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The lymphoproliferative disorders represent a large group of diseases with a significant variation in presentation and clinical course. There has been a trend of increasing incidence for some of these disorders, and despite advances in therapies, a significant number of patients either respond poorly or have early relapses. For this reason there is a need to investigate novel therapies to be used either alone or as adjunct treatment in combination with conventional therapies. Gene therapy is a relatively new field that takes advantage of our increased understanding of molecular biology with the aim of treating a variety of diseases including cancer. It is defined as the introduction of genetic material into cells for therapeutic intent. Methods to improve gene delivery efficiency have been the focus of a large amount of research and to date the optimal procedure uses viruses such as oncoretroviruses, lentiviruses, adenoviruses, adeno-associated viruses and herpes simplex viruses. There are four main gene therapy strategies that might be used for the treatment of lymphoproliferative disorders. First, immunotherapy using tumour vaccines or techniques to enhance the function of immune effector cells has been investigated with some success in patients with B-cell malignancies. Second, the introduction of prodrug-activated 'suicide' genes into cells has been explored, in particular in patients with post-transplantation lymphoproliferative disease. Third, direct lysis of tumour cells using viruses shows some early promise, especially in the treatment of B-cell disorders by manipulating the measles virus to target the CD20 antigen. Finally, anti-gene strategies such as anti-sense therapy, ribozymes, and most recently RNA interference, could be used to suppress expression of specific target genes. RNA interference in particular has tremendous potential and has been studied in the context of anaplastic large cell lymphoma as well as Epstein-Barr virus-associated malignancies. Whilst we are still in the early days of this field and to date results have been modest, there is still a significant potential for gene therapy to play a role in the future treatment of these disorders.

Summary In Australia, manufacture of blood, tissues and biologicals must comply with the federal laws and meet the requirements of the Therapeutic Goods Administration (TGA) Manufacturing Principles as outlined in the current Code of Good Manufacturing Practice (cGMP). The Therapeutic Goods Order (TGO) No. 88 was announced concurrently with the new cGMP, as a new standard for therapeutic goods. This order constitutes a minimum standard for human blood, tissues and cellular therapeutic goods aimed at minimising the risk of infectious disease transmission. The order sets out specific requirements relating to donor selection, donor testing and minimisation of infectious disease transmission from collection and manufacture of these products. The Therapeutic Goods Manufacturing Principles Determination No. 1 of 2013 references the human blood and blood components, human tissues and human cellular therapy products 2013 (2013 cGMP). The name change for the 2013 cGMP has allowed a broadening of the scope of products to include human cellular therapy products. It is difficult to directly compare versions of the code as deletion of some clauses has not changed the requirements to be met, as they are found elsewhere amongst the various guidelines provided. Many sections that were specific for blood and blood components are now less prescriptive and apply to a wider range of cellular therapies, but the general overall intent remains the same. Use of ’should’ throughout the document instead of ’must’ allows flexibility for alternative processes, but these systems will still require justification by relevant logical argument and validation data to be acceptable to TGA. The cGMP has seemingly evolved so that specific issues identified at audit over the last decade have now been formalised in the new version. There is a notable risk management approach applied to most areas that refer to process justification and decision making. These requirements commenced on 31 May 2013 and a 12 month transition period applies for implementation by manufacturers. The cGMP and TGO update follows the implementation of the TGA regulatory biologicals framework for cell and tissue based therapies announced in 2011. One implication for licenced TGA facilities is that they must implement the 2013 cGMP, TGO 88 and other relevant TGOs together, as they are intricately linked. This review is intended to assist manufacturers by comparing the 2000 version of the cGMP, to the new 2013 cGMP, noting that the new Code extends to include human cellular therapy products.

Mesenchymal stromal cells (MSCs) are a non-homogeneous population of plastic-adherent cells which were initially isolated from post-natal bone marrow. They have the capacity to differentiate to multiple mesodermal lineages including bone, cartilage and adipose tissue. In stringent culture conditions, MSCs can also be induced to differentiate into different cell types of endoderm and neuroectoderm lineages. To date, no specific marker identifies MSCs, although a number of cell surface antigens have been described which enrich for MSCs. Mesenchymal stromal cells possess a number of properties which have generated considerable interest in diverse cellular therapeutic applications. The capacity of MSCs to differentiate into multiple different cell lineages has seen them actively explored for tissue repair, particularly in cardiac, orthopaedic and neurological applications. A large body of data indicates that MSCs possess immunomodulatory properties. Mesenchymal stromal cells are immunosuppressive, interacting with T lymphocytes, antigen presenting cells, B lymphocytes, and natural killer cells. In addition, they are immunoprivileged, allowing transplantation across allogeneic barriers. These immunomodulatory properties have seen infusion of MSCs for the treatment of steroid refractory graft versus host disease, a life threatening complication of haemopoietic cell transplantation, with promising results. Furthermore, these immune functions may lead to roles in the facilitation of engraftment, induction of tolerance and as therapy in autoimmune disease.