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European Biopharmaceutical Review

Advancing Xenogeneic Therapy

Although xenotransplantation has disadvantages and safety concerns specific to the product class, the availability of organs, tissues and cells from animals remains a significant advantage to the technology. As a result, there is continuing interest in xenogeneic cellular therapy, with a number of products in development – including porcine pancreatic islets and a bioartificial liver using porcine hepatocytes (1,2).

Many development issues to be addressed for xenogeneic cellular therapies are similar to those for other cellular therapies – for example, biodistribution and persistence, formation of ectopic tissue, and so on. Others, such as immune rejection and inter-species retroviral transfer, are more pronounced or specific to xenogeneic cells.

Non-Clinical Safety Assessment

In addition to the confirmation that transplanted cells remain functional following implantation, there are certain areas that should be addressed in a non-clinical safety assessment programme for a xenogeneic cell product.

Guidance documents specific to xenogeneic therapies are available in Europe and the US. A single species is usually sufficient for non-clinical toxicology testing of xenogeneic therapeutics where the transplantation procedure and/or device combination requires the use of a large animal species.

Toxicity testing can often be combined with efficacy end-points by conducting the study in spontaneous, non-spontaneous or transgenic animal models of disease – for example, testing porcine islet xenotransplantation in non-human primates, or dogs rendered diabetic by total pancreatectomy (3,4).

Issues to Evaluate

Toxicology studies should assess both local and systemic toxicity at several dose levels, and examine the time of onset and reversibility of effects. Therefore, while it is possible to include other end-points – such as tumorigenicity or biodistribution – in the toxicity study, the complexity of the research and animal numbers often require separate biodistribution studies.

Assessment of adverse pharmacological effects on critical organ systems should be considered on a case-by-case basis and is dependent on the characteristics of the cell product, site of implantation, and so on. Where required, assessments are often included as part of the toxicology study.

The evaluation of potential immune rejection should include assessment of inflammatory cell infiltration, necrosis of implanted cellular material and fibrotic overgrowth at the site of implantation by histopathology. Alteration in the number or function of immune cells in other compartments such as blood can be evaluated by routine haematology assessment, flow cytometry or immunophenotyping, and in lymph nodes local to the site of implant using histopathology.

In addition to the pathological and haematological assessment, it is important to assess the integrity, function and durability of any barrier or other encapsulation method used to protect the xenogeneic cells from the host immune system. This typically involves both a histopathological assessment of the barrier itself and a functional assessment of the cellular product as an indication of barrier integrity. Lastly, the possibility of acute or chronic graft versus host disease (GvHD) – as manifested in damage to the liver, skin mucosa, gastrointestinal tract, haematopoietic system, and so on – should be assessed in the toxicology study.

Immunosuppression


Although immunosuppression regimes are sometimes used clinically with xenogeneic cell products, their use in preclinical studies is not recommended. This is because of the toxicity associated with immunosuppressive drugs and the difficulty in establishing whether other effects, such as increased rate of infections, are due to the xenogeneic product or the immunosuppression regime.

Many xenogeneic products now employ a barrier system to protect the implanted cells from host immune-mediated rejection, although this is not always possible. When immunosuppressive drugs are used, care should be taken to separate toxicity elicited by the immunosuppressive drugs and toxicity due to the transplanted cell product, by including a group treated with the immunosuppressive drugs alone.

Consideration should be given to both host and source species metabolism of the immunosuppressive drugs used, as small differences in metabolism and pharmacokinetics may significantly affect their activity and/or toxicity. Dose levels of immunosuppressive drugs should be selected carefully due to the potential for toxicity and also because immunosuppressive treatment may be permissive to GvHD.

Viral Infection Risk


One of the safety issues of particular concern to xenogeneic products is the possibility of cross-species infectious agent transfer from donor animal cells to the recipient. Addressing possible viral transfer starts with sourcing of animals; quarantine and isolation procedures; animal husbandry; and production and quality control methods. Donor animals should be screened for a wide range of potential viral infections of the source species, including endogenous retroviruses, zoonotic agents that are transmissible to humans – as well as those not normally considered zoonotic – transmissible spongiform encephalopathy diseases, infectious agents with high-mutation rates, antibiotic-resistant bacteria, and known infectious agents of humans.

Non-clinical safety assessment related to infectious agent transfer should be modified based on the source animal species and the manner in which the xenogeneic cell-based product will be used clinically. The primary aim of safety assessment is typically testing for endogenous retroviral transfer. In vitro assessment of viral mobilisation is followed by in vivo assessment if required, typically by quantitative reverse transcriptase polymerase chain reaction (RT qPCR) assessment of viral RNA in blood and tissues.

