations used to focus on later lines of treatment when patients have exhausted other options, the new data are showing options for earlier patient segments as well.

More seems like it may be better as more triplet therapies are being approved and utilized, while even quadruplets are being tested now. This is something he expects will be discussed at length at the conference as doctors are realizing that adding new therapies to the foundation of an immunomodulator may drive better outcomes.

“Three years ago, most patients were getting doublets, and people were questioning the need for triplets,” Souverijns said. “Today, people are talking about quadruplet therapy. It’s amazing how quickly cancer care is progressing, making each ASCO more extraordinary than the last.”

For all the potential advancements, Celgene’s Vice President, U.S. Medical Affairs Teng Jin Ong, M.D., pointed to precision medicine at this year’s conference.

“Our increasing insight into the biology of cancer drives the discovery of new therapies that are targeting very specific cancer mutations and allow for greater improvements in outcomes for patients with such mutations,” said Dr. Ong. “We’ll remember 2018 as the tipping point for precision medicine and showing how it could work in practice.

To learn more about how CAR T cells may help immune cells identify cancer cells, read “Revealing Cancer Cells to the Immune System.”

 

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On this year’s International Thalassemia Day (May 8), the beta-thalassemia community is hopeful that advances in gene therapy may lead to new treatment options. While Dr. Antonio Piga from the San Luigi Gonzaga University Hospital in Torino, Italy, shares that hope, he believes gene therapy remains distant.

DR. ANTONIO PIGA FROM THE SAN LUIGI GONZAGA UNIVERSITY HOSPITAL BELIEVES THAT SLOWING DOWN THE OVERPRODUCTION OF INEFFECTIVE RED BLOOD CELLS COULD HELP PATIENTS WITH BETA-THALASSEMIA.

DR. ANTONIO PIGA FROM THE SAN LUIGI GONZAGA UNIVERSITY HOSPITAL BELIEVES THAT SLOWING DOWN THE OVERPRODUCTION OF INEFFECTIVE RED BLOOD CELLS COULD HELP PATIENTS WITH BETA-THALASSEMIA.

“Even with recent advances, gene therapy approaches for beta-thalassemia are less than perfect,” Piga said. “Gene therapy may be a viable treatment for a majority of patients in 20 years. But what do we do until then? What if we could correct the downstream process that is broken in beta-thalassemia?”

That process is the production of healthy red blood cells, which are highly specialized for supplying oxygen to tissues and organs in the body. Produced in the bone marrow, these cells mature into little more than shipping containers for a large, multi-part protein called hemoglobin.

Within hemoglobin, iron molecules are ideally positioned to grasp oxygen molecules and transport them throughout the body. Iron-bound hemoglobin complexes give red blood cells their signature color and are essential to their maturation and function.

DURING THE PRODUCTION OF RED BLOOD CELLS, (1) FUNCTIONAL HEMOGLOBIN IS PRODUCED IN THE BONE MARROW AND (2-3) PLACED INTO RED BLOOD CELLS, GIVING THEM THEIR SIGNATURE COLOR.

DURING THE PRODUCTION OF RED BLOOD CELLS, FUNCTIONAL HEMOGLOBIN IS PRODUCED IN THE BONE MARROW AND PLACED INTO RED BLOOD CELLS, GIVING THEM THEIR SIGNATURE COLOR.

But in patients with beta-thalassemia, mutations disrupt the production of working hemoglobin in the quantities needed, so red blood cells do not mature properly; instead, they are like pale and abnormal small bags. Most importantly, they can’t pick up enough oxygen from the lungs and drop it off throughout the body.

IN PATIENTS WITH BETA-THALASSEMIA, (4) MUTATIONS DISRUPT THE PRODUCTION OF WORKING HEMOGLOBIN, (5-6) LEADING TO AN OVERPRODUCTION OF ABNORMAL RED BLOOD CELLS THAT ARE PINK-HUED AND UNABLE TO TRANSPORT OXYGEN EFFECTIVELY.

IN PATIENTS WITH BETA-THALASSEMIA, MUTATIONS DISRUPT THE PRODUCTION OF WORKING HEMOGLOBIN, LEADING TO AN OVERPRODUCTION OF ABNORMAL RED BLOOD CELLS THAT ARE PINK-HUED AND UNABLE TO TRANSPORT OXYGEN EFFECTIVELY.

