Goal 3: Advance Translational Research

Should Allogeneic stem cell transplantation be considered as an upfront treatment in high risk double hit DLBCL?

Double-hit lymphomas (DHL’s) are high-grade B-cell lymphomas characterized by chromosomal rearrangements of MYC gene with BCL2 and less commonly, BCL6.Large analysis of patients with de novo DLBCL have shown that conventional chemotherapy does not improve the survival of DHL Aggressive upfront chemotherapy followed by autologous stem cell transplantation (ASCT) has become a standard treatment in eligible patients. Retrospective ...more »

Submitted by (@shahram.mori.md)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

There are currently no recommendations regarding upfront allogeneic stem cell transplantation of high-risk DHL patients in CR. Harnessing graft versus lymphoma activity may be a potential strategy to improve responses in such patients

Feasibility and challenges of addressing this CQ or CC :

The challenge of this question is the definition of DHL. FISH is commonly used to characterize DHL’s but may miss a significant portion of patients with aggressive disease. Including the cohort DLBCL patients identified by IHC expands the number of patients. Majority of patients with DHL are older but the ability to perform reduced-intensity and haploidentical -transplants will increase the number of eligible patients. The use of post-transplant therapies is needed to keep the lymphoma in check while graft versus lymphoma responses take effect.

Name of idea submitter and other team members who worked on this idea : Shahram Mori

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Goal 3: Advance Translational Research

Regenerative Medicine 2.0 in Heart and Lung Research - Back to the Drawing Board

Stem cell therapies have been quite successful in hematologic disease but the outcomes of clinical studies using stem cells for cardiopulmonary disease have been rather modest. Explanations for this discrepancy such as the fact that our blood has a high rate of physiologic, endogenous turnover and regeneration whereas these processes occur at far lower rates in the heart and lung. Furthermore, hematopoietic stem cells ...more »

Submitted by (@jalees)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Some barriers to successfully implementing cardiopulmonary regeneration include the complex heterogeneous nature of the heart and lung.

 

Hematopoietic stem cells can give rise to all hematopoietic cells but the heart and lung appear to contain numerous pools of distinct regenerative stem and progenitor cells, many of which only regenerate a limited cell type in the respective organ. The approach of injecting one stem cell type that worked so well for hematopoietic stem cells is unlikely to work in the heart and lung.

 

We therefore need new approaches which combine multiple regenerative cell types and pathways in order to successfully repair and regenerate heart and lung tissues. These cell types will likely also require specific matrix cues since there are numerous, heterogeneous microenvironments in the heart and lung.

 

If we rethink our current approaches to regenerating the heart and lung and we use combined approaches in which multiple cell types and microevironments are concomitantly regenerated (ideally by large scale collaborations between laboratories), we are much more likely to achieve success.

 

This will represent a departure from the often practiced "Hey, let us inject our favorite cell" approach that worked so well in hematologic disease but these novel, combined approaches targeting multiple endogenous and/or exogenous regenerative cells could fundamentally change our ability to treat heart and lung disease.

Name of idea submitter and other team members who worked on this idea : Jalees Rehman

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Goal 1: Promote Human Health

Funding of Stem Cell/Lung Regeneration Research

How to "cure" a chronic, incurable disease - A potential giant step in saving the lives of many thousands of Americans, and potentially millions worldwide, who are afflicted with COPD, the third leading cause of death in the U.S. The financial effect of COPD in the United States alone is well over $50 billion per year. It is estimated that some 30 million Americans have COPD, which of course means that at least that ...more »

Submitted by (@jimandmarynelson)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

COPD is chronic and presently incurable. Although it sickens and disables nearly 30 million Americans, and kills 140,000 of them each year, the only "cure" is a lung transplant. Due to the scarcity of organ donors and the requirements that lungs be removed from the donor in a hospital setting, only about 1,400 lung transplants are performed in the Unites States each year. Unfortunately, transplants are fraught with complications, side effects, and potential rejections, and on the average, add only about 5 years to the life of the recipient. The best potential solution lies with the stem cell and lung regeneration research that is presently occurring at a few centers around the country. Ideally, the re-engineered lungs would be composed of the patient's own stem cells, eliminating a great many of the current transplant issues.

Feasibility and challenges of addressing this CQ or CC :

Research is presently in process on construction or reconstruction of human organs. There has been success in creating some of the simpler organs, such as the esophagus and bladder, and a Medical Center in Galveston has implanted re-engineered lung is a pig. As of my latest conversation with the lead Doctor on the project, results so far are promising.

