Showing 8 ideas for tag "hct"

Goal 3: Advance Translational Research

Can we leverage exisiting registries to perform prospective trials and advance reduce the cost of doing research?

Current costs for multicenter randomized or non randomized trials are astronomical, and a major obstacle to rapid implementation of potential lifesaving discoveries.
In the field of hematopoietic cell transplantation (HCT) their is a federal mandate to have a treatment outcome registry.
Funds should be made available to leverage that registry to perform prospective trials either randomized or not since HCT programs need... more »

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

Details on the impact of addressing this CQ or CC

This would allow for rapid exploration of novel concepts. Would reduce the time and cost of doing research in the HCT field. Would allow to explore questions related to best supportive care practices in HCT

Feasibility and challenges of addressing this CQ or CC

Very feasible. Last year we prepared a proposal in response to an RFA demonstrating that all elements are in place.
The CIBMTR has already shown that prospective observational studies are feasible and useful

Name of idea submitter and other team members who worked on this idea sergio giralt

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123 net votes
154 up votes
31 down votes
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Goal 2: Reduce Human Disease

What are the mechanisms of lung injury after HCT

Despite major advances in supportive care and tissue typing non relapse mortality rates for adults undergoing hematopoietic cell transplantation are still between 15-20 % at 2 years.
Lung injury and respiratory failure is a major causes of death after HCT.
Although the BMT-CTN has a focused agenda on GVHD, reduction of lung toxicities will be important to improve outcomes.
NHLBI should encourage researched from the... more »

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

Details on the impact of addressing this CQ or CC

Discovery of mechanisms of lung injury in the HCT setting are likely to be relevant for the non HCT setting.
The BMT CTN prospectively collects data on lung toxicity on all HCT recipients on trial, samples exist in the repository that could be used for biomarker discovery.

Feasibility and challenges of addressing this CQ or CC

Main challenge is to get the two teams of investigators working together

Name of idea submitter and other team members who worked on this idea Sergio Giralt

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59 net votes
88 up votes
29 down votes
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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 »

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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106 net votes
129 up votes
23 down votes
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Goal 2: Reduce Human Disease

Personalized therapy of HCT complications

Can biomarkers make all the use of new predictive biomarkers enable earlier and more effective treatment of acute GVHD? Can biomarkers accurately guide reduction in therapy for patients who will respond to standard steroid treatment? Can biomarkers enable earlier and thus more effective therapy for high risk GVHD? Can new biomarkers (proteomic, genomic or a combination) also predict patients who are risk of relapse?

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

Details on the impact of addressing this CQ or CC

Despite enormous advances in immunology over the past several decades, there are no validated new therapies for acute GVHD, the major complication of allogeneic HCT. Several biomarkers have now been identified at the onset of GVHD that can predict response to treatment and provide a personalized profile of patients. But these biomarkers have not yet been used to guide therapy, and definitive clinical trials are needed to answer this question

Feasibility and challenges of addressing this CQ or CC

Need for consistent and accurate biomarker determination available for a large number of centers

Name of idea submitter and other team members who worked on this idea John Levine and James Ferrara

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74 net votes
99 up votes
25 down votes
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Goal 3: Advance Translational Research

What is the best time to undergo a stem cell transplant (HCT)?

In this era of all the new therapies in cancer treatment, I believe stem cell transplants run the risk to be delegated to be used as last ditch effort to treat patients when all other therapy fails. Historically this has not been the group that benefitted the most from a transplant. I believe that better national studies need to be designed and funded to address the optimal use of transplant to benefit our patients... more »

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

Details on the impact of addressing this CQ or CC

Optimize responsibly the care of cancer patients and other non cancer diseases treated with HCT

Feasibility and challenges of addressing this CQ or CC

Need to design studies and run through cooperative groups so patients enrolled at time of diagnosis . Need to provide sufficient funding to institutions to participate in the studies and collect the data. Currently cooperative group funding is not able to cover the true costs of enrollment and follow-up expenses of an institution for participating in studies.

Name of idea submitter and other team members who worked on this idea Leoan A Holmberg MD, PhD

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47 net votes
78 up votes
31 down votes
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Goal 3: Advance Translational Research

Maximizing anti-tumor immunity following allogeneic HCT with biomarkers

Allogeneic hematopoietic cell transplantation (allo-HCT) is one of the most effective forms of tumor immunotherapy available to date. Allo-HCT can be life-saving for patients with aggressive malignancies that cannot be cured through other strategies. The immunotherapeutic efficacy of allo-HCT depends on donor T cell recognition of alloantigens on leukemic cells, which is known as the graft-versus-tumor effect (GVT). No... more »