“This inability to make sufficient hemoglobin contributes to chronic anemia,” Piga said. “But another distinctive and aggravating aspect of the disease is that the bone marrow works up to 30 times above, even ineffectively, with a lot of negative consequences including bone deformities.”

Piga is exploring whether it’s possible to disrupt the signals that send the bone marrow into overdrive. The hope is to treat anemia by boosting the number of red blood cells that have sufficient hemoglobin. While Piga admits the strategy would not cure beta thalassemia, it could improve quality of life for many patients living with this inherited blood disorder.

We’re hopeful that we can reduce the need for costly, time-consuming transfusions for patients.

Currently, most patients with severe forms of the disease need regular blood transfusions to shut down the bone marrow’s production of ineffective cells and augment the supply of normal red blood cells. Transfusions are cumbersome, costly and associated with risks, and they can cause complications through all the extra iron from the transfused blood cells. Since the body has no natural way to expel this metal, which can be dangerous at high levels, patients must be treated with chelation therapy to remove the excess iron.

While work remains to be done to understand how to curb the overproduction of ineffective red blood cells and the potential in alleviating chronic anemia, Piga remains optimistic.

“We’re hopeful that we can soon reduce the need for costly transfusions for patients as we continue to search for a cure,” Piga said. “That’s the best message that I can give to the beta-thalassemia community on this year’s International Thalassemia Day.”

To learn more about why new treatments are needed to reduce the need for transfusions in anemia, read “Beta-Thalassemia: Current Treatments Not Enough.”

When Dr. Timothy Vollmer sees patients with multiple sclerosis (MS), they talk about the symptoms they are experiencing today. But Vollmer tries to get them thinking further down the road. Most people with MS are diagnosed between the ages of 20 and 40, but might not feel the full impact of the disease until their 60s.

“The best bet at slowing the progression of disability later in life is at the beginning of the disease,” said Vollmer, a neurologist at the University of Colorado Denver. “But many patients — and even neurologists — don’t fully understand how MS affects the brain over a lifetime and why brain preservation is important.”

The Death of the Neurons

DR. TIMOTHY VOLLMER FROM THE UNIVERSITY OF COLORADO DENVER BELIEVES THAT THE BEST WAY TO SLOW DISABILITY PROGRESSION LATER IN LIFE IS TO TREAT MULTIPLE SCLEROSIS EARLY.

DR. TIMOTHY VOLLMER FROM THE UNIVERSITY OF COLORADO DENVER BELIEVES THAT THE BEST WAY TO SLOW DISABILITY PROGRESSION LATER IN LIFE IS TO TREAT MULTIPLE SCLEROSIS EARLY.

Damage in the brain for patients with MS is driven at least in part by a critical component of the immune system called B lymphocytes, also known as B cells, which recruit other immune cells and cause an inflammatory reaction. Why B cells begin attacking neurons is not fully understood, but what can be clearly seen is the damage they leave behind in the form of lesions that appear as bright white spots on a patient’s magnetic resonance imaging (MRI) scan.

When Vollmer analyzes a patient’s MRI, he pays particular attention to the appearance of lesions in the grey matter of the brain, the region involved in muscle control and sensory perception. As the grey matter continues to be attacked, causing new lesions to develop, symptoms such as fatigue and memory loss become more common, and cognitive impairment tends to increase.

But lesions often don’t appear steadily and consistently throughout a patient’s lifetime. Instead, the number of lesions tends to be highest at the onset of MS and then decreases over time. By the time a person with MS reaches 60 years old, new lesions are relatively rare.

“We don’t know why these lesions appear to decrease over time,” Vollmer said. “But if we wait to treat patients, the damage has already been done and what we’re left with is an accelerated pace of brain volume loss.”

Neurological Reserve

By the age of 40, everyone’s brain begins shrinking due to the loss of neurons as a result of the normal aging process. However, brain shrinkage happens faster in people with MS; while healthy individuals lose 0.1 to 0.5 percent of their brain volume per year, people with MS lose 0.5 to 1.35 percent per year, a significantly faster rate than those without the disease.

It’s important that neurologists understand how MS affects the brain throughout a person’s lifetime.

