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PubMed2000

Monoclonal antibodies targeting cancer: 'magic bullets' or just the trigger?

The first monoclonal antibodies (mAbs) approved for cancer therapy are now in Phase II and III trials, but the critical mechanism(s) determining efficacy and response in patients are still largely undefined. Both the direct antigen-binding (Fab) and constant (Fc) regions of mAbs can contribute to their biological activity. However, Clynes et al (Nat Med 2000, 6:443) recently suggested that the latter (at least in experimental models) might be the dominant component in vivo, triggering host responses to destroy cancer cells. Those workers showed that in mice lacking 'activation' Fc receptors (Fc(gamma)RI and Fc(gamma)RIII), anti-tumour effects of certain mAbs were significantly reduced. In contrast, mice deficient in the 'inhibitory' receptor Fc(gamma)RIIB responded with tumour growth inhibition and enhanced antibody-dependent cellular cytotoxicity (ADCC). These observations suggest that mAbs might be engineered for preferential binding to Fc(gamma)RIII to maximise therapeutic benefit. However, further work is needed to establish a definitive cause-effect relationship in experimental models that are more clinically relevant, to determine whether human Fc(gamma)R isoforms behave in a similar fashion, and to confirm that therapeutic mAbs and host cells can adequately access solid tumour deposits to mediate effective ADCC in situ. Finally, the 'cost-benefit' ratio of such modified macromolecules will need to be measured against mini-mAb constructs, antisense oligonucleotides, peptidomimetics and emerging drugs capable of inhibiting key tumour cell signalling pathways.

Animals↗
PubMed2026

Cancer Immunotherapy: Therapeutic Limitations and Next-Generation Precision Strategies.

Cancer immunotherapy has reshaped oncology, largely through immune checkpoint inhibitors that release the brakes on tumor-reactive T cells. Yet the benefit remains uneven, and that unevenness traces back to a few basic biological limits. Checkpoint blockade amplifies immunity that is already present; it does not create tumor specificity de novo. Poor Ag quality, defective Ag presentation, a suppressive microenvironment, and epigenetically fixed T-cell exhaustion together set a ceiling on what checkpoint release can achieve. Next-generation strategies try to move past these limits by reorganizing immunotherapy around the functional layers of the immune response. Cancer vaccines define tumor-specific neoantigens and expand the responses against them. Ab-based approaches tune inhibitory signaling, draw immune cells toward the tumor, and trigger immunogenic cell death. Cellular therapies-chimeric Ag receptor T cell, TCR-engineered T cells, and tumor-infiltrating lymphocytes (TILs)-boost effector potency, with TIL therapy notable for preserving tumor-reactive repertoires shaped in vivo. Rather than rivals, these modalities are best seen as complementary layers-Ag definition, immune priming, effector optimization, and microenvironmental conditioning-to be combined in a programmable way. As genomic profiling, immunopeptidomics, and high-dimensional immune monitoring mature, the field is shifting from checkpoint-centered release toward precision immunoengineering, in which tumor-specific immunity is deliberately designed, aligned, and sustained.

Cancer vaccines↗
PubMed1999

[Is there an alternative to the amaril 17D vaccine?].

The live attenuated yellow fever vaccine 17D was found as early as 1936 by M. Theiler of the Rockfeller Foundation. This strain of yellow fever is still the only one used today. The experience acquired with this vaccine has led to various changes in its composition: use of the seed lot system (in 1941) following the accidents observed in Brazil; elimination of human plasma as stabilising agent because of hepatitis B transmission (1942); preparation of a vaccine free of avian leukemia; perfection of a thermostable vaccine (1984). These various successive improvements resulted in one of the most effective vaccines. Over the past years, different ways of improving the vaccine have been envisaged: change of cellular substrate, purifications, development of a new vaccine through genetical engineering. We will review these different approaches in order to gauge their advantages and drawbacks both from a legislative and pharmaceutical point of view. It has been recently suggested that an infected cDNA clone from the 17D strain be used as a yellow fever vaccine or as a gene-vector for other flaviviruses. This most promising approach raises questions, notably ones of security and legislation which we will discuss.

Animals↗
PubMed1999

The application of ribozymes to HIV infection.

