Disease Team Planning
Acute lung injury is a major cause of acute respiratory failure than develops in adult and pediatric critically ill patients following major trauma and shock, severe pneumonia, sepsis, and aspiration syndromes. Mortality from acute lung injury is high, with approximately 75,000 deaths per year in the United States alone. Also, most patients who recover from this cause of respiratory failure require extended rehabilitation, although the longer term prognosis for return to normal lung function in survivors is excellent. There has been some progress in treatment of victims of acute lung injury. For example, lung protective mechanical ventilation strategies have improved clinical outcomes. However, there is no specific drug or other treatment that can reduce lung injury and mortality. Based on recent experimental studies from several investigators, allogeneic mesenchymal stem cells are effective for reversing acute lung injury and improving survival in animal models. There is also evidence that intrapulmonary administration of allogeneic human mesenchymal cells induces a nearly complete reversal of acute lung injury in an ex vivo perfused human lung preparation. Thus, there is a major opportunity to translate allogeneic human mesenchymal stem cells to clinical trials in patients with acute lung injury. A well organized planning program is needed to integrate both basic and clinical scientists from several California universities and private institutions with the objective of developing an effective and efficient network for translating mesenchymal stem cell studies to patients with acute lung injury. Faculty and staff from California institutions with expertise in immunology, cell based therapeutics, and clinical trials will form the core team to combine their expertise in preclinical and clinical studies to develop a plan for testing the safety and the effectiveness of allogeneic mesenchymal stem cells in patients with lung injury. Industrial partners with expertise and experience in the clinical use of cell based therapies will also be included in the team. The planning work will use a certified Good Medical Practice facility to culture and grow allogeneic mesenchymal stem cells from normal donors, and test them for safety for human use, as well as to evaluate their biological activity. The final planning product from this Disease Team Planning effort will include specific milestones for meeting the FDA regulatory steps to obtain approval for evaluating mesenchymal stems cells in critically ill patients with acute lung injury. At the end of the 6 month planning period, there will be detailed plans for evaluation this promising new therapy in critically ill patients with acute lung injury at 6 California hospitals.
Statement of Benefit to California:
Acute lung injury is a common cause of acute respiratory failure in critically ill patients. Based on recent studies, acute lung injury occurs annually in approximately 24,000 patients in California alone with an estimated mortality of 40% in those patients. Acute lung injury can develop in normal individuals who have been injured in major trauma, such as following an automobile accident or from exposure to smoke fumes in a fire. It also can occur in otherwise normal individuals who develop severe pneumonia from a viral infection, such as the flu. Acute lung injury also develops in patients with a variety of chronic medical illnesses including diabetes, chronic lung diseases, liver disease and dialysis dependent kidney failure. Acute lung injury develops in both pediatric and adult patients and treatment is required in an intensive care unit where patients can receive life support with mechanical ventilation and other life saving therapies. In spite of progress in supportive care for this syndrome of acute respiratory failure, 40% of patients with acute lung injury do not survive. Also, the patients who do survive require long periods of hospitalization to recover and also require extended periods of rehabilitation in specialized facilities. Thus, the emotional, social, financial and economic costs to the citizens of California is high, and therefore innovative approaches to treatment of acute lung injury are needed. New evidence indicates that allogeneic mesenchymal stem cells can potentially provide an effective and safe new treatment for both children and adults with this syndrome of severe acute respiratory failure. By forming a California based team of basic and clinical investigators from universities and industry, we can develop a comprehensive plan to develop and test this new therapy for acute lung injury patients. The first anticipated benefit will be an increased survival in California residents who develop this form of acute respiratory failure. The second anticipated benefit be a reduction in the need for life support in an intensive care unit, leading to more rapid rehabilitation and return to productive, independent lives.
