Category Archives: Cell Medicine

1. Intracranial response rate of 55% was reported in patients receiving cabozantinib with progressing brain metastases with no concomitant brain-directed local therapy

2. Cabozantinib was well-tolerated with common adverse events such as fatigue, diarrhea and palmar-plantar erythrodysesthesia

Evidence Rating Level: 2 (Good)

Study Rundown: Patients with metastatic renal cell carcinoma (RCC) may develop brain metastases, increasing their morbidity and mortality. Currently, the standard treatment of care includes local therapies targeting metastases (e.g., stereotactic radiosurgery, whole-brain radiotherapy). RCC patients with brain metastases were poorly represented in other clinical trials and the aim of this study was to characterize cabozantinib monotherapy in the treatment of progressive brain metastases. This study aimed to evaluate the efficacy and safety of cabozantinib for the treatment of brain metastases in patients with metastatic RCC. Patients were divided into two cohorts. Cohort A comprised of patients with progressing brain metastases who did not receive brain-directed local therapy concomitantly. Cohort B comprised of patients with stable brain metastases who received brain-directed local therapy concomitantly. Cabozantinib showed a notable intracranial response rate of 55% and 47% in cohorts A and B, respectively. Commonly reported adverse events included fatigue, diarrhea and palmar-plantar erythrodysesthesia. Limitations to the study include having a low number of patients in each cohort and the lack of information regarding other concomitant medications that the patients may be on, which could influence the safety profile of cabozantinib. Overall, this study demonstrated that cabozantinib could be an effective treatment for patients with brain metastases from RCC, particularly patients with progressive brain metastases. However, further investigation is required to confirm the findings and establish a more comprehensive efficacy and safety profile of cabozantinib in patients with brain metastases, including in combination with other therapies.

Click to read the study in JAMA Oncology

Relevant Reading: Cabozantinib in Renal Cell Carcinoma With Brain Metastases: Safety and Efficacy in a Real-World Population

In-Depth [retrospective cohort]: This was a multicenter, international, retrospective cohort study of 88 patients at 15 academic centers in the United States, Belgium, France, and Spain. Patients were eligible if they had brain metastases from RCC and received cabozantinib between January 2014 and October 2020. The patients were divided into 2 cohorts. Cohort A included patients with progressing brain metastases at the start of cabozantinib who were not receiving concomitant brain-directed local therapy. Cohort B included patients with stable brain metastases at the start of cabozantinib who were receiving brain-directed local therapy concomitantly. The study examined the intracranial and extracranial objective response rates (ORRs) as well as the safety profile of cabozantinib. The intracranial ORR for Cohort A and B were 55% (95% confidence interval [CI]: 36%-73%) and 47% (95% CI: 33%-61%), respectively. 32% of the patients in Cohort A experienced stable disease compared to 42% of patients in Cohort B. 13% of the patients in Cohort A and 11% of patients in Cohort B experienced progressive disease. The extracranial ORR for Cohort A and B were 48% (95% CI: 31%-66%) and 38% (95% CI: 25%-52%), respectively. The median overall survival was 16.0 months (95%CI, 12.0-21.9months). Commonly reported adverse events included fatigue (77%), diarrhea (46%) and palmar-plantar erythrodysesthesia (32%). There were no reported deaths and neurological toxic effects (e.g., seizure, brain hemorrhage, stroke).

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Cabozantinib is associated with an intracranial response in the treatment of brain metastases from renal cell carcinoma - 2 Minute Medicine

In this companion article, Dr. Jared Weiss provides key insights into recent advancements in the standard of care for extensive-stage small cell lung cancer and examines challenges affecting treatment.

While patients with small cell lung cancer can be responsive to initial treatment with chemotherapy, relapse is an important consideration for clinicians. Many patients will also present with advanced disease at diagnosis, so it is essential that clinicians continue to optimize the management of extensive-stage small cell lung cancer (ES-SCLC).

The treatment of ES-SCLC has included the use of platinum chemotherapy (cisplatin, carboplatin) in combination with etoposide. However, in 2019, the IMpower133 clinical trial led to the approval of atezolizumab in combination with etoposide and carboplatin in the first-line setting. Combination therapy with durvalumab, etoposide, and platinum chemotherapy was also approved in the first-line setting with the CASPIAN clinical trial in 2020. Although these new treatment approaches have advanced the standard of care in ES-SCLC, there continue to be challenges affecting optimal patient management and important areas of unmet need that must be addressed.

In this new Precision Medicine Perspectives in Small Cell Lung Cancer series, experts in the management of ES-SCLC reflect on the current therapeutic landscape and highlight some challenges affecting optimal treatment. In the first interview of the series, Jared Weiss, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina provides an overview of recent advancements in the standard of care and underscores the importance of utilizing effective therapeutic approaches while also mitigating and managing the toxicity associated with treatment.

TARGETED ONCOLOGY: What do you consider the biggest challenges in treating ES-SCLC?

WEISS: In my opinion, the unambiguously greatest challenge in treating extensive-stage small cell lung cancer is the lack of therapeutic efficacy. I've been frustrated with extensive-stage small cell lung cancer treatment for some time, as I think many have. It's very frequent that we get these rapid, dramatic, and even complete responses. You have a high log cell kill, you're close to cure, and then you don't get there. This was true even in the era before modern therapeutics. Even back in the era of CAV (cyclophosphamide, doxorubicin, vincristine), we would get complete responses that were not curative. For a long time, we've recognized that, in terms of cell count number, we're getting close to a cure, yet we just about never get there. We're so close, yet for decades have never crossed that finish line.