There is general agreement among the researchers with whom I have communicated that we are between 5 and 20 years away from human trials of re-generated lungs using the patient's own stem cells, but more funding means more research which means more possibilities of the saving of lives.

Name of idea submitter and other team members who worked on this idea : Jim Nelson - COPD Foundation MASAC/CAC/BOARD Committee Member

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Goal 3: Advance Translational Research

Increasing Regenerative Medical Strategies in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a complex, progressive condition characterized by high blood pressure in the lungs and restriction of flow through the pulmonary arterial system. Current PAH therapies mainly act of the vasoconstrictive component of the disease; however there is a widely accepted view that another contributor to the disease is an abnormal overgrowth of cells that line the pulmonary arteries, which ...more »

Submitted by (@michaelg)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

In the past twenty years, 12 PAH targeted-therapies have been approved by the FDA. This increase in disease state awareness and in the treatment armamentarium have contributed to an increase in average survival from 2.8 years to an estimated 8-10 years. However, current treatments primarily address the vasoconstrictive component of the disease and do not address the now accepted theory of post-apoptotic overgrowth of hyperproliferative cells of the pulmonary vessels. A number of circulating stem and progenitor cells, derived from the bone marrow, have been identified that could have roles in repair of the pulmonary vascular system when interacting with the quickly, abnormally growing cells in the lung vessels. Work in this area has been named as a future research opportunity in the NHLBI-ORDR Strategic Plan for Lung Vascular Research (Erzurum S, et al. 2010).

Feasibility and challenges of addressing this CQ or CC :

Basic and translational research support is needed—including high-throughput approaches such as phage display and large-scale proteomic analysis—to better understand the relationship between circulating bone marrow-derived cells, lung-resident stem and progenitor cells, and endothelial cells of the pulmonary arterial system.

Name of idea submitter and other team members who worked on this idea : Pulmonary Hyeprtension Association, Michael Gray, Katie Kroner

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Goal 3: Advance Translational Research

Can hair follicle stem cells be transformed into new cells or organs?

Dr. Cotsarelis of the Univ. of Pennsylvania identified the bulge area of the hair follicle, which is now thought to contain the hair's stem cells. These cells would seem to be readily available and unique to an individual person. Can further work be done to transform these cells into now only hair cells but other organ tissues?

Submitted by (@info00)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

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Goal 3: Advance Translational Research

Translational research supporting stem cell therapy for cardiovascular disease

Translational research supporting stem cell therapy for cardiovascular disease, including: core laboratories for preclinical IND-enabling studies (e.g., PACT), and clinical trials networks for evaluating promising new treatments (e.g., CCTRN).

Submitted by (@judith.l.bettencourt)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

The most cost effective scientific procedure ever utilized to answer the risk benefit question posed by a new intervention to be used in humans is a clinical trial. Major clinical trials are their most effective when planted in controversial ground (MRFIT, CAST, ALLHAT). Like these studies, which were caught in a controversial dynamic of uncertainties and disparate sets of expectations, a clinical trial network to assess cell therapy is precisely what is needed.

Experienced researchers recognize the current inimical environment of cell therapy. Now - as before - some forces argue that new therapy offers no benefits, while other equally vehement constituents contend that the benefits of therapy are so great, and the risks so small, that the treatment requires little if any regulation and should be available at once to the US public. Each side provides thunder, but little light.

It is precisely in this contentious environment where passions argue beyond the data that clinical trials are required. Their construction of the most objective view of the strengths and weaknesses of the intervention comes at a cost, but the answers these well designed and concordantly executed studies provide is the clearest illuminations of the benefits and risks of human cell therapy.

Feasibility and challenges of addressing this CQ or CC :

Based on the unmet clinical needs in the treatment of cardiovascular disease and the compelling early evidence for the promise of cell therapy, NHLBI created the Cardiovascular Cell Therapy Research Network in 2007. Now in its ninth year, the Network has completed three major clinical trials in cell therapy. It has published 35 manuscripts in prestigious clinical journals including JAMA, Circ, and Circ Research. Its biorepository has published two manuscripts relating baseline phenotype findings to measures of left ventricular function. A fourth clinical trial is underway assessing the effect of cell therapy on peripheral vascular disease. The Network is also proceeding with the largest effort to assess the effect of CSC cells in patients with heart failure - the first clinical trial that will assess the effect of combined cell therapy in heart failure patients. In addition, CCTRN will study the effect of allogeneic mesenchymal stem cells in patients with anthracycline-induced cardiomyopathy. Each of these protocols is NHLBI and FDA approved.

