Category: <span>Cell & Gene Therapy</span>

The globalization and sustained growth of the biotechnology market has brought the issue of biological packaging to the fore, particularly for those companies invested in cell and tissue bioproducts, such as engineered tissues and cells used for cell therapy. Biological packaging can be defined as the sum total of the physical device, temperature regulating and monitoring systems, type of preservation solution, and storage protocol(s) necessary to maintain cells or tissues in a “state of suspended animation” during transport or storage. The ideal biological package provides for the transport of cells and tissues throughout the global marketplace while maintaining both the viability and the function of the biological system at levels equivalent to those measured prior to shipment. Cells and tissues are currently shipped and stored under hypothermic (4–8ºC) or cryopreserved (–80 to –196ºC) conditions. These two processes have remained relatively unchanged over the past several decades, limiting their utility in the storage of modern bioproducts. However, recent evolutions in biological packaging have begun to provide scientific and financial benefits to researchers, clinicians, and corporate entities…

Biologics Production Cell & Gene Therapy

More than 70 percent of all prospective gene transfer/gene therapy protocols are designed to treat metastatic cancer. A large number of such protocols involve strategies to attempt cancer immunization via cell-based gene transfer of cytokines or tumor antigens, while others involve the delivery of oncolytic viruses or vectors bearing prodrugs, chemoprotective agents, antisense constructs, or tumor suppressor genes. However, a major unresolved problem that has impeded the progress of cancer gene therapy to the clinic is that of inefficient gene delivery to target cells in vivo. In this regard, the advent of pathotropic targeting launches a new paradigm in cancer gene therapy. By targeting the histopathology of the cancerous lesion — rather than the cancer cells per se — to effectively concentrate the gene vector within primary and metastatic tumors, the safety and efficacy of intravenously administered vector nanoparticles were increased significantly in animal models of cancer. This article describes the development of the pathotropic Targeted Delivery System (TDS) that now serves as the guidance system for “smart” nanoparticles bearing designer killer genes for cancer gene therapy…

Cell & Gene Therapy

The modern era of interest in gene transfer as a methodology for treating disease began around 1985 with the first use and publication of mouse-based retroviruses that could transduce human cells. In fact, the use of gene transfer as a clinically useful method is probably older than any other therapy commonly used today — it forms the basis for the vaccinia vaccination against smallpox, popularized in Western medicine by Jenner. Another antecedent is phage therapy for bacterial infection, which was largely but not completely superseded by antibiotics (although it may make a comeback in this era of drug-resistant pathogenic bacterial strains.) Other examples include the other live viral vaccines: measles/mumps/rubella, polio, varicella, tuberculosis, influenza, the use of bacillus Calmette-Guérin (BCG) as a therapeutic for bladder cancer bone marrow transplants, and even the use of maggots to clean wounds…

Cell & Gene Therapy Viral Vectors

Various types of viral vectors are being employed extensively as gene therapeutics to treat cancer and genetic diseases. Among the viruses that have been produced for human clinical trials (i.e. retrovirus, adenovirus, poxvirus, adeno-associated virus, and herpesvirus vectors) adenoviruses exhibit the lowest pathogenicity yet still infect an extensive range of cell types with high efficiency. These key characteristics make recombinant adenoviruses efficient gene-delivery vehicles and excellent research tools. However, the time-consuming and complex processes of generation, amplification, purification, and quality testing associated with production of recombinant adenoviruses make it difficult for many researchers to utilize these vectors. This is particularly true with respect to cell culture optimization and the virus propagation protocols employed in vector production. In this regard, the development of innovative cell culture techniques has become vital for optimizing vector production for gene therapy…

Biologics Production Cell & Gene Therapy Viral Vectors

The use of virus-based vectors for gene transfer has become an important delivery method for both in vitro applications and in vivo experimental clinical therapies. In small-scale experimental applications, most vectors can easily be concentrated and purified by simple methods (for example, ultracentrifugation.) However, it is challenging to scale up centrifugation-based vector purification methods for the large-scale production required for clinical use. In particular, when considering production of vector for human use, additional steps such as final sterilization by filtration must be taken to ensure the purity and safety of the vector preparation. Because the vector aggregates when pelleted by centrifugation, sterile filtration will eliminate vector particles from the solution. An efficient vector purification process that maintains vector potency is an important step in vector production for gene therapy…