Even if you step back and say that we don't cure most stage 4 cancers and that we should be a little more realistic, even still, the duration of control that we get is grossly inadequate, and our survival is grossly inadequate. Along the way, our patients suffer not just from the adverse effects of what we do to themalthough I would list that as another really important unmet needthey also suffer from the effects of our therapy, so we need therapies that are more effective. Ideally, curing some or really all patients, we need treatments that are less toxic.

TARGETED ONCOLOGY: How do these challenges affect a patient's treatment plan?

WEISS: When thinking about how to treat a patient, we have to recognize that small cell lung cancer tends to present very symptomatically. It likes to grow in the central area of the chest with a lot of lymphadenopathy, so you get central chest syndromes. You get pain, and you get trouble breathing from clipping off the central airways and the central vessels, so there's often an urgency to treat small cell lung cancer. Of the solid tumors, it is the one that I treat the most inpatient. This is probably true for most consultative physicians.

The good part of this, though, is that the chemotherapy works. If you have a patient in the hospital, even in an extreme situation like on a ventilator, when you give them a cycle of chemotherapy, days later, they're doing much better. The major treatment consideration is efficacy. Fortunately, in the short run, efficacy is quite good.

Then of course, another consideration is toxicity minimization. If you look at the historic evolution of cytotoxic chemotherapy in the preimmunotherapy era and look at the front-line evolution from CAV to platinum and etoposide and the second-line evolution from CAV to topotecan, we really don't have an improvement in survival. What we have is an improvement in toxicity profile and patient convenience profile; this matters, even if we wanted more out of it. Then of course, as we entered the immunotherapy era, there is finally an advantage in survival. Not as much as we'd like, but real.

These historic considerations are the same that we face in clinic every day. What do we need to address our patients immediate needs? What's the best regimen to give them long-term control? And of course, how can we minimize the adverse effects of therapy? Small cell treatment is toxic; the most common toxicities are myelosuppression and their downstream sequalae, like fatigue. There is need for supportive care interventions because our patients are very much suffering from the treatment in addition to suffering from the disease.

TARGETED ONCOLOGY: Regarding recent approvals, first line use of atezolizumab, carboplatin, and etoposide gained approval in 2019, and then durvalumab, carboplatin or cisplatin, and etoposide gained approval in 2020. How have these approvals changed decision-making for first-line therapy for ES-SCLC?

WEISS: First-line treatment of extensive-stage small cell lung cancer changed dramatically in 2019 with the approval of atezolizumab. For a very long time until then, the evolution of frontline regimens never improved survival. Enter IMpower-133: This was a randomized study of carboplatin and etoposide, plus either placebo or the PD-L1 inhibitor atezolizumab. We have an improvement in progression-free survival, we have an improvement in overall survival, and there was not much extra toxicity. There were some immune-related adverse events that you see with the addition of atezolizumab, of course, but looking at the safety profile globally, there was not a terribly big increase.

The same was pretty much replicated in 2020 in the CASPIAN study with the addition of the PD-L1 inhibitor durvalumab to platinum and etoposide. This was a 3-arm randomized study; the third arm had the CTLA-inhibitor tremelimumab. That really didn't improve outcomes any further, so I'll focus on what was approved, deservedly: the addition of durvalumab.

If you look at the forbidden but omnipresent cross-trial comparisons, the curves were nearly superimposable from IMpower-133, which to me reflects that the agents are more similar than different and that both companies conducted their trials fairly and appropriately. There were minor differences in inclusion criteria and enrolled patients, but the main meaning of having 2 trials with similar safety, PFS (progression-free survival), and OS (overall survival) is that it is true. In science, we like to have everything confirmed with another case study. The addition of the PD-L1 inhibitor, the approved ones being atezolizumab or durvalumab, to standard platinum and etoposide improved survival in extensive-stage small lung cancer. This, of course, has changed the standard of care. In the US and other countries that can afford it, the absolute unambiguous standard of care for patients eligible for a checkpoint inhibitor is platinum, etoposide, and a checkpoint inhibitor.

TARGETED ONCOLOGY: What do you consider the most significant unmet needs in the management of ES-SCLC?

WEISS: We've spoken already about the unmet need of actually curing people, and even if we can't do that, of having more durable control with the drugs. We have spoken about the unacceptable toxicity profile of our current standards of care. The 1 additional theme that I might mention for unmet needs is dealing with the patient and their systems as a whole.

While I love my smokers and non-smokers the same and have no desire to stigmatize anybody, we do need to recognize that smoking brings with it smoking-associated comorbidities. In addition to decreased socioeconomic resources, the patients bodies come to their cancer more beaten up with things like COPD (chronic obstructive pulmonary disease) and more limited blood counts. They're less able to tolerate and benefit from the standard of care in addition to the greater difficulty in traveling to academic centers and getting trials. Optimal care of the patient with extensive-stage small cell lung cancer involves not only less toxic therapy, better supportive care, and therapies that work better, but it also requires an extensive network to support the patient to be able to get those more advanced standards of care applied to them.

