Immunological memory, as provided by antibodies, depends on the continued presence of antibody-secreting cells, such as long-lived plasma cells of the bone marrow. Survival niches for these memory plasma cells are limited in number. In an established immune system, acquisition of new plasma cells, generated in response to recent pathogenic challenges, requires elimination of old memory plasma cells. Here, we review the adaptation of plasma cell memory to new pathogens...

Broadly neutralizing anti-HIV antibodies are rare and have proved hard to elicit with any immunogen. We have tested in vitro the notion that such antibodies or other antiviral proteins could be made by lentivirus-mediated gene transfer into human hematopoietic stem/progenitor cells (HSPCs), followed by differentiation of the transduced cells into B cells, the most potent antibody-producing cells...

Investigational therapy can be successfully undertaken using viral- and nonviralmediated ex vivo gene transfer. Indeed, recent clinical trials have established the potential for genetically modified T cells to improve and restore health. Recently, the Sleeping Beauty (SB) transposon/transposase system has been applied in clinical trials to stably insert a chimeric antigen receptor (CAR) to redirect T-cell specificity...

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10 years. MPS I results from defi- ciency of α-L-iduronidase (IDUA) in lysosomes and subsequent accumulation of glycosaminoglycans (GAG). Clinical enzyme replacement therapy (ERT) with intravenous laronidase reverses some aspects of MPS I disease...

Allogeneic bone marrow transplantation is the most effective treatment for Hurler syndrome but, since this therapy is not available to all patients, we have considered an alternative approach based on transfer and expression of the normal gene in autologous bone marrow. A retroviral vector carrying the full-length cDNA for a-L-iduronidase has been constructed and used to transduce bone marrow from patients with this disorder...

Adoptive transfer of T cells expressing a CD19-specific chimeric antigen receptor (CAR) is being evaluated in multiple clinical trials. Our current approach to adoptive immunotherapy is based on a second generation CAR (designated CD19RCD28) that signals through a CD28 and CD3-f endodomain. T cells are electroporated with DNA plasmids from the Sleeping Beauty (SB) transposon/transposase system to express this CAR...

T cells can be reprogrammed to redirect specificity to tumor-associated antigens (TAAs) through the enforced expression of chimeric antigen receptors (CARs). The prototypical CAR is a single-chain molecule that docks with TAA expressed on the cell surface and, in contrast to the T-cell receptor complex, recognizes target cells independent of human leukocyte antigen...

Antigen-specific serum antibodies are protective for long periods of time. These serum antibodies, the “humoral memory”, are secreted by plasma cells derived from activated, antigen-specific B lymphocytes. Given their crucial role in immunity, surprisingly little is known about the biology of plasma cells. One of the fundamental questions is whether persisting protective serum antibody responses are maintained by long-lived plasma cells, or by short-lived plasma cells generated continuously from activated memory B cells...

Background—The Sleeping Beauty (SB) transposon system is a non-viral vector system that can integrate precise sequences into chromosomes. We evaluated the SB transposon system as a tool for gene therapy of mucopolysaccharidosis (MPS) types I and VII...

Recently the Sleeping Beauty (SB) transposon/transposase system has been applied in clinical trials to redirect T-cell specificity through the addition of a transgenic cassette that drives expression of a chimeric antigen receptor (CAR). We have focused on issues relating to insertional mutagenesis in the context of the plasticity of human genomes, the unexpected variability in human genomes elucidated by recent high-throughput, wholegenome sequencing projects of hundreds of individuals and cells therein, and the recently discovered high rates of remobilization of endogenous transposable elements...

In the 21st century, we can expect a revolution in the delivery of therapeutics. We can expect genetic medicines that will confer permanent solutions to chronic and acute ailments. How these genetic medicines will be delivered and controlled, without adverse side effects, are the pressing issues facing modern medicine. Gene therapy theoretically represents the best form of treatment for some medical disorders because natural biological products rather than chemicals are employed for their natural function...

Antibodies continuously secreted by plasma cells play a central role in humoral immune protection of the organism. These plasma cells are generated during the germinal center reaction, and it is likely that they here acquire the potential to develop into long-lived cells. To achieve longevity, these cells require factors provided by the microenvironment...