Cell & Gene Therapy Viral Vectors

Conventional medical technologies to address tissue and organ dysfunction have resulted in a host of approaches, largely device-based. Examples include maintenance dialysis for renal dysfunction, use of pacemakers, stents, oxygenators, and valves to neutralize the effects of cardiovascular dysfunction, and replacement of large joints with mechanical substitutes. Advances in transplantation science have led to increasing success in replacing diseased kidneys, livers, hearts, pancreata, and lungs. There are, however, significant and severe limitations to these conventional therapies, most notably the demand by a growing and aging population. There is a well-recognized limitation in the supply of tissues and organs. In the year 2000, for example, 77,000 people were awaiting organ transplants, while only 23,000 were performed. High tech medicine is costly; U.S. healthcare expenditures as a percent of gross domestic product are expected to reach 16.7% by 2007…

Cell & Gene Therapy

On January 31, 2003, FDA under the leadership of Commissioner Dr. Mark McClellan, issued a report entitled “Improving Innovation in Medical Technology: Beyond 2002.” One of the goals described in this report is to “speed potentially important emerging technologies to the market by reducing regulatory uncertainty and increasing the predictability of product development.” The technology areas of cell therapy and gene therapy were specifically identified. This article highlights some of the challenges for manufacturers and regulators of these products and describes ongoing efforts at FDA — as well as opportunities to partner with FDA — to improve the product development process for cell therapy and gene therapy products…

Cell & Gene Therapy Manufacturing Regulatory

A clinical-scale manufacturing process has been developed for the ex vivo expansion of autologous cytolytic T lymphocytes (CTLs) directed against cells infected with the hepatitis B virus (HBV). The process is based on the Rapid Expansion Method (REM) technology originally developed at the Fred Hutchinson Cancer Research Center in Seattle, WA by Greenberg and Riddell. Preparations are underway to initiate a company-sponsored Phase I clinical trial in which REM will be used to expand rare autologous HBV-specific CTLs that will then be infused to patients chronically infected with HBV. Earlier studies have shown that such patients mount only a weak CTL response to HBV. Chronic hepatitis B can lead to severe liver damage such as cirrhosis and hepatocellular carcinoma. By infusing clinical-scale quantities of autologous HBV-specific CTLs into chronic HBV patients, it may be possible to boost the immune system so that it can control the viral infection…

Biologics Production Cell & Gene Therapy Manufacturing

The first HIV-based lentiviral vector to be used in humans, VRX496, is currently being tested in Phase I clinical trials (initiated in January 2003). With each new therapeutic comes the need to establish quality control (QC) testing designed specifically for that product. The QC testing for VRX496 was developed in accordance with the Code of Federal Regulations (CFR) 21 for pharmaceutical and bulk chemical GMPs, Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals (1993) from the Center for Biologics Evaluation and Research (CBER) at FDA, and the United States Pharmacopeia (USP) 1046 for Cell and Gene Therapy Products. This report describes the QC testing of lot VRX496V02-009 of our clinical grade vector, which is being used in an ongoing clinical trial evaluating the first lentiviral gene therapy vector in humans. All assays are performed according to established standard operating procedures (SOPs) and in accordance with the principles of cGMP regulations…

Cell & Gene Therapy Viral Vectors

With the advent of whole cell-based therapeutics has come a growing standardized quality control and quality assurance of the processes employed for developing and manufacturing cellular materials, similar to the controls over traditional drugs and biologicals. Cellular therapeutics present unique process and quality control challenges due to the innate complexities of living cells, making it important to use whole cell assays to provide detailed pictures of the status and consistency of cell preparations that will be used to treat patients. This article illustrates how a cellular assay from Guava Technologies addresses these issues…

Biologics Production Cell & Gene Therapy