Additionally, lung cancer is a heavily stigmatized cancer that disproportionately affects patients with fewer financial resources and social capital to bring to their treatment. If you contrast this, for example, with a patient with estrogen receptor positive breast cancer, or a patient with HPV (human papillomavirus)-positive head and neck cancer, these are patients who can afford to travel for trials, who can get many opinions. In contrast, many of my patients with small cell lung cancer have trouble paying for the tank of gas to get to the doctor's visit.

TARGETED ONCOLOGY: Chemotherapy-induced myelosuppression (CIM) can result from some treatment regimens. How significant of an issue is CIM and to what extent does it affect a patients treatment course?

WEISS: The problem is actually quite common if you look at the toxicity tables of the regimens that have defined our standard of care. If you look at IMpower-133, if you look at CASPIAN, if you look at the phase I basket results of lurbinectedin, and if you look at any of the dozen or so topotecan trials, what you can see is that the majority of patients are experiencing adverse events. The most common of these are myelosuppressive events, which until very recently we couldn't do a whole lot about.

Chemotherapy-induced myelosuppression is a major harm to treatment. While dose density doesn't have a great impact on survival in small cell lung cancer the way it does in breast cancer or some lymphomas, there are meaningful harms to needing to delay and reduce doses. It is inconvenient for patients. It's inconvenient for providers. It causes substantial anxiety.

Further, neutropenia very much hurts people. Febrile neutropenia can be a fatal event, it can delay chemotherapy, and it results in the need for drugs like pegfilgrastim that have adverse effects like bone pain. When you get to anemia, which causes fatigue, fatigue is the quality-of-life issue that perhaps we have the most trouble controlling in clinic, and for many patients, this affects them the most.

I think myelosuppression deserves a renewed focus. For years, we haven't thought that much about myelosuppression other than maybe neutropenia because we had a bit of a learned helplessness. This was the cost of business for giving cytotoxic drugs, and we started to say, "Well, of course, you get tired. Of course you get anemic." The introduction of effective drugs to protect neutrophils has changed this. Trilaciclib, which can help with the myelosuppression, now means that we can actually do something about it.

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EP. 2B: Challenges Affecting the Management of Extensive-Stage Small Cell Lung Cancer - Targeted Oncology

CARLSBAD, Calif.--(BUSINESS WIRE)--Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, reported today that updated interim results from a Phase 1/2a clinical study of its lead product candidate, OpRegen, an investigational retinal pigment epithelium cell transplant therapy currently in development for the treatment of dry age-related macular degeneration (AMD), will be featured in a presentation at the 2021 American Academy of Ophthalmology (AAO) 125th Annual Meeting, to be held at the Ernest N. Morial Convention Center, New Orleans, LA (November 12 15, 2021). The presentation, OpRegen Trial: Phase 1/2a Dose Escalation Study of Human Embryonic Stem-Cell Derived Retinal Pigment Epithelium Cells Transplanted Subretinally in Patients with Advanced AMD, will be presented on November 13, 2021 at 2:38 pm EDT as part of the Gene and Cell-Based Therapies Session, by Michael S. Ip, M.D., Professor, Department of Ophthalmology at the David Geffen School of Medicine at the University of California - Los Angeles.

In addition to Dr. Ips presentation, Lineage also intends to announce updated interim results from the Phase 1/2a study next month, which will include a minimum of 12 months of follow-up in all 24 patients treated with OpRegen, including all 12 patients treated in Cohort 4, which had better baseline vision and smaller areas of GA at baseline than earlier cohorts. OpRegen is well-positioned among product candidates in development for dry AMD as the only experimental therapy that has demonstrated an ability to halt or reverse the expansion of geographic atrophy as well as restore layers of retinal tissue in three patients to date. Specifically, outer retinal layer restoration was observed via optical coherence tomography (OCT) and was evidenced by the presence of new areas of retinal pigment epithelium (RPE) monolayer with overlying ellipsoid zone, external limiting membrane, and outer nuclear layer, all of which were not present at the time of baseline assessment. These findings are suggestive of integration of the new RPE cells with functional photoreceptors in areas that previously showed no presence of any of these cells.

The American Academy of Ophthalmology is the worlds largest association of eye physicians and surgeons. The mission of the American Academy of Ophthalmology is to protect sight and empower lives by serving as an advocate for patients and the public, leading ophthalmic education, and advancing the profession of ophthalmology. For more information, please visit https://www.aao.org/ or follow the association on Twitter @aao_ophth.

About OpRegen

OpRegen is currently being evaluated in a Phase 1/2a open-label, dose escalation safety and efficacy study of a single injection of human retinal pigment epithelium cells derived from an established pluripotent cell line and transplanted subretinally in patients with advanced dry AMD with geographic atrophy (GA). The study enrolled 24 patients into 4 cohorts. The first 3 cohorts enrolled only legally blind patients with Best Corrected Visual Acuity (BCVA) of 20/200 or worse. The fourth cohort enrolled 12 better vision patients (BCVA from 20/65 to 20/250 with smaller mean areas of GA). Cohort 4 also included patients treated with a new thaw-and-inject formulation of OpRegen, which can be shipped directly to sites and used immediately upon thawing, removing the complications and logistics of having to use a dose preparation facility. The primary objective of the study is to evaluate the safety and tolerability of OpRegen as assessed by the incidence and frequency of treatment emergent adverse events. Secondary objectives are to evaluate the preliminary efficacy of OpRegen treatment by assessing the changes in ophthalmological parameters measured by various methods of primary clinical relevance. OpRegen is a registered trademark of Cell Cure Neurosciences Ltd., a majority-owned subsidiary of Lineage Cell Therapeutics, Inc.