Executive Summary The applicant proposes to establish a multi-disciplinary and multi-institutional team for allogeneic mesenchymal stem cell (MSC) therapy for the treatment of acute lung injury (ALI). Acute lung injury develops in adult and pediatric patients following trauma, shock, pneumonia, sepsis or aspiration syndrome. Currently there is no curative treatment for the disease. Proof of concept studies carried out by the Principal Investigator (PI) in ex vivo perfused human lung preparation as well as in vivo mouse model for ALI have shown benefit of MSC in reducing experimentally induced lung injury and improving survival. The applicant proposes to produce clinical grade allogeneic MSC under cGMP conditions for a regulatory filing within two years leading to a multi-center phase I and phase II clinical trial in critically ill patients with acute lung injury. There was a general agreement among the reviewers that ALI is a disease with unmet medical need. Some reviewers also agree with the scientific rationale outlined in the proposal on the use of allogeneic MSC cell therapy for the treatment of ALI, although one reviewer felt that the case for using MSC as a cellular therapy for the treatment of ALI is not compelling and pointed out that the mechanistic basis of the approach/effect is unknown. Furthermore, there is no discussion in the proposal about using other cell populations or why MSC may or may not be better than other sources of stem cells. The reviewers agreed that the PI has extensive experience in translating preclinical observations into clinical trials as evidenced by the number of Phase II and Phase III ALI clinical trials headed by the PI. He/she has nice track record of publications, including both medical and basic science journals. Consultants and contractors have been clearly defined, including members from both academia and private sector. The approach for producing human bone marrow (BM)-derived MSC under cGMP conditions for the clinical trial has been clearly defined. However, one of the reviewers wondered why the PI has not considered setting up collaboration with a company that is producing clinical grade BM-derived MSC for similar purposes. Other criticisms on the proposal included the lack of studies to optimize the dose of MSC and the delivery route. One reviewer felt that the proposed method for establishing dosing for human studies was inadequate, and suggested the use of a large animal model for that purpose instead. It was also noted that the studies proposed in the application are eligible for federal funding. Reviewer Synopsis The applicant proposes to establish a multidisciplinary network across multiple institutions focused on the utilization of allogeneic mesenchymal stem cells (MSC) as a novel cellular therapy for the treatment of acute lung in jury (ALI). The PI, who has extensive experience in clinical trials of ALI, has previously shown in studies in mice that intra-tracheal administration of MSC reduces lung injury in an E. coli endotoxin-induced model of ALI resulting in reduced pulmonary edema and increased survival. The benefits of MSC were through paracrine antiinflammatory effects and were independent of engraftment of MSC in the lung. Similar benefits of MSC were observed by the PI in a novel ex vivo perfused human lung preparation. The applicant proposes cGMP manufacture of human BM-derived MSC which is proposed as a prerequisite for their subsequent application for phase I and II clinical trials for ALI. Reviewer One Comments PI: Michael Matthay Institution: UC San Francisco Disease Target: Acute Lung Injury Concept: Allogeneic MSC for acute lung injury. 200,000 patients per year, with 75,000 deaths. Preliminary data in mouse models suggests MSC infusion can improve survival (perhaps by indirect paracrine effects). Novel “ex vivo” lung perfusate model also suggests MSC can reverse endotoxin-induced ALI. Plan is to partner with several other California institutes (Stanford, CHORI, USC). Strengths: 1. UCSF GMP facility for MSC production 2. EJ Read as consultant. 3. Rapid advancement to the clinic (predicted 2 years) 4. Good preliminary data in murine model 5. Interesting ex vivo perfusate model. 6. Impressive list of consultants/subcontractors with expertise in MSC biology, clinical production, and treatment options for ALI. A team of basic and clinical scientists, both academic and industry, is already in place. Weaknesses: 1. No discussion of why MSC may or may not be better than other sources of stem cells. 2. Further exploration of optimal delivery route needed. 3. Prior safety studies on IV infusion of MSC may not directly translate as it relates to the proposed direct lung perfusion. 4. No apparent attempt to determine optimal dose? 5. MSC research can receive federal funding. 