CCTRN’s reputation of conducting and then promulgating the results of high quality clinical trials makes it the most effective mechanism to assess the benefits of cell therapy in cardiovascular disease. It is important to continue to fund the infrastructure already in place to ensure its continued high quality operation and its place as the cornerstone of cardiovascular clinical cell therapy research in the United States.

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Goal 2: Reduce Human Disease

The role of Extracorporeal Photopheresis (ECP) in the prophylaxis and treatment of acute & chronic Graft Versus Host Disease

In Acute Graft Versus Host Disease (aGVHD), we would like to examine whether early and intensified delivery of ECP as part of standard prophylaxis will decrease overall corticosteroid exposure while preserving expected relapse rates in patients undergoing unrelated donor hematopoietic stem cell transplantation (HSCT). Chronic GVHD (cGVHD) is common after HSCT (30-50% recipients) and is a major contributor to late transplant-related ...more »

Submitted by (@js2745)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Patients who develop aGVHD undergo toxic therapy with high-dose corticosteroids, often for long durations, resulting in high morbidity and treatment related mortality. Alternatively, T cell depletion of the donor graft to reduce GVHD is associated with high rates of infection and relapse of the disease that led to the HSCT. Targeting other pathways of GVHD pathogenesis may preserve the beneficial immune reconstitution and graft-versus-tumor (GVT) effects, while ameliorating the severity of GVHD. One such pathway involves regulatory T cells (T regs), which inhibit T cell alloreactivity, and are correlated with the incidence and severity of GVHD without loss of GVT. To date, there is no consensus on a standard second-line therapy for aGVHD, and current approaches focus mainly on intensification of immunosuppression. Addressing this compelling question will help to decrease overall corticosteroid exposure while preserving the expected relapse rates in patients undergoing unrelated donor HSCT.

 

Appropriate initial therapy for cGVHD involves high doses & prolonged use (yrs) of corticosteroids, while patients still develop irreversible sclerotic manifestations of disease. Early intervention prior to disease onset may help prevent cGVHD development or lessen its severity, requiring less corticosteroid exposure. Addressing the compelling question for cGVHD will help decrease exposure to drugs with associated morbidity, while preserving expected relapse rates in these patients.

Feasibility and challenges of addressing this CQ or CC :

Feasibility:

 

* GVHD has relatively high incidence after HSCT and at the same time there is a lack of consensus on standard second line therapy for the disease. Thus, there will be increased interest in developing and participation in those studies.

 

** ECP is generally well tolerated and complications are infrequent.

 

*** There is a great potential for multi-discipline collaboration approach in this patients’ population.

 

*** There is an opportunity to engage industry partners in the design and support for these studies.

 

**** There are numerous scientific opportunities for meritorious science as there have been limited systematic studies of ECP mechanisms of as well as standardization of apheresis protocols based on GVHD disease state.

 

 

 

Challenges:

 

* Limited number of institutions providing ECP treatment.

 

** Cost of the procedures (although Centers for Medicare and Medicaid Services now covers ECP for cGVHD).

 

*** There is a very limited number of animal models available for apheresis research in general, and studies of the mechanism(s) of action of photopheresis have been very limited as well as difficult and expensive to perform. However understanding pathological mechanisms and its relationship to response to apheresis is critical for optimization and advancement of patient care.

 

****Lack of infra-structure for apheresis research.

Name of idea submitter and other team members who worked on this idea : Joseph Schwartz on behalf of ASFA

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126 up votes
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Goal 3: Advance Translational Research

Spinal Cord Injury: hype, unmet promises, and misery which does not need to be

Research to "fix" spinal cord injury in humans, has been insanely hyped, rare in reality, and very disappointing in its clinical applicability to human patients. After a parade of rat models, mouse models, cat models, dog models, African green monkey models, pig models, guinea pig models, hamster models, rabbit models, gerbil models, etc. one wonders whether most researchers or funders will ever have any interest in ...more »

Submitted by (@mgwmgw)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

So, how about we put a moratorium on FDA approval of all research related to a cure for spinal cord injury when done by any persons or organizations who have not published every single one of their past experiments in the time required, and for any research which involves other species than humans.

 

Also, how many different ways of creating stem-like cells do we need? Let's stop creating stem-like cells and start applying the ones we have to human patients.