About Age-Related Macular Degeneration

AMD is an eye disease that can blur the sharp, central vision in patients and is the leading cause of vision loss in people over the age of 60. There are two forms of AMD: dry (atrophic) AMD and wet (neovascular) AMD. Dry (atrophic) AMD is the more common of the two forms, accounting for approximately 85-90% of all cases. In atrophic AMD, parts of the macula get thinner with age and accumulations of extracellular material between Bruch's membrane and the retinal pigmented epithelium, known as drusen, increase in number and volume, leading to a progressive loss of central vision, typically in both eyes. Global sales of the two leading wet AMD therapies were in excess of $10 billion in 2019. Nearly all cases of wet AMD eventually will develop the underlying atrophic AMD if the newly formed blood vessels are treated correctly. There are currently no U.S. Food and Drug Administration, or European Medicines Agency, approved treatment options available for patients with atrophic AMD.

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineages programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineages clinical programs are in markets with billion dollar opportunities and include three allogeneic (off-the-shelf) product candidates: (i) OpRegen, a retinal pigment epithelium transplant therapy in Phase 1/2a development for the treatment of dry age-related macular degeneration, a leading cause of blindness in the developed world; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; and (iii) VAC2, an allogeneic dendritic cell therapy produced from Lineages VAC technology platform for immuno-oncology and infectious disease, currently in Phase 1 clinical development for the treatment of non-small cell lung cancer. For more information, please visit http://www.lineagecell.com or follow the Company on Twitter @LineageCell.

Forward-Looking Statements

Lineage cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as believe, may, will, estimate, continue, anticipate, design, intend, expect, could, can, plan, potential, predict, seek, should, would, contemplate, project, target, tend to, suggest, or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to the projected timing of future announcements or presentations of updated or additional data from the Phase 1/2a clinical study of OpRegen, the potential benefits of treatment with OpRegen in dry AMD patients with GA, the significance of clinical data reported to date from the ongoing Phase 1/2a study of OpRegen, including the findings of retinal tissue restoration, Lineages plans to meet with the FDA to discuss OpRegens clinical development, the potential utilization of OCT imaging to measure efficacy in a pivotal clinical trial of OpRegen for the treatment of dry AMD with GA, and the potential for Lineages investigational allogeneic cell therapies to provide safe and effective treatment for multiple, diverse serious or life threatening conditions. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Lineages actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including risks and uncertainties inherent in Lineages business and other risks in Lineages filings with the Securities and Exchange Commission (SEC). Lineages forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. Further information regarding these and other risks is included under the heading Risk Factors in Lineages periodic reports with the SEC, including Lineages most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q filed with the SEC and its other reports, which are available from the SECs website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Lineage undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

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OpRegen Data Update to Be Featured at 2021 American Academy of Ophthalmology Annual Meeting in Presentation by Michael S. Ip, M.D. - Business Wire

Parkinsons disease (PD) is the most common neurodegenerative movement disorder, afflicting more than 10 million people worldwide and more than one million Americans. While there is no cure for PD, current therapies focus on treating motor symptoms and fail to reverse, or even address, the underlying neurological damage. In a new study, researchers at the Medical University of South Carolina (MUSC) have identified a novel role for the regulatory protein Bach1 in PD. Their results, published on Oct. 25 in the Proceedings of the National Academy of Sciences, showed that levels of Bach1 were increased in postmortem PD-affected brains, and that cells without Bach1 were protected from the damages that accumulate in PD. In collaboration with vTv Therapeutics, they identified a potent inhibitor of Bach1, called HPPE, that protected cells from inflammation and the buildup of toxic oxidative stress when administered either before or after the onset of disease symptoms.

This is the first evidence that Bach1 is dysregulated in Parkinsons disease, said Bobby Thomas, Ph.D., professor of Pediatrics in the College of Medicine and the SmartState COEE Endowed Chair in Pediatric Neurotherapeutics.

In PD, brain cells that produce the chemical messenger dopamine begin to die as the disease progresses, resulting in tremors and other disruptions to motor function. Additionally, as we age, neurons accumulate damage through inflammation and the buildup of toxic oxidative stress.

There are many genes that combat these destructive pathways, many of which are controlled by two key proteins: Nrf2 and Bach1. Nrf2 functions to turn on the expression of over 250 genes that are involved in protecting the cell from these stressors. Conversely, Bach1 prevents these genes from being activated.

Thomas lab found that levels of Bach1 are increased in autopsied brains of patients with PD, as well as toxin-based preclinical PD models, suggesting that high levels of Bach1 may contribute to PD pathophysiology. To confirm this, the researchers depleted Bach1 in a PD mouse model and showed that dopamine-producing neurons were protected from some of the destructive stress pathways.

To determine how the loss of Bach1 protected neurons from accumulated stress, they analyzed the entire genome of brains from Bach1-depleted mice and looked at which genes were activated.