During the past decade major advances have been made in combating HIV infection and reducing the incidence of AIDS in the western world. Despite optimism about such progress, there is accumulating evidence to suggest that new forms of therapy may be necessary to combat viral resistance to current drugs as well as to provide alternatives to life-long drug use. Genetic forms of therapy are considered to be an important alternative to current drug therapy. One therapeutic agent that can be tailored to inhibit viral infection is catalytic RNA or ribozymes. These RNAs can be engineered to site-specifically cleave targeted RNAs, thereby minimizing cellular toxicity associated with conventional drugs. A potential advantage of ribozymes over other forms of genetic therapy aside from target specificity is their potential for interfering with different stages of the viral life cycle. Ribozymes can be designed and expressed to interfere with viral entry, messenger RNA function and viral packaging. For the two simplest ribozyme motifs, the hammerhead and hairpin, there are hundreds of potential sites along the viral genome. Combinatorial use of ribozymes allows multiple HIV-1 sequences to be attacked simultaneously, thereby circumventing viral resistance through mutation. Ribozymes can also be designed to inhibit expression of cellular targets, which are required for HIV-1 infection. The successful applications of ribozymes against HIV-1 in preclinical settings has now set the stage for their testing in patient trials and several first phase clinical trials are currently underway.

Animals↗
PubMed1990

The use of lacZ gene fusions in the studies of mammalian development: developmental regulation of mammalian homeobox genes in the CNS.

1. Mammalian cells can produce bacterial beta-galactosidase when they carry the lacZ gene under the control of mammalian regulatory elements. The single cell resolution of the beta-galactosidase histochemical detection method makes this molecule an excellent marker in studies of development at the cellular and molecular level. Different lacZ fusion genes can be engineered to study the histological diversification of cell lineages, the developmental regulation of isolated genes, or to recognize and clone genes with new expression profile. 2. Transgenic mice carrying lacZ gene fusions provide information on the cell type, developmental stage and spatial specificity of cis-acting regulatory regions linked to a mammalian homeobox gene. We describe our strategy for designing the gene fusions. 3. The scord region of the Hox 1.3 gene is sufficient to determine spatially restricted expression of a heterologous protein in the midgestational spinal cord. We propose to use this region to alter the expression pattern of other homeobox gene products. Developmental alterations due to a variant expression pattern would point to the function of the misexpressed gene.

Animals↗
PubMed1997

Herpes simplex virus vectors for gene transfer to the nervous system.

Herpes simplex virus (HSV) represents a candidate gene transfer vector for the treatment of nervous system disease. It has many natural biological features which make it attractive for gene delivery to a variety of tissues. The virus naturally establishes a latency in sensory neurons of the peripheral nervous system, wherein the virus in maintained as an extrachromosomal DNA element in the absence of viral lytic gene expression without altering the metabolism of the host neuron. The virus possesses a neuronal latency-specific promoter system which remains active long-term, while other viral and cellular promoters are repressed. Replication defective virus recombinants have been engineered to delete multiple essential immediate early gene functions rendering these new mutants significantly less cytotoxic to neurons and other cells in culture. Further developments in regulating transgene expression and reducing virus toxicity will continue to aid the design and use of these vectors for therapeutic applications for the nervous system.

Animals↗
PubMed2000

Cytokine delivery and tissue engineering.

Tissue engineering has been applied to various tissues, and particularly significant progress has been made in the areas of skin, cartilage, and bone regeneration. Inclusion of bioactive factors into the synthetic scaffolds has been suggested as one of the possible tissue engineering strategies. The growth factors are polypeptides that transmit signals to modulate cellular activities. They have short half-lives, for example, platelet-derived growth factor (PDGF), isolated from platelets, has a half life of less than 2 minutes when injected intravenously. Extended biological activity and the controlled release of growth factor are achieved by incorporating growth factor into the polymeric device. This review will focus on growth factor delivery for tissue engineering. Particular examples will be given whereby growth factors are delivered from a tissue-engineered device to facilitate wound healing and tissue repair.

Animals↗
PubMed2000

Advances in immunotherapy of hematologic malignancies: cellular and humoral approaches.