 

How about spending the animal model money instead on improving the quality of life for people living with disabilities. Let us start with actually enforcing the ADA on all new enough buildings.

 

When we make technology for doctors to use, we consult doctors. When we make technology for teachers to use, we consult teachers. When we make technology for disabled people to use… we consult insurance companies, and medical professionals who are not and have never been disabled. We fail to apply the most basic usability testing to the tools which disabled people must use. For example, has any wheelchair designer tried to propel a manual wheelchair uphill on wet grass? How about across a cobblestone street? or down a normally bumpy sidewalk? Now imagine that your butt has atrophied and you are sitting on your hip bones. How painful would that be? Now remember that pressure sores resulting from this bad design can be fatal, and then tell me why we do not take this more seriously.

Feasibility and challenges of addressing this CQ or CC :

The misery which does not need to be is not a new idea: http://badcripple.blogspot.com/2015/01/obsession-with-walking.html

 

Let's get the price of tools for disabled people down to the point where most patients can really afford them, or where the insurance can actually cover them. Let's get exoskeletons price-competitive with wheelchairs, for example, instead of using them to make soldiers able to carry heavier packs in war.

Name of idea submitter and other team members who worked on this idea : Mary-Anne Wolf (inspired by the Bad Cripple blog of William Peace and by the Wheelchair Driver website forum)

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Goal 3: Advance Translational Research

How can we develop more selective immunosuppression for allogeneic hematopoietic cell transplantation?

Graft versus host disease (GVHD) remains the most significant complication of allogeneic hematopoietic stem cell transplantation (HCT). While the use of HCT has grown significantly safer and has demonstrated broad efficacy in the setting of a broad range of blood diseases, immunosuppressive therapy has not dramatically evolved since the introduction of calcineurin inhibitor-based approaches decades ago. The availability ...more »

Submitted by (@kkomanduri)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

GVHD remains a critical problem and major barrier to the more widespread utilization of HCT, especially for nonmalignant diseases, where tolerance of treatment-related mortality is understandably low.

 

There is a compelling need for novel immunosuppressive agents that can effectively limit alloreactivity mediated by donor T and B cells, while relatively sparing pathogen-specific T cells, including those mediating antiviral T cell responses important in the post-HCT interval.

 

In the past decade, drug development has facilitated the introduction into preclinical and clinical trials of a broad range of agents that in addition to targeting pathways of interest in target cells (e.g., aberrant signaling in cancer cells) may also effectively inhibit T and/or B cell responses. Examples include hypomethylating agents (e.g., azacitidine), HDAC inhibitors (e.g., vorinostat), MEK inhibitors (e.g., trametinib) and BTK inhibitors (e.g., ibrutinib). Each of these classes of agents has been demonstrated in preclinical and/or clinical studies to also limit alloreactive T cells, and/or augment regulatory T cell responses, leading to a net reduction of alloreactivity. Unlike traditional agents (e.g., the calcineurin inhibitors) these agents appear to be more selective, and in some cases may have dual benefit in reducing relapse.

 

The NHLBI can facilitate the identification and translation to clinical practice in the setting of HCT trials of novel immunosuppressive agents.

Feasibility and challenges of addressing this CQ or CC :

Research funding targeted to improving the pipeline of novel immunosuppressive agents could have immediate and dramatic impact in the field of HCT, especially impacting its application for nonmalignant diseases. Patients lacking optimal registry donors, especially those from underrepresented minority groups, will particularly benefit from improvements in immunosuppression, as patients receiving less than optimally matched donors are at much higher risk of GVHD.

 

The NHLBI can encourage and facilitate research that tests compounds that have already passed through the drug development process, but in many cases were not intended to function as immunosuppressive agents. Compelling preclinical studies have suggested that targeted inhibition of T and B cells, and/or epigenetic modifiers can lessen alloreactivity while preserving beneficial cellular immune responses and facilitating immune reconstitution.

 

It will be far easier to appropriate therapeutic agents already developed for another purpose than to do novel drug development from scratch. In many cases, preclinical studies have highlighted the therapeutic potential in immunosuppression for agents that have been developed to treat malignancies, but yielded suboptimal success. Research that encourages the development of these drugs as part of a combined immunosuppressive/immunomodulation approach may rescue such compounds, while yielding potential dramatic advances in clinical HCT.

Name of idea submitter and other team members who worked on this idea : Krishna Komanduri, M.D.