What we found was that Bach1 not only represses the expression of protective genes that are under the control of Nrf2, but it also regulates the expression of many other genes not directly regulated by Nrf2, said Thomas. So there are additional advantages to inhibiting Bach1 besides just activating Nrf2. Ideally you would want a drug that inhibits Bach1 and also activates Nrf2.

To that end, Thomas partnered with the North Carolina-based company vTv Therapeutics to develop Bach1 inhibitors. Using its proprietary TTP Translational Technology platform, vTv discovered several potential candidates that were validated by Thomas. The top candidate, HPPE, functioned as a superior Bach1 inhibitor in in vitro models. Importantly, HPPE was also a potent activator of Nrf2.

Therefore, pharmacological intervention using HPPE provided the dual benefit of stabilizing Nrf2 and inhibiting Bach1. But how would HPPE work in a preclinical PD mouse model?

The effectiveness of HPPE was tested in a neurotoxin-based PD mouse model. HPPE alleviated toxin-induced PD symptoms when given either before the induction of disease or after the onset of disease symptoms. Further analyses showed that HPPE protects neurons from destructive pathways by turning on antioxidant genes and turning off pro-inflammatory genes.

Interestingly, HPPE worked better at protecting neurons than current FDA-approved Nrf2 activators, such as Tecfidera (dimethyl fumarate). Current activators function as electrophiles they permanently bind to and modify proteins which can lead to cellular toxicity or activation of the immune system and have many side effects.

The most interesting aspect of the study is that the Bach1 inhibitor is a non-electrophile, so it doesnt work like the FDA-approved Nrf2 activators, said Thomas. As a result of this difference, hopefully, HPPE will not demonstrate as many side effects.

Disruption of Bach1 and the simultaneous activation of Nrf2 clearly provide a strong basis for using HPPE as a potential therapeutic in PD. But several questions remain unanswered. While there were no side effects observed with acute treatment using HPPE in the PD mouse model, one key goal moving forward is to determine what impacts, if any, long-term use of HPPE might have. Another key question centers on the benefits of modulating this pathway in more chronic models of PD, other cell types in the brain and potentially other dementias.

Thispathway may be beneficial whenever you have impairments in anti-inflammatorypathways or mitochondrial dysfunctions, said Thomas. I think any disease thathas these kinds of etiologies would benefit from modulating this pathway.

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Deterioration of brain cells in Parkinson's disease is slowed by blocking the Bach1 protein, preclinical study shows - Medical University of South...

Dr. Michael Kaplitt, a professor of neurological surgery at Weill Cornell Medicine and a longtime leader in developing cutting-edge surgical therapies for movement disorders, leads a team that has been awarded a three-year, $8.9 million grant from the Aligning Science Across Parkinsons (ASAP) initiative. The grant will fund an ambitious and innovative multi-institutional collaborative effort to study how abnormal protein aggregates may spread from the gut to the brain to drive the early stages of Parkinsons disease.

Dr. Michael Kaplitt. Credit: Stephanie Diani

ASAP is a coordinated research initiative to advance targeted basic research for Parkinsons disease. Its mission is to accelerate the pace of discovery and inform the path to a cure through collaboration, research-enabling resources and data sharing. The Michael J. Fox Foundation for Parkinsons Research is ASAPs implementation partner and issued the grant.

I am so grateful to ASAP and The Michael J. Fox Foundation for this exciting opportunity, said Dr. Kaplitt, who is also vice-chair for research in the Department of Neurological Surgery at Weill Cornell Medicine and a neurosurgeon at NewYork-Presbyterian/Weill Cornell Medical Center. Interaction between the body and the brain is a very exciting and important area of research, and it is increasingly clear that, at least in some cases, Parkinsons disease may begin in the gut, with the disease spreading through nerve connections to the brain and eventually throughout the brain.

Parkinsons disease is a progressive neurodegenerative disease that is considered chiefly a movement disorder, although it typically features many other signs and symptoms, from sleep problems and low blood pressure to dementia. Parkinsons affects more than 10 million people worldwide and has no cure.

One clue to the cause of the disorder is the presence of abnormal clumps of protein within brain cells in affected brain regions. These clumps mainly consist of tiny, fiber-like aggregates of the brain-cell protein alpha synuclein. The synuclein fibrils tend to spread through the brain in a characteristic pattern during the course of Parkinsons. There is evidence suggesting that, in many cases, these disease-linked fibrils form initially in nerve cells in the intestines and trigger the classic signs of Parkinsons only after they travel to the brain, via a large gut-to-brain nerve called the vagus nerve.

Dr. Kaplitt and his collaborators will use a recently developed mouse model of this gut-to-brain disease-seeding process to explore in detail how it begins in the intestines, how it relates to early, pre-motor Parkinsons signs including sleep disorders, and whether it differs between maleswho are known to get Parkinsons at a higher rateand pre-menopausal females. Ultimately the researchers will try to develop methods for the early detection of gut alpha-synuclein aggregates and the blocking of their spread to the brain to prevent full-blown Parkinsons. Dr. Kaplitt will draw on his extensive experience in developing and testing experimental gene therapies for Parkinsons.

Bringing our nearly 30 years of experience with gene therapy to this project will allow us to not only understand how this gut-to-brain transmission happens, but also potentially intervene genetically to improve brain function and stop the spread of disease, said Dr. Kaplitt, who is also a professor of neuroscience in the Feil Family Brain and Mind Research Institute, a professor of neurological surgery in neurology and of neurological surgery in otolaryngology at Weill Cornell Medicine.