6. Minimal details provided regarding the composition of the advisory group. Principal Investigator: PI: Dr. Matthay has been a full Professor at UCSF for over 15 years, and is PI on several grants focused on Lung injury. Included is a recently completed Phase II trial of activated protein C for treatment of ALI, since this is ending Dr. Matthay will have more free time to devote to preparation of CIRM proposal. Also of note is a current Phase III trial of aerosolized beta-2 agonists being managed through a Clinical Research Network, as well as evaluation of lung activity in brain dead organ donors. Finally, Dr. Mattthay runs a core facility to provide cells, tissues, and mouse models for ALI research. Planning Approach: Planning Approach: 1. Dr. Matthay will direct activities a. Two-day conference in August with team members b. Focus on practical details i. Harvesting, testing MSC ii. Regulatory issues iii. Plan for IND filing c. “Strong” advisory group – conference calls (video) once/month d. Second team meeting in November Reviewer Two Comments Concept: - The proposal attacks the development of a novel treatment for patients with acute lung injury effecting both adults and infants, and can be caused by trauma, shock, pneumonia, sepsis, or aspiration syndromes. Current clinical strategies for this disease include lung protective, which improves the situation but does not cure it. Promising recent studies establish in the mouse model have established that mesenchymal stem cells (MSCs) work effectively in reversing the syndrome. Preliminary data in human suggests that it might lead to the same outcome. These two facts together represent an extremely strong rationale and significance, and thus a great opportunity to translate this work in clinical trials for patients with lung injury. This is one of those projects that is scientifically ready and mature for direct human assays. - Strengths of this proposal include the importance and scientific readiness to be transferred to clinic, multidisciplinary, UCSF wonderful environment for the pursuit of this type of research. Principal Investigator: - 10% effort dedicated by PI. - Complete list of consultants and contractors has been clearly defined, including members from both academia and private sector (total of five). - The PI has an extensive curriculum. After obtaining a BA in English from Harvard, he obtained his medical degree from U Penn, did residency and research from the University of Colorado in Denver and UCSF. He has been a professor at UCSF since 1992. - Nice track record of publications, including both medical and basic science journals. Planning Approach: -The effort will include investigators from UCSF, Stanford, Childrens Hospital in Oakland, and USC – and thus is multi-institutional. - It also is multidisciplinary, in the sense that it includes researchers with expertise in immunology, cell-based therapy, and pre-clinical and clinical trials. - UCSF GMP facility will be used to culture and propagate the MSCs. - The PI estimates 6 months planning period with the milestone goal of obtaining FDA and IND within two years of the initiation of the project. - Patients in six California hospitals will be used for the clinical trials. Reviewer Three Comments Concept: • Diseases of the respiratory system collectively represent a considerable area of unmet medical need. Acute lung injury is a major cause of respiratory failure for which there has been no progress toward identifying appropriate therapies. • Although administration of MSC has been shown to alleviate symptoms in various models of lung injury, including a mouse model of ALI by the PI, the PI cites the encouraging results of clinical studies with MSC as a treatment for myocardial infarction and the alleviation of GVHD as ‘compelling evidence that human MSC have a high likely hood of being effective in the treatment of ALI”. Despite the PI’s own preclinical studies, the case for using MSC as a cellular therapy for the treatment of ALI is not compelling Principal Investigator: PI has extensive experience in translating preclinical observations into clinical studies as evidenced by: • NIH ARDS Network phase III clinical trial of beta-agonist therapy for ALI (PI Dr. Matthay is the PI) • Phase II clinical trial of Activated Protein C for ALI • Dr. Mattay is PI of an NHLBI SCCOR of ALI Collectively his role in these studies suggests he is considered an expert in the ALI field, an impression reinforced by his extensive publications in this area. The PI’s extensive experience in running clinical trials in ALI has facilitated his assembly of a multi-disciplinary team of basic and clinical scientists with an interest in developing MSC as a cellular therapy for ALI. Planning Approach: A major facet of the planning approach revolves around preparing allogeneic human bone marrow derived MSC to cGMP. While much thought has clearly gone into this it is surprising that the PI has not considered setting up a collaboration with a company that can supply clinical grade MSC (such as Osiris). A second approach is based upon preparing plans for phase I and II clinical trials across the State which will involve obtaining IRD, IRB and FDA approvals. The proposed trial will involve delivery of MSC to injured lobes of the lung of patients with ALI using a cell dose based upon the PI’s studies of MSC in the ex vivo perfused human lung model. It would seem appropriate that strong consideration should be given to developing a large animal model to establish the appropriate cell dose prior to initiating human studies.