Abstract
Science Wire
Attack of the TCRs
The genetic introduction of T cell receptor (TCR) genes into T cells has been developed over the past decade as a strategy to induce defined antigen-specific T cell immunity against tumors and pathogens. The potential value of this approach has been established in murine models and at least two phase 1 clinical trials. 1,2 Yet, results by Bendle and colleagues now reveal a potential safety issue that may need to be considered in future applications of TCR gene therapy. 3 The researchers show that TCR-modified T cells can shuffle the components of their native and transgenic TCRs and as a result lose their cancer-targeting activity and gain specificity against normal host tissues, producing a lethal variant of graft-versus host disease (GvHD).
In the study by Bendle and colleagues, the authors introduced a transgenic α and β TCR directed against ovalbumin (OVA-TCR) into the T cells of mice and then infused these cells into a mouse model that closely mimicks the clinical setting for patients with cancer (i.e., animals were lymphodepleted by low-dose irradiation). Fourteen days after adoptive transfer of the OVA-TCR transgenic T cells into mice, the authors observed that the mice had developed some of the features of GvHD including bone marrow failure, severe cachexia, lymphopenia, and a high frequency of colitis and pancreatitis. Subsequent analysis revealed that all these pathologies were due to the formation of hybrid receptors with endogenous TCR molecules and that the introduction of even a single α or β OVA-transgenic receptor chain was sufficient to produce the effect. Importantly, the authors demonstrate that this pathology can be limited or prevented through the use of systems in which the pairing of endogenous and exogenous TCR chains is reduced or in which the diversity of the endogenous TCR repertoire of the transduced T cells is highly limited.
To date, this is the first study to show that autoimmune pathology can occur in mouse models of TCR gene therapy under various conditions that promote the in vivo function of TCR-transduced T cells. These effects have not been reported in human studies in which patients are given transgenic cytotoxic T lymphocytes. The authors suggest that the lack of severe autoreactivity in human subjects may be due to a fortunate choice of transgenic TCRs. Alternatively, the authors argue that it may reflect the longer and greater ex vivo expansion of transgenic T cells required for human studies, and that such manipulations reduce subsequent in vivo growth and autoreactivity. (sk)
References
Regulatory Wire
New Healthcare Law Opens Way for Biosimilars
After many failed attempts over the years, the health reform bill signed by President Obama and approved by the U.S. Congress has finally created an approval pathway for generic versions of biologic drugs (biosimilars). Biologic therapies include a wide range of medicinal products such as gene therapy, vaccines, blood and blood components, allergenics, somatic cells, tissues, and recombinant therapeutic proteins created by biological processes (as distinguished from chemistry). Although the European Union has had a regulatory pathway for biosimilars since 2006, the United States, which is considered the world's largest potential market for biosimilars, has not—until now. According to the new law, manufacturers of original biologic drugs will have at least 12 years of market exclusivity. This is unlike generic chemical drugs, which can be approved in as little as 5 years after introduction of the original molecule. Nonetheless, the potential cost-savings of the new biosimilar legislation is expected to be significant. In fact, a study by the Express Scripts Foundation estimated potential 10-year savings of more than $71 billion from just four classes of biologics that are expected to be among the first to have biosimilar competition: interferons for multiple sclerosis, erythropoietins for anemia, growth hormones for growth failure, and insulin for diabetes. 1 (sk)
The major provisions under the new biosimilars legislation include the following: The original biologic drugmaker is granted 12 years of protection before the drug can be subject to competition from biosimilar versions. The biosimilar producer must demonstrate that its drug has no clinically meaningful differences in safety, purity, and potency when compared with the original biologic product. The U.S. Food and Drug Administration (FDA) will determine final standards for approving biosimilars, based on whether the product could be substituted for the original and produce the same clinical result in any given patient, and whether it could be substituted for the original without physician approval.
Reference
Introducing the CAT: Europe's Regulatory Agency for Gene Therapy Products
The main regulatory body overseeing advanced therapy medical products (ATMPs) in Europe is the Committee for Advanced Therapies (CAT). ATMPs are medicinal products for human use, and are based on gene therapy, somatic cell therapy, or tissue engineering. Established in 2007 by the European Medicines Agency (EMA), the CAT fully began its operations in 2009. The organization is composed of a multidisciplinary scientific committee of experts representing all member states of the European Union and countries from the European Economic Area and the European Free Trade Association as well as representatives from patient and medical associations. The CAT's main responsibility is to prepare a draft opinion on each ATMP application submitted to the EMA, before the Committee for Medicinal Products for Human Use (CHMP) adopts a final opinion on the granting, variation, suspension, or revocation of a marketing authorization for the medicine concerned. To be approved by the CAT, the applicant must demonstrate that the ATMP is consistently manufactured to a predefined quality, and that it is safe and efficacious in patients. The CAT has developed extensive guidelines for potential applicants of novel gene therapy products. A recent article by the CAT discusses some of the typical issues raised by developers of ATMPs, and highlights the opportunities available to companies and research groups for working with the EMA and the CAT as regulatory advisors during the development process. 1 (sk)
Reference
Industry Wire
Biotech Industry in Recession Times: Boom … or Bust?
Several recent reports shed light on the complexity of the financial viability of the biotech sector. According to a report by London-based
In parallel,
A third analysis, provided by the