Disease Team Planning
The human immune system is comprised of cells that have differentiated into specific types (such as red, B or T) and hematopoietic stem cells (HSCs) that are not fully differentiated. HSCs grow and are capable of producing more HSCs and differentiated cells to perform a specific function. HSC transplant therapy represents an increasingly important modality in treating and curing human disease. HSC transplantation involves the use of HSCs to replace and initiate the production of cells that are missing or damaged due to disease or injury. Today, HSC transplantation is commonly used non-controversial treatment for hematopoietic diseases. HSC transplant therapy is a medical procedure in which bone marrow or processed circulating blood (all of which contain HSCs) are infused into the patient’s circulatory system, where they home to the bone cavity. Once established, they begin to grow and produce healthy blood and immune cells. Cells for this procedure are obtained from a donor, though, in some cases, the patient’s own cells may be used. Despite successful use, several limitations remain, including unavailability of appropriate donors and individuals treated with chemotherapy are unable to use their own HSCs. Umbilical cord blood cells has emerged as an excellent source of HSCs for individuals who lack an appropriate donor or cannot utilize their own HSCs, but at present have limited utility because of low HSC numbers per transplant leading to delayed recovery. Growing HSCs outside the body is an attractive strategy to obtain increased numbers of HSCs for transplantation because successful HSC transplants have been correlated with HSC dose. Extensive research has been employed to identify the growth conditions to expand HSCs , but to date the critical factors remain unknown. Therefore, to identify compounds that promote HSC expansion we performed a high-throughput screening assay and identified small molecules that expand HSCs outside the body. HSCs grown with the most potent compound produced ten times more HSCs compared with control. The goal of this proposal is to develop this compound for clinical applications. HSCs expanded with this compound may be used to: replace diseased bone marrow with healthy, functioning bone marrow for patients with blood diseases such as aplastic anemia; replace bone marrow damaged by high-dose chemotherapy or radiation therapy; used to treat patients with a variety of cancers such as leukemia and lymphoma; and provide genetically healthy and functioning bone marrow to treat patients with genetic diseases such as sickle cell anemia. To reach these goals we will assemble a team of scientists, hematologists and oncologists to plan the appropriate experiments leading to human trials. Because HSC are the only approved stem cell therapy and HSC transplants are routinely performed this project is achievable within the next five years, and these experiments may result in the first regenerative stem cell drug.
Statement of Benefit to California:
Small molecule controlled ex vivo HSC expansion will have a profound benefit on the treatment of many blood diseases. Ex vivo expanded HSCs may be used to accelerate the hematopoietic reconstitution and immune cell function during autologous or allogeneic transplantation for the treatment of patients with inherited immunodeficiency, autoimmune disease and diverse hematopoietic disorders. HSC transplantation is also used to restore the hematopoietic and immune system after myeloablative effects following high-dose chemotherapy or ionizing radiation therapy in cancer patients. In addition, ex-vivo HSC expansion will extend the utility of the Cord Blood registry by circumventing the low number of functional HSC available for transplant. For example, umbilical cord blood transplantation (UCBT) has become an established therapy for patients without matched related or unrelated donors. Compared to bone marrow transplants, UCB collection is easier and safer. It is also quicker to perform UCBT from the time of beginning of donor search. One of the major advantages is the naïve nature of the newborn’s immune system. This allows transplantations with less restriction of the HLA system, and with fewer graft versus host disease cases. Owing to a limited number of stem cells available in a typical UCB unit and therefore delayed engraftment when compared to marrow or mobilized peripheral blood, the prime focus for this therapy continues to be the pediatric patient. Nevertheless this form of transplant is emerging as a viable alternative in adults, provided there are sufficient cells in the UCB unit and the patient is a small to average-sized adult. Although UCBT permits the use of mismatched donors and are available more quickly than matched unrelated donor grafts, the main problems after the infusion of an UCB unit are delayed engraftment of neutrophils and platelets and aberrant immune reconstitution - both leading to a higher mortality. In 2004, two large retrospective UCBT studies on adults transfused with a median of 2.3 x 107 total nucleated cells (TNC)/kg showed no difference in leukemia-free survival between the human leukocyte antigen (HLA)-mismatched cord blood group and the HLA-matched marrow groups using allele matching at HLA-DRB1 and serologic matching at HLA-A and -B. Based on these results, UCBT could become the treatment of choice if a HLA class I and class II (eight out of eight) matched unrelated adult donor is not available. Unfortunately 90% of adults referred for a UCBT are ineligible to receive an UCB graft based on their weight at the recommended cell dose and with no more than two HLA mismatches. Thus efforts to increase the number of HSC infused are paramount. Using a small molecule, like the one we identified, will allow for ex vivo expansion of UCB HSCs and make UCBT available to more patients, decrease engraftment times and allow more rapid immune reconstitution post transplant.