Monoclonal antibodies have become an important modality for cancer therapy. Genetically engineered chimeric and humanized antibodies have demonstrated activity against overt lymphoma and leukemia, as well as minimal residual disease. Radioimmunotherapy in both nonmyeloablative and myeloablative regimens has produced significant responses and also minimized radiation exposure to normal tissues. Targeted alpha-particle therapy offers the possibility of selective tumor cell kill. Antibody-drug conjugates have produced remissions in acute leukemia. Many proteins potentially act as leukemia or lymphoma-specific antigens for major histocompatibility complex-restricted T cell cytotoxicity. These include the idiotype proteins, breakpoint cluster region (bcr)-abl and other fusion oncoproteins, myeloid-specific differentiation antigens and minor histocompatibility antigens. Clinical trials exploiting the new understanding of the T cell immunology are underway.

Antibodies, Monoclonal↗
PubMed2003

Optimal induction of T-cell responses against hepatitis C virus E2 by antigen engineering in DNA immunization.

Although DNA immunization is a safe and efficient method for inducing cellular immune responses, it generates relatively weak and slow immune responses. Here, we investigated the effect of hepatitis C virus (HCV) antigen modifications on the induction of T-cell responses in DNA immunization. It is likely that the strength of T-cell responses has an inverse relationship with the length of the insert DNA. Interestingly, a mixture of several plasmids carrying each gene induced a higher level of T-cell responses than a single plasmid expressing a long polyprotein. Moreover, the presence of a transmembrane domain in HCV E2 resulted in stronger T-cell responses against E2 protein than its absence. Taken together, our results indicate that the tailored modifications of DNA-encoded antigens are capable of optimizing the induction of T-cell responses which is required for eliminating the cells chronically infected with highly variable viruses such as HCV and human immunodeficiency virus.

Animals↗
PubMed2003

Current state of cartilage tissue engineering.

Damage to cartilage is of great clinical consequence given the tissue's limited intrinsic potential for healing. Current treatments for cartilage repair are less than satisfactory, and rarely restore full function or return the tissue to its native normal state. The rapidly emerging field of tissue engineering holds great promise for the generation of functional cartilage tissue substitutes. The general approach involves a biocompatible, structurally and mechanically sound scaffold, with an appropriate cell source, which is loaded with bioactive molecules that promote cellular differentiation and/or maturation. This review highlights aspects of current progress in cartilage tissue engineering.

Animals↗
PubMed2006

ARACNE: an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context.

BACKGROUND: Elucidating gene regulatory networks is crucial for understanding normal cell physiology and complex pathologic phenotypes. Existing computational methods for the genome-wide "reverse engineering" of such networks have been successful only for lower eukaryotes with simple genomes. Here we present ARACNE, a novel algorithm, using microarray expression profiles, specifically designed to scale up to the complexity of regulatory networks in mammalian cells, yet general enough to address a wider range of network deconvolution problems. This method uses an information theoretic approach to eliminate the majority of indirect interactions inferred by co-expression methods. RESULTS: We prove that ARACNE reconstructs the network exactly (asymptotically) if the effect of loops in the network topology is negligible, and we show that the algorithm works well in practice, even in the presence of numerous loops and complex topologies. We assess ARACNE's ability to reconstruct transcriptional regulatory networks using both a realistic synthetic dataset and a microarray dataset from human B cells. On synthetic datasets ARACNE achieves very low error rates and outperforms established methods, such as Relevance Networks and Bayesian Networks. Application to the deconvolution of genetic networks in human B cells demonstrates ARACNE's ability to infer validated transcriptional targets of the cMYC proto-oncogene. We also study the effects of misestimation of mutual information on network reconstruction, and show that algorithms based on mutual information ranking are more resilient to estimation errors. CONCLUSION: ARACNE shows promise in identifying direct transcriptional interactions in mammalian cellular networks, a problem that has challenged existing reverse engineering algorithms. This approach should enhance our ability to use microarray data to elucidate functional mechanisms that underlie cellular processes and to identify molecular targets of pharmacological compounds in mammalian cellular networks.

Algorithms↗
PubMed2005

Custom design of the cardiac microenvironment with biomaterials.

