Author Correction: At the end of the beginning: immunotherapies as living drugs.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Proceedings: cell therapies for Parkinson's disease from discovery to clinic.

In March 2013, the California Institute for Regenerative Medicine, in collaboration with the NIH Center for Regenerative Medicine, held a 2-day workshop on cell therapies for Parkinson's disease (PD), with the goals of reviewing the state of stem cell research for the treatment of PD and discussing and refining the approach and the appropriate patient populations in which to plan and conduct new clinical trials using stem cell-based therapies for PD. Workshop participants identified priorities for research, development, and funding; discussed existing resources and initiatives; and outlined a path to the clinic for a stem cell-based therapy for PD. A consensus emerged among participants that the development of cell replacement therapies for PD using stem cell-derived products could potentially offer substantial benefits to patients. As with all stem cell-based therapeutic approaches, however, there are many issues yet to be resolved regarding the safety, efficacy, and methodology of transplanting cell therapies into patients. Workshop participants agreed that designing an effective stem cell-based therapy for PD will require further research and development in several key areas. This paper summarizes the meeting.

Proceedings: international regulatory considerations on development pathways for cell therapies.

Regenerative medicine is a rapidly evolving field that faces novel scientific and regulatory challenges. In September 2013, the International Workshop on Regulatory Pathways for Cell Therapies was convened to discuss the nature of these challenges and potential solutions and to highlight opportunities for potential convergence between different regulatory bodies that might assist the field's development. The workshop discussions generated potentially actionable steps in five main areas that could mitigate cell therapy development pathway risk and accelerate moving promising therapies to patients. These included the need for convergence of regulatory guidelines on donor eligibility and suitability of lines for use in clinical trials and subsequent commercialization for cell therapies to move forward on a global basis; the need to challenge and encourage investigators in the regenerative medicine field to share information and provide examples of comparability studies related to master cell banks; the need for convergence of guidelines across regulatory jurisdictions on requirements for tumorigenicity studies, based on particular cell types and on biodistribution studies; the need to increase transparency in sharing clinical trial information more broadly and disseminating results more rapidly; and the need to establish a forum for sharing the experiences of various approaches being developed to expedite regulatory approvals and access for patients to innovative cell and regenerative therapies in the different regulatory jurisdictions and to assess their potential strengths and weaknesses.

The potential for immunogenicity of autologous induced pluripotent stem cell-derived therapies.

Induced pluripotent stem cell (iPSC) technology offers the promise of immune-matched cell therapies for a wide range of diseases and injuries. It is generally assumed that cells derived from autologous iPSCs will be immune-privileged. However, there are reasons to question this assumption, including recent studies that have tested iPSC immunogenicity in various ways with conflicting results. Understanding the risk of an immune response and developing strategies to minimize it will be important steps before clinical testing. Here, we review the evidence for autologous iPSC immunogenicity, its potential causes, and approaches for assessment and mitigation.

The Alpha Stem Cell Clinic: a model for evaluating and delivering stem cell-based therapies.

Cellular therapies require the careful preparation, expansion, characterization, and delivery of cells in a clinical environment. There are major challenges associated with the delivery of cell therapies and high costs that will limit the companies available to fully evaluate their merit in clinical trials, and will handicap their application at the present financial environment. Cells will be manufactured in good manufacturing practice or near-equivalent facilities with prerequisite safety practices in place, and cell delivery systems will be specialized and require well-trained medical and nursing staff, technicians or nurses trained to handle cells once delivered, patient counselors, as well as statisticians and database managers who will oversee the monitoring of patients in relatively long-term follow-up studies. The model proposed for Alpha Stem Cell Clinics will initially use the capacities and infrastructure that exist in the most advanced tertiary medical clinics for delivery of established bone marrow stem cell therapies. As the research evolves, they will incorporate improved procedures and cell preparations. This model enables commercialization of medical devices, reagents, and other products required for cell therapies. A carefully constructed cell therapy clinical infrastructure with the requisite scientific, technical, and medical expertise and operational efficiencies will have the capabilities to address three fundamental and critical functions: 1) fostering clinical trials; 2) evaluating and establishing safe and effective therapies, and 3) developing and maintaining the delivery of therapies approved by the Food and Drug Administration, or other regulatory agencies.

Perspective: communications with the Food and Drug Administration on the development pathway for a cell-based therapy: why, what, when, and how?

Effective interaction between key stakeholders and the U.S. Food and Drug Administration (FDA) is central to successfully navigating the regulatory process and advancing new therapies into clinical trials. This is especially true when developing cell-based therapies, which pose unique challenges to demonstrating safety and effectiveness. There are numerous opportunities for developers of a new cell therapy to interact with the regulatory agency, through both formal and informal processes. It is important to understand how to maximize the productivity of dialogue with the FDA and develop an effective regulatory strategy. This article provides an overview of the types of interactions with the FDA that are available throughout the regulatory process. This article also notes some common pitfalls to avoid and directs readers to additional references and resources to help inform cell therapy researchers and product developers and enable successful regulatory interactions.

Translation of stem cell research: points to consider in designing preclinical animal studies.