The effects of this brain volume and neuron loss may not be immediately apparent, though, because their brains and central nervous system tap into a neurological reserve to supplement this decline. However, those reserves are then used up sooner and, coupled with the normal aging process, result in the increased cognitive impairment and disability seen in people with MS.

With this long-term understanding of how MS affects the brain and CNS, Vollmer is traveling to conferences, giving lectures and trying to drive an international consensus on the issue. He’s reminding his patients and colleagues that it’s important to focus on measuring not only relapses, but also lesions and brain volume loss.

“It’s important that neurologists understand how MS affects the brain throughout a person’s lifetime,” Vollmer said. “Then they will understand why treating patients early and encouraging healthy lifestyles is essential to improving their patients’ lives down the line.”

To learn more about the MS journey for patients, read “The Search Continues for More Multiple Sclerosis Treatment Options.”

 

When doctors evaluate if a treatment is working for one of their patients with ulcerative colitis (UC), an inflammatory bowel disease that causes damage to the mucosal layer of the digestive tract, they will ask their patient about symptoms, such as bleeding, diarrhea and pain. But when researchers are evaluating the effectiveness of potential new treatments in a clinical trial, they need to include an objective assessment of disease activity as well.

So researchers are increasingly using endoscopy, a procedure using a flexible tube equipped with a video camera to look at patients’ digestive tracts, and examining tissue samples removed during a biopsy under a microscope to determine how well the mucosa is responding to an investigational therapy. In this Q&A, Dr. Keith Usiskin, executive director at Celgene, explains how by combining these two measurements, an assessment of mucosal healing can be made.

DR. KEITH USISKIN, EXECUTIVE DIRECTOR AT CELGENE, BELIEVES THAT COMBINING ENDOSCOPIC AND HISTOLOGIC MEASUREMENTS PROVIDES A DETAILED VIEW OF MUCOSAL HEALING IN ULCERATIVE COLITIS.

DR. KEITH USISKIN, EXECUTIVE DIRECTOR AT CELGENE, BELIEVES THAT COMBINING ENDOSCOPIC AND HISTOLOGIC MEASUREMENTS PROVIDES A DETAILED VIEW OF MUCOSAL HEALING IN ULCERATIVE COLITIS.

Why is mucosal healing important?

“Ulcerative colitis causes massive damage to the mucosa, weakening blood vessels and, eventually, leading to ulcers. Doctors and researchers are finding that achieving mucosal healing correlates with a better quality of life and other measurable benefits for patients with UC.

“For instance, studies have found that patients with UC in remission and with no signs of microscopic inflammation are less likely to be hospitalized or to experience relapse, in which their UC symptoms return. The data isn’t as strong as we’d like just yet, but we see a definite trend beginning to take shape.”

How is mucosal healing assessed in UC trials?

“Organizations conducting UC clinical trials assess mucosal healing often use both endoscopic appearance — what a gastroenterologist sees regarding redness, inflammation and ulcers during an endoscopy — and histological appearance — what a pathologist sees under a microscope regarding inflammation when they examine a tissue sample from a biopsy.”

Why are both endoscopies and biopsies needed to assess mucosal healing?

“While UC causes mucosal damage continuously, not every part of the mucosa is affected to the same extent. So endoscopies provide researchers with a bird’s eye view of the mucosa throughout the entire rectum and large intestine, including regions that are very inflamed and those that are less so.

“But endoscopic appearance doesn’t tell you everything. Studies have found that up to 24 percent of patients whose mucosa looks good in endoscopic assessments still have evidence of microscopic inflammation when a pathologist looks at a biopsy taken from the mucosa. That inflammation suggests the mucosa still is not fully healed and that the patient is at higher risk for relapses.”

Mucosal Healing: An Increasingly Accepted Endpoint in Studies of Ulcerative Colitis Treatments

What constitutes mucosal healing in these assessments?

“Defining mucosal healing remains one of the biggest challenges in UC clinical studies. The medical community and regulatory agencies have not come to a clear consensus on what constitutes mucosal healing in UC.

“Several scoring systems have been proposed for endoscopic and histologic assessments, but researchers have not decided which should be used. In Celgene’s studies, we use a widely used index for disease activity by endoscopic assessment in UC developed by researchers at the Mayo Clinic and a grading scale for histological assessment in UC developed by Dr. Karel Geboes at the University Hospitals Leuven in Belgium. We classify mucosal healing as a Mayo score less than or equal to one and a Geboes histologic score of less than two.”