Dr. Kaplitt will collaborate with co-investigators Dr. Ted Dawson, director of the Johns Hopkins Institute for Cell Engineering and professor of neurology at the Johns Hopkins University School of Medicine, and Dr. Per Svenningsson, a professor of neurology at Karolinska Institutet and Karolinska University Hospital in Sweden, on the research. Co-investigator Dr. Roberta Marongiu, assistant professor of neuroscience research in neurological surgery and assistant professor of research in neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, will conduct the research examining sex and menopause effects.

It is exciting to be part this fantastic team of international investigators, said Dr. Dawson. There is a growing amount of evidence of the guts role in Parkinsons disease, and we are developing excellent scientific models to study the diseases progression from the start. Our multidisciplinary approach holds tremendous promise in identifying innovative ways to treat Parkinsons disease.

"It is very stimulating to work on this excellent team to increase our understanding of mechanisms underlying the propagation of alpha-synuclein from the gut to the brainstem,"added Dr. Svenningsson.

We are excited to work with our outstanding international team of leading investigators to address different aspects of this question, said Dr. Kaplitt.

It is extremely exciting to work alongside this outstanding team of investigators, said Dr. Marongiu. My group will study how sex and menopause influence the spread of Parkinsons disease pathology from the gut to the brain in the early stages of the disease. This will help us understand more about the intricate relationship between hormones and onset of Parkinsons and has the potential to identify novel precision medicine approaches for men and women.

Other members of Dr. Kaplitts team include Drs. Chris Schaffer and Nozomi Nishimura, associate professors at the Meinig School of Biomedical Engineering at Cornell University, who will use innovative methods they have developed to image vagus-linked gut neurons, to track the spread and the physiological effects of early synuclein pathology. Dr. Babacar Cisse, assistant professor of neurological surgery at Weill Cornell Medicine, a neurosurgeon at NewYork-Presbyterian/Weill Cornell Medical Center and an expert in immune cells in the brain called microglia, will investigate whether microglia are responsible for some of the patterns of spread once the pathology enters the brain from the gut.

"We are so honored that Dr. Kaplitt and his team have been selected for this grant," said Dr. Philip E. Stieg, chair of neurological surgery at Weill Cornell Medicine and neurosurgeon-in-chief of NewYork-Presbyterian/Weill Cornell Medical Center. "There is no neurosurgeon in the world better qualified than he is to do this work. Dr. Kaplitt has been a pioneer in functional neurosurgery, particularly for movement disorders, for many years now and is a true leader in the field.

Bringing together this international team of the most forward-thinking, most innovative researchers in Parkinson's disease holds so much promise for patients, he added. We all look forward to the discoveries that come from this research, which has the potential to create effective new treatments for this debilitating disease."

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$9M Grant Funds Study of Gut-Brain Connection in Parkinson's Disease - Weill Cornell Medicine Newsroom

News Release

Friday, October 15, 2021

Intravenous immune globulin (IVIG) a common treatment for multisystem inflammatory syndrome in children (MIS-C) likely works by depleting immune cells called neutrophils, according to a recent study funded by the National Institutes of Health (NIH). MIS-C is a rare condition that usually affects school-age children who initially had only mild COVID-19 symptoms or no symptoms at all. The researchers also found that IVIG works in a similar manner for treating Kawasaki disease, another rare inflammatory condition that affects children and shares symptoms with MIS-C. The findings are published in the Journal of Clinical Investigation.

MIS-C is marked by severe inflammation of two or more parts of the body, including the heart, lungs, kidneys, brain, skin, eyes and gastrointestinal organs. Its symptoms overlap with Kawasaki disease, and treatments for MIS-C are guided in part by what is known about treating Kawasaki disease. IVIG, which is made up of antibodies purified from blood products, is a common and effective treatment for heart complications caused by Kawasaki disease. For MIS-C patients, however, IVIG alone does not always resolve symptoms, and healthcare providers may need to prescribe additional anti-inflammatory drugs.

To better understand how IVIG works and to improve treatments for children with MIS-C, researchers led by Ben A. Croker, Ph.D., and Jane C. Burns, M.D., from the University of California San Diego School of Medicine, profiled immune cells from patients with MIS-C or Kawasaki disease. The team sampled cells before treatment began as well as 2 to 6 weeks after patients received IVIG. The researchers found that neutrophils from these patients were highly activated and a major source of interleukin 1 beta (IL-1), which is one driver of inflammation in the body. After IVIG treatment, these activated neutrophils were significantly depleted in patients with MIS-C or Kawasaki disease.

According to the study authors, their findings are the first to explain why IVIG is effective for both conditions. However, more work is needed to understand how IVIG causes cell death in these activated neutrophils and why certain patients with MIS-C require additional anti-inflammatory treatments. Overall, the research will help healthcare providers as they determine the most effective methods to treat patients with MIS-C.

The study is funded by NIHs Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of General Medical Sciences (NIGMS). The work is supported by NIHs CARING for Children with COVID, PreVAIL kIds and RADxSM-rad research programs.

Rohan Hazra, M.D., acting director of NICHDs Division of Extramural Research, is available for comment.

