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1.
Toxicol Pathol ; 46(2): 131-146, 2018 02.
Article in English | MEDLINE | ID: mdl-29471776

ABSTRACT

Gene-engineered T-cell therapies have the potential to revolutionize the treatment of cancer. These therapies have shown exceptional clinical efficacy specifically in the field of B-cell malignancies and the first products (Kymriah™ and Yescarta™) have recently been approved in the United States for specific indications. The power of these treatments is also linked with a distinct set of toxicities both predicted and unpredicted, including off-tumor activity, cytokine release syndromes, and neurotoxicity, occasionally with fatal consequences. As these therapies begin to reach more patients, it is critical to develop the nonclinical tools to adequately determine the mechanisms driving these toxicities, to assess the safety risks of candidate products, and to develop strategies for safety management.


Subject(s)
Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Neoplasms/therapy , T-Lymphocytes/transplantation , Animals , Humans
2.
Stem Cells Transl Med ; 4(4): 389-400, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25722427

ABSTRACT

The field of stem cell therapeutics is moving ever closer to widespread application in the clinic. However, despite the undoubted potential held by these therapies, the balance between risk and benefit remains difficult to predict. As in any new field, a lack of previous application in man and gaps in the underlying science mean that regulators and investigators continue to look for a balance between minimizing potential risk and ensuring therapies are not needlessly kept from patients. Here, we attempt to identify the important safety issues, assessing the current advances in scientific knowledge and how they may translate to clinical therapeutic strategies in the identification and management of these risks. We also investigate the tools and techniques currently available to researchers during preclinical and clinical development of stem cell products, their utility and limitations, and how these tools may be strategically used in the development of these therapies. We conclude that ensuring safety through cutting-edge science and robust assays, coupled with regular and open discussions between regulators and academic/industrial investigators, is likely to prove the most fruitful route to ensuring the safest possible development of new products.


Subject(s)
Cell- and Tissue-Based Therapy/methods , Pluripotent Stem Cells/transplantation , Stem Cell Transplantation , Stem Cells/cytology , Cell- and Tissue-Based Therapy/adverse effects , Humans , Transplantation, Autologous
3.
Toxicol Appl Pharmacol ; 262(3): 223-31, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22617430

ABSTRACT

Recent breakthroughs in stem cell biology, especially the development of the induced pluripotent stem cell techniques, have generated tremendous enthusiasm and efforts to explore the therapeutic potential of stem cells in regenerative medicine. Stem cell therapies are being considered for the treatment of degenerative diseases, inflammatory conditions, cancer and repair of damaged tissue. The safety of a stem cell therapy depends on many factors including the type of cell therapy, the differentiation status and proliferation capacity of the cells, the route of administration, the intended clinical location, long term survival of the product and/or engraftment, the need for repeated administration, the disease to be treated and the age of the population. Understanding the product profile of the intended therapy is crucial to the development of the nonclinical safety study design.


Subject(s)
Stem Cell Transplantation/methods , Animals , Graft Rejection/immunology , Humans , Mice , Neoplasms/etiology , Patient Safety , Pluripotent Stem Cells/immunology , Stem Cell Transplantation/adverse effects , Stem Cells/immunology , Teratoma/etiology
4.
Microbiology (Reading) ; 145 ( Pt 8): 2135-2144, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10463180

ABSTRACT

Multimer formation is an important cause of instability for many multicopy plasmids. Plasmid CoIE1 is maintained stably because multimers are converted to monomers by Xer-mediated site-specific recombination at the cer site. However, multimer resolution is not the whole story; inactivation of a promoter (Pcer) within cer causes plasmid instability even though recombination is unaffected. The promoter directs the synthesis of a short transcript (Rcd) which is proposed to delay the division of multimer-containing cells. Mapping of the 5' terminus of Rcd confirms that transcription initiates from Pcer. The 3' terminus shows considerable heterogeneity, consistent with a primary transcript of 95 nt being degraded via intermediates of 79 and 70 nt. Secondary structure predictions for Rcd are presented. Of four mutations which abolish Rcd-mediated growth inhibition, one reduces the activity of Pcer while the other three map to the rcd coding sequence and reduce the steady-state level of the transcript. RNA folding analysis suggests that these three mutant transcripts adopt a common secondary structure in which the major stem-loop differs from that of wild-type Rcd. A survey of 24 cer-like multimer resolution sites revealed six which contain Pcer-like sequences. The putative transcripts from these sites have similar predicted secondary structures to Rcd and contain a highly conserved 15 base sequence. To test the hypothesis that Rcd acts as an anti-sense RNA, interacting with its target gene(s) through the 15 nt sequence, we used DNA hybridization and sequence analysis to find matches to this sequence in the Escherichia coli chromosome. Our failure to find plausible anti-sense targets has led to the suggestion that Rcd may interact directly with a protein target.


Subject(s)
Bacteriocin Plasmids , Escherichia coli/genetics , RNA, Antisense/genetics , RNA, Messenger/genetics , Transcription, Genetic , Base Sequence , Blotting, Northern , Cell Cycle/genetics , Chromosome Mapping , Escherichia coli/growth & development , Hydroxylamine/pharmacology , Molecular Sequence Data , Mutagenesis , Nucleic Acid Conformation , Promoter Regions, Genetic , RNA, Antisense/chemistry , RNA, Antisense/metabolism , RNA, Bacterial/chemistry , RNA, Bacterial/genetics , RNA, Bacterial/metabolism , RNA, Messenger/chemistry , RNA, Messenger/metabolism , Transformation, Bacterial
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