What are the challenges in assessing mucosal healing?

“Clinician bias has been one of the most significant limitations in assessing mucosal healing. If the patient says they’re doing great, the clinician is more likely to report that the mucosa looks better, even if it seems the same as before starting treatment. The inverse can be true as well. We use central readers who do not know the patient’s health status to eliminate that bias. They can grade the endoscopies and biopsies based solely on their best judgment and experience.”

“The combination of endoscopy and pathology assessment of biopsies is key to the assessment of mucosal healing.”

Does the invasive nature of this assessment affect patient retention?

“Some patients are hesitant to enter a clinical trial if there are too many colonoscopies or endoscopies. Clinical researchers try to limit that when designing protocols for studies to minimize procedures that patients may find uncomfortable.

“We try to make it clear to patients what is expected of them when they sign up for a clinical trial and limit the burdens as much as possible. But we still have to make these assessments to determine the efficacy of potential new treatment options for UC.”

What could improve the assessment of mucosal healing?

“In the future, we may identify biomarkers that correlate with clinical symptoms, benefits and outcomes for patients with UC. Celgene is participating in an initiative to identify such biomarkers, and one day, noninvasive biomarkers may eliminate the need for endoscopy or biopsies. Imaging techniques such as MRIs and CT scans also may prove useful to assessing mucosal healing in future clinical trials and in the clinic. But right now, the combination of endoscopy and pathology assessment of biopsies is key to the assessment of mucosal healing for both scientific and regulatory purposes.”

To learn more about clinical trials for ulcerative colitis and other inflammatory bowel diseases, read “The Importance of Clinical Trials for Inflammatory Bowel Disease.”

Building on a long history of cellular therapy development and buoyed by the advancement of significant programs in cellular immunotherapy, Celgene completed the first phase of a renovation at its Summit West campus that will house a state-of-the-art cellular immunotherapy manufacturing center.

The 135,000 square-foot facility was completed months ahead of the original plan and will enable the company to expand investigational programs and eventually the potential commercial launch related to bb2121, its chimeric antigen receptor (CAR T) therapy being developed for certain multiple myeloma patients in conjunction with its partner bluebird bio. With CAR T technology, immune cells are removed from a patient, genetically modified and multiplied and placed back into a patient to create an individualized therapy.

“We wanted to ensure that we had a patient-centric model that supports our goal of flawless execution and rapid, compliant production,” said Mayo Pujols, Vice President of CAR T Manufacturing and Technology for Celgene. “We aim to see every patient getting their therapy back in that manner and so it made sense for us to build the capability in house.”

Celgene has a long history of cellular therapy development through its Celgene Cellular Therapeutics business that investigated placenta-derived and other stem cell therapies in multiple diseases. Celgene’s expertise and capabilities in cell therapy development and manufacturing have continued to be leveraged at its facility in Warren, NJ, where bb2121 has been manufactured thus far for clinical trials.

“We are proud to be able to contribute to the mission of improving the lives of patients with multiple myeloma,” said Greg Russotti, Ph.D., Celgene’s Vice President of Cell Therapy Process and Analytical Development. “Due to the infrastructure that we have been able to build over the years and the focus and investment from our leadership in cellular therapy processes and manufacturing, we are well-positioned to help accelerate this important area of science.”

In recent years, Celgene has expanded its commitment to this important research through multiple partnerships in the area of cellular immunotherapy. With bluebird, the company is collaborating to develop bb2121 as a potential therapy for previously treated multiple myeloma patients who express b-cell maturation antigen (BCMA) – bringing together two of Celgene’s historical areas of expertise in cellular therapy and multiple myeloma. Additionally, the company has partnered with Juno Therapeutics to develop CAR T therapies targeting the CD19 protein, and recently announced a definitive agreement to acquire Juno. These therapies are part of a potential new wave of treatments that aim to engage the patients’ immune systems to help identify and fight cancers.