Zu YP et al., Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C. JCI DOI: 10.1172/JCI147076 (2021)

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): NICHD leads research and training to understand human development, improve reproductive health, enhance the lives of children and adolescents, and optimize abilities for all. For more information, visit https://www.nichd.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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Antibody treatment for MIS-C works by depleting inflammatory immune cells - National Institutes of Health

CAMBRIDGE, Mass., Oct. 15, 2021 (GLOBE NEWSWIRE) -- Generation Bio Co. (Nasdaq: GBIO), a biotechnology company innovating genetic medicines for people living with rare and prevalent diseases, today announced an oral presentation at the European Society of Gene and Cell Therapy (ESGCT) Annual Virtual Congress taking place October 19-22. The presentation will highlight preclinical advances from the companys retina therapeutic area.

We are excited to share our preclinical data demonstrating broad access to key cell types with our lipid nanoparticle developed for the retina, said Matthew Stanton, Ph.D., chief scientific officer of Generation Bio. Many inherited retinal diseases remain out of reach for viral-based gene therapies due to limited cargo capacity. We believe our non-viral delivery technology could overcome this barrier and expand the potential of our genetic medicine platform to treat more diseases.

The presentation will be streamed online for registered attendees on October 22, and a recording of the presentation will be made available for attendees for 30 days following the event.

Generation Bio will present:

About Generation BioGeneration Bio is innovating genetic medicines to provide durable, redosable treatments for people living with rare and prevalent diseases. The companys non-viral genetic medicine platform incorporates a novel DNA construct called closed-ended DNA, or ceDNA; a unique cell-targeted lipid nanoparticle delivery system, or ctLNP; and a highly scalable capsid-free manufacturing process that uses proprietary cell-free rapid enzymatic synthesis, or RES, to produce ceDNA. The platform is designed to enable multi-year durability from a single dose, to deliver large genetic payloads, including multiple genes, to specific tissues, and to allow titration and redosing to adjust or extend expression levels in each patient. RES has the potential to expand Generation Bios manufacturing scale to hundreds of millions of doses to support its mission to extend the reach of genetic medicine to more people, living with more diseases, around the world.

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For more information, please visit http://www.generationbio.com.

Contacts:

InvestorsMaren KillackeyGeneration Bio541-646-2420mkillackey@generationbio.com

MediaAlicia WebbGeneration Bio847-254-4275awebb@generationbio.com

Lisa RaffenspergerTen Bridge Communications617-903-8783lisa@tenbridgecommunications.com

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Generation Bio to Present at European Society of Gene and Cell Therapy 2021 Annual Virtual Congress - Yahoo Finance

Harry Paul Erba, MD, PhD, discusses the evolution of treatment in mantle cell lymphoma.

Harry Paul Erba, MD, PhD, instructor, clinical investigator, Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, member, Duke Cancer Institute, director, Leukemia Program and Phase I Development in Hematologic Malignancies, Duke Health, discusses the evolution of treatment in mantle cell lymphoma (MCL).

Similar to acute myeloid leukemia, the goal of therapy in MCL should be the key focus from treatment initiation. For example, a younger patient with limited comorbidities should be considered for curative-intent therapy or treatment with a time-limited regimen to elicit deep responses and prolonged progression-free survival, Erba says.

High-dose cytarabine-based therapies, such as the Nordic regimen known as maxi-CHOP, and autologous stem cell transplant could be considered for patients with MCL, Erba explains. Oral therapies, including BTK inhibitors, are also available options for patients with relapsed/refractory MCL or older patients who cannot tolerate intensive chemotherapy, Erba concludes.

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Dr. Erba on the Evolution of Treatment in MCL - OncLive

Brad S. Kahl, MD, discusses the potential utility of frontline CAR T-cell therapy in mantle cell lymphoma.

Brad S. Kahl, MD, professor of medicine, Department of Medicine, Oncology Division, Medical Oncology, Washington University School of Medicine in St. Louis, discusses the potential utility of frontline CAR T-cell therapy in mantle cell lymphoma (MCL).

CAR T-cell therapy has the potential to move into earlier lines of treatment, including the frontline setting, in MCL; however, longer follow-up is needed with CAR T-cell therapy in the relapsed/refractory setting before frontline clinical trials can be explored, Kahl says. Currently, CAR T-cell therapy is demonstrating high response rates at 12 and 18 months of follow-up in the relapsed/refractory setting, but it is unknown whether these responses will remain durable at 3 or 5 years.

Positive 3-year data in the relapsed/refractory setting could provide the clinical rationale to evaluate CAR T-cell therapy in the frontline setting, Kahl says. Pending these results, CAR T-cell therapy could replace autologous stem cell transplant as consolidative therapy or offer a standard option for patients with high-risk biologic features, such as TP53 mutations, Kahl concludes.

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Dr. Kahl on the Potential Utility of Frontline CAR T-Cell Therapy in MCL - OncLive

In my mind, the question is not who should get chemotherapy, but who can avoid chemotherapy in this day and age.

As more and more targeted therapy options emerge in the cancer space, investigators continue to see positive impacts on long-term outcomes. However, this wider, advanced, individualized range of treatment options that may be offered to patients requires more sophisticated molecular testing techniques.