Cell Migration


Cells from implanted xenogeneic cell products may migrate within the host, presenting clinical concerns regarding adverse reactions from displaced, bioactive cells or unexpected anatomical impediments. This is likely to be the case where cells are incompletely differentiated, so it is important to consider not only the cells intended for transplantation, but also other cell types that may inadvertently be transplanted with the intended cell population. Evaluation is often performed in a standalone study due to the number of animals required to assess multiple time-points. Assessment of cell fate, biodistribution and persistence is determined by methods such as immunohistopathology, flow cytometry or RT qPCR.

Xenogeneic cell products usually include fully differentiated cells, which makes the likelihood of tumorigenicity significantly lower than for stem cellbased products. However, there is still a risk of increased tumour incidence associated with some xenogeneic cell products due to endogenous viruses, significant ex vivo manipulations and altered cell growth regulation after transplantation, and so on.

The requirement for tumorigenicity assessment should be considered on a case-by-case basis, but must be addressed prior to first-in-human studies. Where there is a significant risk, consideration should be given to evaluation of tumorigenicity both in vivo and in vitro. In vivo assessment, where needed, should be conducted in well-designed, robust Good Laboratory Practice studies. It may be possible to include tumorigenicity end-points in other in vivo studies with careful study design and planning.

Clinical Safety Assessment

A small number of clinical studies with xenogeneic cell therapies for the treatment of diseases such as diabetes and severe liver failure have been completed recently, with recent announcements of trials in Parkinson’s patients (5,6).

Patient populations eligible for inclusion into such studies are restricted to those with serious or life-threatening diseases for whom adequate safety and effective alternative therapies are not available, and where there is a potential for a clinically signifi cant benefi t. The advancement in such studies has identifi ed many challenges in terms of clinical safety assessment and regulatory requirements, which are often retrospective to the treatment.

Leading the Way

Xenogeneic cellular therapies offer some advantages to other cellular therapies, but possess a number of potential safety issues that need to be addressed to ensure safe development.

A growing body of work now exists on the non-clinical testing strategies for xenogeneic products, and these studies have enabled the safe progression of early products from animal models into clinical studies where they are showing promise in the treatment of various diseases. As the technology and understanding of how to mitigate risks develops, it seems likely that other products will follow these fi rst products into clinical trials.

References

1. Ekser B et al, Comparison of hematologic, biochemical, and coagulation parameters in α1,3- galactosyltransferase gene-knockoutpigs, wild-type pigs, and four primate species, Xenotransplantation 19(6): pp342-354, 2012
2. Lee S-W, Wang X, Chowdhury NR and Roy-Chowdhury J, Hepatocyte transplantation: State of the art and strategies for overcoming existing hurdles, Annals of Hepatology 3(2): pp48-53, 2004
3. Cardona K et al, Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways, Nat Med 12(3): pp304-346, 2006 4. Edamura K et al, Xenotransplantation of porcine pancreatic endocrine cells to total pancreatectomized dogs, Journal of Veterinary Medical Science 65(5): pp549-556, 2003
5. Elliot RB et al, Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation, Xenotransplantation 14: pp157-161, 2007
6. Van De Kerkhove MP et al, Phase I clinical trial with the AMC-bioartifi cial liver, The International Journal of Artifi cial Organs 25(10): pp950-959, 2002

Other Reading


Bruin JE et al, Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice, Diabetologia 56(9): pp1,987-1,998, 2013

Morsiani E et al, Long-term insulin independence following repeated islet transplantation in totally pancreatectomized diabetic pigs, Cell Transplant 11(1): pp55-66, 2002

Tartour E et al, Phase I clinical trial with IL-2- transfected xenogeneic cells administered in subcutaneous metastatic tumours: clinical and immunological fi ndings, Br J Cancer 83(11): pp1,454-1,461, 2000


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Peter Gaskin is a Senior Regulatory Toxicology Consultant at PPD, providing strategic, technical and regulatory support for clients. He has experience developing non-clinical strategy, protocol design and regulatory submissions for cellular therapeutic products, and has worked in multiple therapeutic areas supporting programmes from early discovery to post-marketing. Peter holds a PhD in Toxicology and a BSc in Biochemistry, and is a UK- and European-registered Toxicologist. He is a member of The Organisation for Professionals in Regulatory Affairs and a member of a collaborative group within PPD working on the development/ regulatory landscape of advanced therapies.

Kathryn Parsley is Regulatory Affairs Associate Manager at PPD, leading global Phase 1-4 clinical studies involving chemical, biological and advanced-therapy medicinal products. Prior to joining PPD, she worked as a clinical scientist in the R&D, translation, manufacture and management of geneand cell-based Phase 1/2 clinical trials at the Institute of Child Health and Great Ormond Street Hospital NHS Trust, UK. Kathryn holds a PhD in Molecular Biology and an MPhil in Microbiology/ Immunology. She is also a member of a collaborative group within PPD working on the development/regulatory landscape of advanced therapies.
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