Importantly, the establishment of this new facility reinforces Celgene’s growth in the city of Summit and the strong relationship with the community and state of New Jersey that may result in hundreds of new jobs over the next three years. For more information – visit our CAR T careers page at http://www.celgene.com/careers/car-t-opportunities/

“Each individual involved in this project, from the design, to the construction, to the activities to come, has pushed forward with the idea that what we do here may have a significant impact on the lives of patients,” said Joanne Beck, Ph.D., Celgene’s Executive Vice President, Global Pharmaceutical Development and Operations. “We are partnering with many state and national organizations, such as the New Jersey Innovation Institute, to identify, hire and train the workforce needed to staff this facility. We see it as a huge competitive advantage to be based here, in the State of New Jersey, having access to both state and national talent pools and to the disruptive innovations needed to bring this exciting new technology forward.”

For more information, see our information sheet here.

BB2121 and the CAR T therapies targeting the CD19 protein are investigational therapies.  Neither is approved for any indication by any regulatory authority. 

New Jersey is well-positioned for strong economic growth, and biopharmaceutical innovation is a significant driver of that potential. In 2011, the biopharmaceutical industry supported 322,049 direct and indirect jobs and created $87 billion in economic output in the Garden State. To ensure a high-growth N.J. economy for the future, the biopharmaceutical industry is helping to strengthen the state’s ecosystem of innovation by supporting emerging companies, job growth and pro-innovation policies.

“Historically, New Jersey has been a powerhouse in the biopharmaceutical industry,” said Debbie Hart, president and CEO of BioNJ, a non-profit that promotes the state’s biotechnology industry. “Because of its strong foundation in life sciences, increasing early-stage medical innovation is one of the greatest growth opportunities in New Jersey.”

One reason for New Jersey’s historical and continued leadership in the global biopharma industry is its highly skilled and educated workforce. The state has skilled biopharmaceutical talent and more scientists and engineers per square mile than anywhere else in the world. This workforce is supported by the five research universities,13 teaching hospitals and four medical schools that call New Jersey home.

Location also makes New Jersey attractive to biotech companies, given its proximity to important collaborators, which include the many established pharmaceutical companies within the state, the U.S. Food and Drug Administration and the National Institutes of Health a train ride away in Maryland, and Wall Street and venture capital across the river in New York.

Startups are particularly important in driving medical innovation in New Jersey’s biopharmaceutical industry. The majority of treatments approved in recent years originated in companies outside of the 30 largest biopharmaceutical firms; 2016 followed that trend, with more than 60 percent of approved therapies coming from companies with a significant New Jersey footprint.

Incubators serve an important role in helping startups establish themselves and grow, providing resources that would otherwise be unavailable

While New Jersey has the right ingredients to attract biopharmaceutical startups, its entrepreneurial ecosystem has the opportunity to offer even better support to home-grown startups, through incubators and business accelerators that offer resources such as funding, mentoring, workspace or equipment to young companies. Currently, New Jersey has 15 business incubators and accelerator programs compared with 375 for California and 179 for New York.

DEBBIE HART, CEO AND PRESIDENT OF BIONJ, BELIEVES NEW JERSEY’S BIOPHARMACEUTICAL INDUSTRY HAS THE POTENTIAL TO DRIVE THE STATE’S ECONOMIC GROWTH.

DEBBIE HART, CEO AND PRESIDENT OF BIONJ, BELIEVES NEW JERSEY’S BIOPHARMACEUTICAL INDUSTRY HAS THE POTENTIAL TO DRIVE THE STATE’S ECONOMIC GROWTH.

“Incubators serve an important role in helping startups establish themselves and grow, providing resources that would otherwise be unavailable to such young companies,” Hart said. “Looking at the biopharma industry in New Jersey, more incubators can certainly help increase early-stage innovation.”

Recognizing this opportunity, Celgene has launched the Thomas O. Daniel Research and Collaboration Center on its campus in Summit, New Jersey. The new center will provide state-of-the-art facilities and resources for high-potential scientists to build on their preclinical research in the important effort to discover innovative therapies for patients with unmet medical needs.

“With its iconic brand and cutting-edge science, the Thomas O. Daniel Research Incubator and Collaboration Center has the potential to attract, create and support companies that will produce the world’s next generation of therapies and cures,” Hart said. “Those treatments will help cut the overall cost of health care, which will benefit the economy, society and—most importantly—our patients.”