Stem cell-based therapies hold tremendous promise for the treatment of serious diseases and injuries. Although hematopoietic stem cell transplantation is routinely used as part of the treatment regime for some malignancies and genetic diseases, most stem cell-based therapeutic products are investigational and still require preclinical and clinical studies to support their many novel therapeutic uses. Because of the multiple sources of stem cells, the plethora of potential applications, and the novel mechanism of action of stem cell-based therapies, there is no single set of universal guidance documents that can be used to inform the preclinical development path for these therapeutics. Specific technical issues relating to the transplantation of human cells in animals, new delivery procedures, and laborious methods to characterize transplanted cells can present further challenges in the design and execution of preclinical animal studies for stem cell-based therapeutic products. In this article, we outline important parameters to guide the design of preclinical studies for stem cell-based therapeutics. In addition, we review the types of preclinical studies that should be considered depending on the nature and specific use of the intended stem cell therapeutic product. Finally, we describe important considerations in the design and execution of specific studies to monitor the efficacy, toxicity, biodistribution, and tumorigenicity of stem cell-based therapeutics.

Oncogenomics 2005 meeting report: dissecting cancer through genome research.

The Oncogenomics Conference was held on February 2 to 5, 2005 at the Omni San Diego Hotel, San Diego, CA. The meeting chairpersons were Dr. Jeffrey Trent (Translational Genomics Research Institute, Phoenix, AZ) and Dr. Nicholas Dracopoli (Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ). This fourth conference sponsored by the AACR brought together a diverse group of scientists working in the fields of genome research, cancer biology, and epidemiology, and explored how genomic research can be used most effectively to impact the clinical response to cancer. Advances in the clinical application of pharmacogenomics to predict response to oncology therapeutic modalities led to a dramatic increase in the number of presentations and posters with a clinical focus at this year's meeting. The keynote address was given by Dr. William Evans (St. Jude Children's Hospital, Memphis, TN) who discussed the pharmacogenomics of acute lymphoblastic leukemia as a cancer paradigm.

Capacity building for the clinical investigation of AIDS malignancy in East Africa.

PURPOSE: To build capacity in the resource-poor setting to support the clinical investigation and treatment of AIDS-related malignancies in a region of the world hardest hit by the AIDS pandemic. METHODS: An initial MEDLINE database search for international collaborative partnerships dedicated to AIDS malignancies in developing countries failed to identify any leads. This search prompted us to report progress on our collaboration in this aspect of the epidemic. Building on the formal Uganda-Case Western Reserve University (Case) Research Collaboration dating back to 1987, established NIH-supported centers of research excellence at Case, and expanding activities in Kenya, scientific and training initiatives, research capital amongst our institutions are emerging to sustain a international research enterprise focused on AIDS and other viral-related malignancies. RESULTS: A platform of clinical research trials with pragmatic design has been developed to further enhance clinical care and sustain training initiatives with partners in East Africa and the United States. An oral chemotherapy feasibility trial in AIDS lymphoma is near completion; a second lymphoma trial of byrostatin and vincristine is anticipated and a feasibility trial of indinavir for endemic Kaposi's sarcoma is planned. CONCLUSIONS: In the absence of published reports of evolving international partnerships dedicated to AIDS malignancy in resource constrained settings, we feel it important for such progress on similar or related international collaborative pursuits to be published. The success of this effort is realized by the long-term international commitment of the collaborating investigators and institutions to sustain this effort in keeping with ethical and NIH standards for the conduct of research; the provision of formal training of investigators and research personnel on clinical problems our East African partners are faced with in practice and the development of pragmatic clinical trials and therapeutic intervention to facilitate technology transfer and enhance clinical practice.

Annual report to the nation on the status of cancer, 1973-1999, featuring implications of age and aging on U.S. cancer burden.

BACKGROUND: The American Cancer Society, the National Cancer Institute, the North American Association of Central Cancer Registries (NAACCR), the National Institute on Aging (NIA), and the Centers for Disease Control and Prevention, including the National Center for Health Statistics (NCHS) and the National Center for Chronic Disease Prevention and Health Promotion, collaborated to provide an annual update on cancer occurrence and trends in the United States. This year's report contained a special feature focusing on implications of age and aging on the U.S. cancer burden. METHODS: For 1995 through 1999, age-specific rates and age-adjusted rates were calculated for the major cancers using incidence data from the Surveillance, Epidemiology, and End Results Program, the National Program of Cancer Registries, and the NAACCR, and mortality data from NCHS. Joinpoint analysis, a model of joined line segments, was used to examine 1973-1999 trends in incidence and death rates by age for the four most common cancers. Deaths were classified using the eighth, ninth, and tenth revisions of the International Classification of Diseases. Age-adjusted incidence and death rates were standardized to the year 2000 population, which places more emphasis on older persons, in whom cancer rates are higher. RESULTS: Across all ages, overall cancer death rates decreased in men and women from 1993 through 1999, while cancer incidence rates stabilized from 1995 through 1999. Age-specific trends varied by site, sex, and race. For example, breast cancer incidence rates increased in women aged 50-64 years, whereas breast cancer death rates decreased in each age group. However, a major determinant of the future cancer burden is the demographic phenomenon of the aging and increasing size of the U.S. population. The total number of cancer cases can be expected to double by 2050 if current incidence rates remain stable. CONCLUSIONS: Despite the continuing decrease in cancer death rates and stabilization of cancer incidence rates, the overall growth and aging of the U.S. population can be expected to increase the burden of cancer in our nation.