In an interview with ONCOLOGY, Charu Aggarwal, MD, MPH, discussed this topic as it relates to her ongoing research, as well as how it may carry to other areas of oncology care outside of her area of expertise in the lung cancer space. She is the Leslye M. Heisler Associate Professor for Lung Cancer Excellence in the Department of Medicine at the University of Pennsylvanias Perelman School of Medicine in Philadelphia as well as co-chair for the 6th Annual International Congress on Immunotherapies in Cancer, hosted by Physicians Education Resource, LLC (PER).

Aggarwal spoke about how liquid biopsies, rather than invasive procedures, can help determine treatment prognosis. She also detailed how immunotherapy has evolved as a mainstay of treatment and how clinicians are now looking at adverse effects (AEs) as a positive sign of treatment efficacy.

A: Molecular genotyping is becoming extremely important in nonsmall cell lung cancer. At least 9 biomarkers1 must now be tested at initial diagnosis, and the gold standard for testing has been to use tissue-based testing. [However], its often a problem to get tissue because these biopsies are small and sometimes not enough tissue or not enough DNA [is present] on these samples. [So then] we asked, Could we complement our ability to test for these mutations using tissue alone by adding in plasma-based sequencing? We conducted a follow-up trial with about 300 patients here [at the University of Pennsylvania] and found that by adding plasma-based approaches, using 2 tubes of blood, we could get [results] relatively easier compared with tissue-based sequencing.2 We were able to increase our detection of molecular alterations from about 20% to about 36%a significant increase. This means that more patients were able to get targeted therapy, receive a drug based on their molecular profile, and have significant benefit. Patients were able to avoid chemotherapy or immunotherapy.

We are currently doing much more with liquid biopsies [and are] really looking at the dynamics of circulating tumor DNA [ctDNA], to guide whether patients are responding to treatment. If the ctDNA goes down, that gives us a sense, an indicator, that the therapy is working, [possibly] before we get a radiographic response, before I even get the CT scan. [Liquid biopsy] is an active area of research that I think will be extremely interesting.

A: Exactly. Thats the point: We can [check progress] in a minimally invasive way.

A: Lung cancer is among the leading cancer subtypes where liquid biopsies are being used. Thats because a significant amount of ctDNA is shed into the bloodstream in patients with advanced disease. [Also], lung cancer has so many different [molecular, actionable] subtypes that now have targetable drugs. We can say [to a patient], You have an EGFR mutation or You have a MET exon 14 [skipping] mutationIm going to give you a pill. There is more actionability in lung cancer than in other diseases. However, breast cancer, gastrointestinal cancer, and genitourinary cancer are all now [using] liquid biopsies and expanding the space to utilize it in the clinical setting.

A: I think we are getting there. Were not completely there, because we still need a few things from tissue samples. We can never characterize the cell type or the architecture of a tumor, which are still very necessary, with a liquid biopsy. Looking at tissue is still extremely important, no matter what. I think plasma or liquid biopsies will be essential to give us information about the rest of the tumor. In fact, it sometimes gives us a clearer picture of the heterogeneous nature of the tumor, so we can get a sense of the cells that may have more metastatic potential and may have a slightly different mutational profile. We can gather that [information] much better than we can with a single small biopsy.

A: The most obvious indication that [a treatment is working is] less tumor. However, were also looking at other things like methylation signatures, RNA sequencing, and changes in mutational profile over time that may help us eventually [determine how treatment is going].

A: We have learned a great deal about when to use targeted therapy in lung cancer. We need to know a patients molecular subtype. One way we [learn] that is by using both tissue and plasma sequencing, which is a must. Once we know the molecular subtype, the next question is how we utilize the information to guide therapy. In my mind, the question is not who should get chemotherapy, but who can avoid chemotherapy in this day and age. I feel that with the explosion of immunotherapy, we can now deliver immunotherapy safely with a survival benefit for most of our patients. There will always be a subset who dont get immunotherapy, but the vast majority of our patients can, and we use PD-L1 testing to determine which patients can get immunotherapy alone. Again, thats only for a small subset of patients; for [the rest, were still] using a combination of chemotherapy and immunotherapy.

A: The premise of immunotherapy is reactivating the immune system and harnessing the power of T cells during cancer treatment. We know that our T cells as well as our bodies are inherently programmed to fight cancer. However, cancer cells may express inhibitory molecules; these can then be inhibited using PD-L1 inhibitors, potentially creating the immune response again. Thats the premise: the immune activation thats inherent in the immune system to fight cancer.

A: Many guidelines now help us with managing irAEs in a stepwise fashion, including guidelines from the National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the American Society of Clinical Oncology. Id [like to] add that recent evidence suggests that the presence of irAEs in patients who receive immunotherapy may be related to better outcomes, depending on the grade of AEs. Preliminary data, at least, suggest that grade 2 and 3 AEs may be better in terms of predicting for an improved outcome to immunotherapy, which I think is very interesting. Its reminiscent of the old days when we used to look at things like rash from EGFR inhibitors [to] tell us that the drug is working, [and] also that they are more likely to see a response.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

1. NCCN. Clinical Practice Guidelines in Oncology. Nonsmall cell lung cancer, version 5.2021. Accessed September 2, 2021. https://bit.ly/3DGrtPb

2. Aggarwal C, Thompson JC, Black TA, et al. Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic nonsmall cell lung cancer.JAMA Oncol. 2019;5(2):173-180. doi:10.1001/jamaoncol.2018.4305

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Modern Treatment Standards Require State-of-the-Art Molecular Profiling - Cancer Network