Prospective researchers, entrepreneurs and companies interested in joining the Incubator will submit applications for residency on the webpage within the Collaboration Center, which will be reviewed by a Celgene selection committee.

“The HealthCare Institute of New Jersey (HINJ) congratulates Celgene on the launch of its incubator, which will enhance New Jersey’s expanding innovation ecosystem,” said Dean J. Paranicas, President and Chief Executive Officer of HINJ.  “We look for this exciting initiative to create opportunities for new life sciences companies to develop novel treatments and cures that will benefit patients everywhere.”

To learn more about  the Thomas O. Daniel Research Incubator and Collaboration Center  and find out how you can apply, visit CelgeneIncubator.com.

The public often only sees the outside symptoms of plaque psoriasis: raised, red patches of skin covered with silvery scales. But the “Psoriasis Inside Out” theme of this year’s World Psoriasis Day (October 29) implores us to look at the “less visible” aspects of the disease.

New research is shining a light on one of those hidden characteristics of psoriasis: the increased risk of developing other diseases. Comorbidities associated with psoriasis include psoriatic arthritis, depression, diabetes, cardiovascular disease and metabolic disease.

Dr. Steven Feldman, a dermatologist practicing at Wake Forest University, explains that the presence of psoriasis comorbidities can affect a patient's health and their care.

Dr. Steven Feldman, a dermatologist practicing at Wake Forest University, explains that the presence of psoriasis comorbidities can affect a patient’s health and their care.

The presence of these comorbidities can not only impact a patient’s health but also affect their care. “For example, if a patient has a comorbidity of diabetes or liver disease, certain medicines may not be the most appropriate choice of treatment because they could increase the risk of liver damage,” explained Dr. Steven Feldman, a dermatologist practicing at Wake Forest University.

Although physicians who treat patients with psoriasis may be aware of comorbidities, dermatologists often focus on the skin, and other specialists may not pay attention to psoriasis as they focus on the particular disease or condition that they have expertise in. As a result, the medical community has struggled to understand the full extent of comorbidities in psoriasis patients.

To paint a clearer picture, Dr. Feldman and his colleagues analyzed insurance claims data from over 460,000 Americans diagnosed with psoriasis from 2008 to 2014. They found that 46 percent of those psoriasis patients were also diagnosed with high cholesterol, 42 percent with high blood pressure and 18 percent with depression. Other common comorbidities in this psoriasis population included diabetes, obesity and heart disease.

“While this approach is good, it’s not perfect,” Dr. Feldman explained. “For instance, if people don’t go to the doctor, then their psoriasis or their comorbidities would not be detected in studies.”

People with psoriasis should have regular health exams and screening tests to monitor their weight, blood pressure and cholesterol.

While the study provides a clearer picture of the burden of comorbidities, the relationship between psoriasis and these coexisting diseases remains less clear. So far, researchers have identified some potential contributing factors including common inflammatory pathways, cellular mediators and genetic susceptibility.

“Also, people living with psoriasis can make lifestyle choices that could reduce their risk of comorbidities,” Dr. Feldman said. “For instance, exercise and a healthy diet may help to prevent cardiovascular disease for people with psoriasis.”

The Most Prevalent Comorbidities in Psoriasis Patients

REFERENCE: SHAH KAMAL, MILLAR’S LILLIAN, CHANGOLKAR ARUN, FELDMAN STEVEN R.. REAL-WORLD BURDEN OF COMORBIDITIES IN US PATIENTS WITH PSORIASIS. JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY. 2017;77.

While dermatologists commonly screen for comorbidities such as psoriatic arthritis and depression, screening for other comorbidities such as cardiovascular disease is often done by the patients’ primary care providers.  Even though we do not understand the underlying factors that link these diseases, the fact remains that it’s important for patients and physicians to be aware of these comorbidities. Increasing awareness can help these psoriatic disease comorbidities and their risk factors from being overlooked and could potentially lead to earlier diagnosis and management.

“We don’t have enough research to know fully how comorbidities should affect our treatment,” Dr. Feldman said. “But given the increased risk of cardiovascular disease, people with psoriasis should have regular health exams and screening tests to track their weight, blood pressure and cholesterol.”

To learn why it’s important for psoriasis patients to obtain access to their recommended medications immediately, read “Psoriasis Patients Deserve Their Prescribed Therapy Without Delay.”