Executive Summary The focus of the proposal is the development of a small molecule for ex vivo expansion of peripheral blood and cord blood hematopoietic stem cells (HSC) for use in various clinical settings including immunodeficiency states, autoimmune and hematopoietic diseases, and following high dose chemotherapy or radiation. The principal investigator (PI) has identified a small molecule that may have this expansion capability. A group of collaborators from the academic institution and industry has been assembled to plan and carry out experiments leading to clinical trials. Reviewers concurred that the ability to expand hematopoietic stem cells ex vivo would greatly enhance the efficacy of cord blood transplantation and other HSC transplantation protocols without increasing the risk of graft versus host disease (GVHD). While the proposed concept is potentially significant, the reviewers’ enthusiasm was limited by the weaknesses of the proposal. Sufficient evidence that the degree of expansion could be achieved was absent from the proposal, making it difficult to assess the maturity of the project. Moreover, no information on toxicity or toxicology studies is presented. Reviewers were also concerned about the lack of a disease focus as no specific disease target has been identified in the proposal. The PI was viewed as a strength of the application, noting his/her relevant experience in the hematopoietic stem cell field. He/She has worked in the biopharmacetical industry and has participated in developing novel therapies for the treatment of immune disorders and is thus well qualified to lead a multidisciplinary project team. The PI has identified and contacted several consultants and collaborators with expertise in hematopoietic cell transplantation, immunotherapy, hematopoietic cell expansion and differentiation. The planning approach seems reasonable, although the list of collaborators is relatively short, considering the broad range of studies needed. One reviewer expressed concern that the institutional support may be an issue for this potential project, as stem cell biology is not a current focus, and the application states that the institution does not currently have the capacity to run clinical trials. In summary the panel did not recommend this application for funding because of the limited evidence presented of the small molecule’s expansion capability, and the lack of a specific disease target. Reviewer One Comments Concept: PI: Michael Cooke Institution: Genomics Institute (Novartis) Disease Target: HSC expansion for autologous/allogeneic transplantation Concept: High-throughput screen has identified small molecules that appear to regulate self-renewal. Proposal is to develop this compound for clinical applications, one option is to expand cord blood progenitors where clinical utility is currently limited by insufficient cell dose. Strengths: 1. Good group of consultants/subcontractors. Mix of academic and industry 2. Preliminary data suggests a 10-fold increase over 14 days (compared to control, not to starting material?). 3. Novartis institute has a focus on multidisciplinary teams. Weaknesses: 1. No specific disease focus, all situations where HSCT is currently employed would be potential targets 2. Emphasis is on novel compound, not on cells. 3. PI is not a recognized leader in this field. 4. Target cells are not excluded from federal funds. 5. Correlation of HSC dose with engraftment time is minimal (small differences in time with very large differences in dose). 6. No other research support indicated? 7. Minimal details on planning approach. 8. Minimal details on team members roles 9. Stated that stem cells expansion is not a focus of Novartis. a. Stated that they do not have the capacity to run clinical trials. Principal Investigator: PI: Director of Gene Discovery at SyStemix for 5 years Planning Approach: 1. Consultants to travel for one day conference. 2. Biweekly teleconferences 3. Website Reviewer Two Comments Concept: The ability to expand hematopoietic stem cells ex vivo would greatly enhance the efficacy of cord blood transplantation and other HSC transplantation protocols without increasing the risk of GVHD. The investigators have identified a compound that may have this capacity, as it apparently increases the number of CD34 cells ten-fold in culture, increases CAFC numbers 9-fold and in a preliminary study led to increased engrafting ability in a NOD-SCID repopulation assay. These data are not presented, making the actual level of stem cell expansion difficult to assess. No information on toxicity or toxicology studies is presented. Moreover, a disease focus does not seem to have been identified. Thus, while an area of high significance has been identified and the rationale is clear, the compound is quite early in its development. Principal Investigator: Dr. Cooke has strong experience in the hematopoietic stem cell field, having been Director of Gene Discovery at SyStemix from 1994 to 1999. He became familiar with clinical, regulatory and business aspects of bringing HSC-based therapies into the clinic during that period. In 1999, he joined the newly established Genomics Institute of the Novartis Research Foundation, a multidisciplinary research institute where he serves as Director of Immunology. Dr. Cooke’s experience as part of a global project team to develop novel therapies to treat immune disorders and his participation in numerous interdisciplinary teams, several of which have successfully advanced novel therapeutics into clinical testing, positions him well to bring new compounds into clinical trials. Planning Approach: Dr. Cooke has identified and contacted several consultants and collaborators with expertise in hematopoietic cell transplantation, immunotherapy, hematopoietic cell expansion and differentiation. This includes Kenneth Kaushansky, Bruce Torbett, Ram Mandalam, Tom Lane and Ted Ball. Because Novartis does not currently have a stem cell-based therapy business focus, the trials will require a team approach. The team would be assembled by networking with leaders locally and nationally, by email, and teleconferences. An initial face-to-face meeting will be organized and experiments will be outlined, including pharmacology, toxicology, and analytical chemistry and cell biology. Decisions for what institutions can perform each type of study, what licenses will be needed, etc., will be determined. The planning and approach seem reasonable, although the list of collaborators is relatively short, considering the broad range of studies needed.