Showing 3 ideas for tag "t"

Goal 2: Reduce Human Disease

The role of Extracorporeal Photopheresis (ECP) in the prevention and treatment of rejection of heart and lung transplants

According to the ISHLT, more than 4,000 patients undergo a heart transplant each year, and almost 4,000 receive single or double lung transplants. Their prognosis depends heavily on the avoidance of rejection, which claims the majority of their lives. For heart transplant recipients, the median survival is 11 years, while for lung transplant recipients, it is approximately 5 years. The current most common anti-rejection... more »

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

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Patients who are fortunate to receive a matched heart or one or two lungs transplants are at high risk of dying from rejection early and even years after the operation. Thus, they are given cocktails of highly toxic anti-rejection drugs for the rest of their lives. Unfortunately, despite compliance with their drug regimens, many patients still suffer repeated episodes of rejection that may be fatal. In addition, they develop serious side-effects such as diabetes, infections, malignancies, renal failure, etc. ECP has been shown efficacy in preventing and treating cardiac transplant rejection, but the data are limited. ECP appears to benefit such patients by causing an increase in the number of circulating T regulatory (“T regs”) cells. T regs are known to mediate immune tolerance, the ultimate goal of a long-term successful transplant. The role of ECP in lung transplantation is mostly unknown. Very preliminary data have been gathered from retrospective studies. We suspect that patients with early bronchiolitis obliterans syndrome (“BOS”) will benefit from ECP prior to developing irreversible pulmonary damage. In both types of transplants, however, it is unknown when should ECP be started, how often it should be employed (treatment schedule), and for how long. Finally, the most compelling argument to use ECP in heart and lung transplantation is its excellent side-effect profile. Furthermore, ECP may allow a decrease in the number of drugs needed to prevent rejection.

Feasibility and challenges of addressing this CQ or CC

Many patients with heart and lung transplants develop severe and often fatal rejection despite the current drug options to prevent rejection. ECP could be added to their treatment regimens and decrease side-effects, improving long-term survival.

ECP is generally well tolerated and complications are extremely infrequent.

There is a great potential for multi-disciplinary collaboration between Apheresis Medicine, Cardiology, and Pulmonary specialists.

It is conceivable that manufacturers of ECP instruments will be interested in contributing to the design and support of these studies.

Such studies could shed light in the mechanism of action of ECP in heart and lung transplantation.

There is a need to develop standardized treatment regimens based on well designed clinical trials to further optimize the use of ECP. Development and standardization of measurable outcomes is critical for the success of clinical studies in apheresis in general, and ECP in particular.

Challenges:

  1. Limited number of institutions providing ECP treatment.
  2. Cost of ECP procedures.
  3. Small number of animal models available for apheresis research. Thus, limited studies of ECP mechanism(s) of action. However, understanding pathological mechanisms and their relationship to response to apheresis is critical for optimization and advancement of patient care in heart and lung transplantation.
  4. Lack of infra-structure for apheresis research.

Name of idea submitter and other team members who worked on this idea Marisa Marques on behalf of ASFA

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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)

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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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Goal 2: Reduce Human Disease

Influence of the Gut Microbiome on Pulmonary Immunity in HIV-Infected Individuals

It has become increasingly clear that gut microbiota have a tremendous impact on human health and disease. While it is well known that commensal gut bacteria are crucial in maintaining immune homeostasis in the intestine, there is also evidence of indirect effects on the lung. Multiple studies have shown that alterations in gut microbiota can lead to severe defects in pulmonary immune responses and reduced ability to... more »

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

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HIV-infected individuals are at significant risk of developing and dying from infectious and non-infectious pulmonary complications. Alteration of gut microbiota have been shown to have dramatic effects on pulmonary immunity and severity of lung infections. For instance, multiple studies have indicated that probiotic treatment with certain Lactobacillus and Bifidobacterium strains results in reduced incidence and severity of upper respiratory tract infections in children. Similarly, a recent study showed that treatment with the minimally absorbed antibiotic neomycin was associated with alterations in gut microbiota composition and concomitant reduced pulmonary immunity and the inability to control Influenza infection in mice. It was recently described that HIV infection is associated with a dramatic alteration in gut microbiota and that these changes persist with antiretroviral therapy (ART). Thus, it is important to understand how these alterations may effect lung immunity, since the majority of HIV-infected individuals develop pulmonary infections. Furthermore, gut microbiota contribute to development of non-infectious complications such as atherosclerosis, metabolic disease, obesity and diabetes. It is thus highly plausible that the gut microbiota may also play a role in the development of non-infectious complications of the lung such as Chronic Obstructive Pulmonary Disease and Pulmonary Hypertension, the rates of which are elevated in HIV-infected individuals.

Feasibility and challenges of addressing this CQ or CC

A better understanding of how alterations in gut microbiota associated with HIV infection affects pulmonary infectious and noninfectious complication could lead to therapies to protect this “at risk” group. Furthermore, manipulation of the gut microbiota in HIV-infected individuals using pro- and/or pre-biotics, antibiotics or diet modification to a composition that is associated with increased pulmonary immunity, reduced infections and lung complications are all low risk therapeutic strategies that could substantially improve lung heath in these individuals.

Name of idea submitter and other team members who worked on this idea Brent Palmer (NHLBI-INHALD group member) and Catherine Lozupone

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