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Goal 2: Reduce Human Disease

Measuring and Improving Physical Fitness to improve outcomes after Hematopoietic Stem Cell Transplantation

Can cardiorespiratory fitness prior to hematopoietic cell transplantation be improved and will this limit morbidity and mortality following transplantation?

Submitted by (@sheat0)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

HCT is associated with high rates of morbidity and mortality from transplant-related complications, the reduction of which would lead to higher transplant-mediated cure rates for life-threatening benign and malignant hematologic disorders. Comorbidity and patient-reported functional status impairment are known to increase the risk for transplant-related mortality, but unlike comorbidity, cardiorespiratory fitness is potentially modifiable. The optimal way to improve fitness through pre-transplant exercise and lifestyle interventions is not known, however, and understanding how to affect through a short term intervention would also benefit other cancer and non-cancer health conditions in which future treatment is intensive and associated with significant risk.

Feasibility and challenges of addressing this CQ or CC :

Feasibility and Challenges of Addressing the CG or CC:

 

Understanding how to improve cardiorespiratory fitness in a short period of time will require a research agenda that addresses the following challenges: how to measure cardiorespiratory fitness in a generalized and scalable way, which may or may not require maximal exercise testing for all participants; how to design intensive exercise interventions that are at least partially home-based in order to minimize resource burden on patients and centers; and how to personalize intervention delivery and testing in a way that is tailored to the baseline fitness levels and capabilities of each participant. Meeting these challenges will enable large-scale, personalized exercise testing and intervention delivery in other non-transplant populations.

Name of idea submitter and other team members who worked on this idea : Thomas Shea and William Wood

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Goal 2: Reduce Human Disease

Stem Cell Biology

There is a need to develop an artificial and functional hematopoietic stem cell (HSC) niche that allows for the expansion of repopulating HSCs.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Methods to expand hematopoietic stem cells have continued to be examined extensively because stem cell numbers in the graft are important for clinical outcomes following transplantation. These numbers are particularly relevant in umbilical cord blood (UCB) transplantation, where low numbers of stem cells are directly related to delayed hematopoietic and immune reconstitution. Improved HSC expansion strategies may significantly impact transplantation outcome, enabling broader applications beyond UCB transplantation. Furthermore, these strategies are also needed to realize the full therapeutic potential of genome editing technologies to correct hematopoietic stem cells derived from patients with hematologic disorders. Since efforts to expand HSCs in cytokine-supported liquid cultures have been largely unsuccessful, efficient expansion will require an appropriate context that is provided by the hematopoietic stem cell niche. Future studies must also evaluate how niche signals regulate stem cell function to optimize cell expansion, and proper humanized mouse models must be developed to help predict stem cell function and regulation by the niche.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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Goal 3: Advance Translational Research

Overcoming barriers to translational regenerative medicine

Current stem cell based approaches to translational medicine predominantly show modest efficacy. Most research rest on accepting existing limitations and focusing upon "tweaks" to the experimental model rather than taking on important barriers head on. The efficacy of stem cell-based regenerative medicine will never be fully realized unless we stop trying overly simplistic approaches such as"more is better" and start ...more »

Submitted by (@heartman4ever)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

The field of regenerative medicine holds great potential but we risk losing the public trust by hyperbolic promises, modest efficacy, and incremental research steps. Truly innovative research will transform the landscape and offer truly novel therapeutic approaches to many current incurable conditions. The result is a dramatic shift in the practice of medicine, new options for treatment, enhanced engagement of the public in biomedical research and new growth opportunities for the NIH and biotech sectors.

Feasibility and challenges of addressing this CQ or CC :

The future is here for regenerative medicine, but for the most part the potential and practice has been unrealized or poorly executed. The challenge is to identify the limiting factors and sweep them aside. There is broad and surprisingly consistent consensus on what the barriers are to successful regenerative therapy, but it seems most researchers are complacent and accept these limitations as inherent in the system rather than try to find truly combative approaches to overcome the barriers to enhancing regenerative processes. So it is essential to change the current mindset and push for a full frontal attack on the barriers that impede successful regeneration rather than minor modifications or uninspired brute force approaches that ignore the underlying mechanistic issues. Also, a major challenge is the hyperbole and overselling of research findings and impact by researchers and their institutions looking to capitalize upon the "discovery de jour." Such overly optimistic and unrealistic promises undermine our position in the public eye and compromise our future ability to earn the public trust.

Name of idea submitter and other team members who worked on this idea : M Sussman

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