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

Details on the impact of addressing this CQ or CC

Allo-HCT represents the only curative therapy for a number of malignant disorders but often results in serious complications, including GVHD. Because GVHD is such a potentially devastating post-transplant complication and because we want to be able to separate GVHD from the GVT effect, it is crucial to try to determine a specific biological pattern link to the favorable GVT effect. The focus of this critical challenge will be to develop a novel, non-invasive GVT signature in patients undergoing HCT. If successful, this will have a major impact, because a GVT-specific proteomic signature may facilitate the clinical therapeutic decision of rapid taper of immunosuppression or increased immunotherapies. The ability to identify patients who will not develop GVT early post-transplant has important therapeutic consequences, including preventative care with donor-lymphocyte infusion (DLI) or tumor-specific vaccines or T cells expressing chimeric antigen receptors (CARs). Equally important is the identification of patients who will develop GVT without GVHD, potentially enabling more rapid tapering of immunosuppressive regimens and thereby promoting even more the GVT reaction as well as reducing long-term toxicity in these patients. With this diagnostic tool, the HCT community may plan to develop preemptive therapeutic trials. In addition, the biomarkers may represent potential GVT-specific therapeutic targets to maximize GVT and/or immunotherapies.

Feasibility and challenges of addressing this CQ or CC

Using proteomics, several GVHD biomarkers were recently identified and validated. For example, high suppression of tumorigenicity 2 (ST2) plasma concentrations were significantly associated with the incidence of GVHD and transplant-related mortality in recipients of unmanipulated graft and cord blood transplants. Consequently, the Blood and Marrow Transplant Clinical Trial network is currently pursuing therapeutic interventions for newly diagnosed GVHD patients based on GVHD biomarkers risk-stratification. Thus, discovering and validating biomarkers post-HCT is feasible. However, the challenges with GVT-specific biomarkers are three-fold: 1) the absence of phenotype, as the only way to define clinical GVT without GVHD, is the absence of relapse and no GVHD post-HCT; 2) the paucity of samples to study GVT, ideally samples following DLI or nonmyeloablative conditioning preparative regimens that permit stable engraftment of donor hematopoietic cells but have little or no direct tumoricidal activity should be available; and 3) the relative lack of knowledge of the biology of GVT. These represent important challenges to solve. In sum, the recent successes of cancer immunotherapies, particularly for the treatment of hematological malignancies, have stimulated interest in the potential widespread application of these approaches, and biomarkers to predict and monitor the responses are required.

Name of idea submitter and other team members who worked on this idea Sophie Paczesny

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32 net votes
52 up votes
20 down votes
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Goal 2: Reduce Human Disease

Transplant to Cure Older Adults with Hematologic Malignancy-Removing the Blindfold

While transplant for patients 60 and older for high-risk hematologic malignancies has increased and observational data are promising, the risks and benefits of translant versus non-transplant remain largely unknown. We now have the tools and mechanisms to remove the blindfold!

The NHLBI should support the cooperative groups in conjunction with the BMT-CTN to establish a common framework for transplant trials in older... more »

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

Details on the impact of addressing this CQ or CC

Hematologic malignancies are more common and less treatable in older patients. This trend will contine as the number and proportion of older people in society increases. Older patients are frequently treated but rarely on studies. The availability of haploidentical and cord donor sources, better supportive care, and more tolerable regimens permits transplant to be widely accessible and utilized.

A critical question for the entire field of hematologic malignancies is determing the risks and benefits of allogeneic transplant for older adults. This question is posed across the country, every day by every patient and physician struggling to treat older adults with hematologic malignancies. The confluence of molecular and cytogenetic disease markers and novel measures of patient health should permit identifying those most likely to be cured and those least likely to benefit. Such data will ultimately inform the next generation of transplant trials in this population.

Feasibility and challenges of addressing this CQ or CC

The number of patients with any of these diseases (e.g., AML, MDS, NHL and perhaps ALL) who are 60 years and older is significant. The challenge is to develop a coordinated effort to prospectively capture disease and patient health data to answer which subgroups benefit or do not.
Methods to capture patient health status have already been developed through a standardized Geriatric Assessment used in the Alliance and other studies. Most of the survey can be done electronically by a patient or by telephone. Disease based molecular markers have emerged as standard measures within cooperative group studies to augment cytogenetic and morphologic classification.

Ensuring cooperative groups develop uniform design and data may be difficult. Yet investigators gain much and lose little by standardizing the data capture of what already occurs (patients moving to transplant on hematologic malignancy trials).

Another challenge is to develop standardized measures after transplant beyond survival such as function free survival and quality of life that are patient centered. Electronic tools to capture data, especially for non-transplant patients, will greatly reduce this burden.

Name of idea submitter and other team members who worked on this idea Andrew Artz

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20 net votes
36 up votes
16 down votes
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Goal 2: Reduce Human Disease

Optimize vaccine responses in HCT recipients and patients with hematologic malignancies

Vaccination responses are poor early after hematopoietic cell transplantation and in the context of cytotoxic chemotherapy. To design effective vaccination strategies it is critical to understand the immune correlates of protection. There is a need to study strategies to study and improve vaccine efficacy in this growing population of immunosuppressed individuals that is increasingly of advanced age.

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

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15 net votes
25 up votes
10 down votes
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