Human Lymphangiogenic Endothelial Cells Derived from Pluripotent Stem Cells with Matrix or Scaffold as Curative Therapy for Secondary Lymphedema Complications of Breast, Gynecological and Other Cancer Treatment
Early Translational IV
$5 069 206
Acquired or secondary lymphedema, the chronic and progressive swelling of an extremity due to trauma to the lymphatic vascular system, is a frequent complication of treatment for cancer. Although most well-documented for breast cancer, with incidence rates of 4% to 70% (depending on methods of assessment and length of follow-up), studies have also reported rates of 20% for gynecologic and 10% for genitourinary cancers and 16% for melanoma. Lymphedema has been called “one of the most dreaded sequelae of breast cancer treatment” due to cosmetic deformity, limited mobility, chronic inflammation, pain and fatigue, lifelong attention to symptom alleviation, and increased medical cost burdens. Currently, there is no advanced pharmacologically-based treatment, and this disorder is known to exact a psychosocial toll that negatively impacts quality of life and survivorship. We will address this huge unmet medical need by producing a novel therapeutic to restore normal lymphatic vessel function in lymphedema patients. Our target product will consist of highly purified pro-lymphatic endothelial cells (cells forming lymphatic vessels) derived from pluripotent stem cells by a process we can already make substantially compatible with FDA guidelines and scale up to anticipated clinical dose levels. This will be combined with a proprietary hydrogel matrix (already under development in clinical-grade form) that can be safely implanted under the skin by physicians after lymphedema onset.
Statement of Benefit to California:
According to a recent report by the American Cancer Society in collaboration with the National Cancer Institute (NCI), along with recent statistics of NCI’s Surveillance, Epidemiology, and End Results (SEER) Program, a continuing overall decline in cancer mortality rates over past decades has led to an estimated 13.7 million cancer survivors in the U.S. as of mid-2012, with almost 18 million survivors projected by 2022. Female breast cancer survivors alone currently account for around 22% of this total, and with roughly 12% of the U.S. population, California harbors a large and growing number of survivors. Preserving an adequate quality of life after cancer treatment and managing healthcare costs related to treatment complications will have increasingly important implications for our state’s healthcare infrastructure and economy. Acquired lymphedema is a chronic, progressive, presently incurable, psychosocially debilitating complication of cancer treatment that negatively impacts both survivorship and healthcare costs. We are attempting to develop a therapeutic candidate able to effect regenerative repair of lymphatic vessels damaged by cancer treatment that resulted in lymphedema. This will consist of specialized endothelial cells that we derive from stem cells and combine with a proprietary hydrogel matrix that can be safely implanted under the skin any time after the onset of lymphedema. This could have beneficial impacts in an area of major unmet medical need.
The objective of this Development Candidate (DC) award proposal is to use a stem cell based approach to treat lymphedema, which is chronic and progressive swelling of an extremity. Lymphedema is caused by trauma to the lymphatic system and is a common complication of cancer treatment. The objective of this proposal is to differentiate lymphatic vessel-forming cells from pluripotent stem cells and combine them with a biocompatible hydrogel matrix that will be injected to help repair lymphatic vessels to treat lymphedema. Objective and Milestones - Although the proposed milestones proposed were considered appropriate, reviewers questioned the ability of the applicant to complete all proposed studies within the award period. - The applicant did not clearly define decision points or the go/no-go decisions in the research plan. - The Target Product Profile lacked detail, particularly with respect to the proposed function of the therapeutic cells and the target dose. Rationale and Significance - Although the rationale to use lymphatic cells for the formation of vascular structures is good, there is little evidence that the cells will be functional in the intended disease settings. - The project does address an unmet medical need. A therapy that can help promote lymphatic vessel growth would have significant clinical benefit if successful. Feasibility and Design - The proposed animal models of lymphedema are not representative of the human post-mastectomy setting. Reviewers were not clear as to how proof of concept of reduction of lymphedema could be shown. - The timeline for the proposed studies was viewed as unrealistic. - Preliminary data were not compelling. They did not clearly demonstrate that the cells behaved as the desired lymphatic endothelial cells, and convincing in vivo data were not provided. -No information was provided about what doses would be tested and how that might relate to clinical translation. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - PI and collaborators have appropriate experience and expertise. - An appropriate multidisciplinary team has been assembled. The team is well versed in cell production and characterization, but the proposed studies raised serious concern about the level of understanding of the primary disease that the applicants are proposing to treat. Collaborations, Assets, Resources and Environment -Assets, facilities, and resources appear to be adequate to conduct the proposed studies. Responsiveness to the RFA - The project is responsiveness to the RFA in that it uses human stem cells to develop a treatment for an unmet medical need.