Many strategies for repairing injured myocardium are under active investigation, with some early encouraging results. These strategies include cell therapies, despite little evidence of long-term survival of exogenous cells, and gene or protein therapies, often with incomplete control of locally-delivered dose of the factor. We propose that, ultimately, successful repair and regeneration strategies will require quantitative control of the myocardial microenvironment. This precision control can be engineered through designed biomaterials that provide quantitative adhesion, growth, or migration signals. Quantitative timed release of factors can be regulated by chemical design to direct cellular differentiation pathways such as angiogenesis and vascular maturation. Smart biomaterials respond to the local environment, such as protease activity or mechanical forces, with controlled release or activation. Most of these new biomaterials provide much greater flexibility for regenerating tissues ex vivo, but emerging technologies like self-assembling nanofibers can now establish intramyocardial cellular microenvironments by injection. This may allow percutaneous cardiac regeneration and repair approaches, or injectable-tissue engineering. Finally, materials can be made to multifunction by providing sequential signals with custom design of differential release kinetics for individual factors. Thus, new rationally-designed biomaterials no longer simply coexist with tissues, but can provide precision bioactive control of the microenvironment that may be required for cardiac regeneration and repair.

Angiogenesis Inducing Agents↗
PubMed1997

New insights into the ontogeny of breathing from genetically engineered mice.

Development of breathing behavior depends on the coordinated maturation of central and peripheral neural pathways, respiratory muscles, airways, and lung tissues. Each of these components contains cellular elements in which derangements of gene expression may perturb development of normal respiratory function. Application in recent years of genetic engineering techniques has led to detailed analyses of gene structure and function. In particular, targeted gene deletions provide the opportunity to relate gene function to physiologic mechanisms in intact animals. This review summarizes recent studies in mice designed to alter, by targeted disruption of specific genes, development of individual components of the respiratory control system. We also discuss an example of the human therapeutic potential of transgenic methods.

Animals↗
PubMed2004

[Current status of tissue engineering in urology. Review of the literature].

In the eighties a new field of the medicine appears wich applies the principles of cellular cultivation to synthetic biodegradable polymers scaffolds with the purpose of creating autologous biological substitutes that could improve, maintain or restore the function of organs or damaged tissues. The Tissue Engineering constitutes a new discipline in full phase of development especially in USA, with multiple potential applications in several medical specialities. Our speciality can't remain indifferent to interest and encouraging future originated by this new science. In this work we have made a wide bibliographical revision in the Medline to know the antecedents, current state and the possible future applications of Tissue Engineering in Urology.

Humans↗
PubMed2000

Invited review: engineering approaches to cytoskeletal mechanics.

An outstanding problem in cell biology is how cells sense mechanical forces and how those forces affect cellular functions. Various biophysical and biochemical mechanisms have been invoked to answer this question. A growing body of evidence indicates that the deformable cytoskeleton (CSK), an intracellular network of interconnected filamentous biopolymers, provides a physical basis for transducing mechanical signals into biochemical signals. Therefore, to understand how mechanical forces regulate cellular functions, it is important to know how cells respond to changes in the CSK force balance and to identify the underlying mechanisms that control transmission of mechanical forces throughout the CSK and bring it to equilibrium. Recent developments of new experimental techniques for measuring cell mechanical properties and novel theoretical models of cellular mechanics make it now possible to identify and quantitate the contributions of various CSK structures to the overall balance of mechanical forces in the cell. This review focuses on engineering approaches that have been used in the past two decades in studies of the mechanics of the CSK.

Animals↗
PubMed2006

Transient gene expression by nonintegrating lentiviral vectors.

Nonintegrating lentiviral (NIL) vectors were produced from HIV-1-based lentiviral vectors by introducing combinations of mutations made to disable the integrase protein itself and to alter the integrase recognition sequences (att) in the viral LTR. NIL vectors with these novel combinations of mutations were used to transduce the human T lymphoid cell line Jurkat and primary human CD34(+) hematopoietic progenitor cells to assess their efficacy measured through transient expression of the enhanced green fluorescent protein (eGFP) reporter gene. The most disabled NIL vectors resulted in initial high levels of eGFP expression (approximately 90% of cells), but expression was transient, diminishing toward background (<0.5%) within less than 1 month. Southern blot analyses of transduced Jurkat cells confirmed the loss of detectable NIL vector sequence (linear form and one- and two-LTR circles) by 1 month. There were low residual levels of integration by NIL vectors (reduced approximately 10(4)-fold compared to wild-type vectors), despite any combination of the engineered changes. Based upon analysis of the sequences of the DNA from the junctions of the vector LTR and cellular chromosomes, these rare integrated NIL vector sequences were not mediated by an integrase-driven mechanism due to reversion of the engineered mutations, but more likely were produced by background recombination events. The development of NIL vectors provides a novel tool for efficient transient gene expression in primary stem cells and hematopoietic and lymphoid cells.

Antigens, CD34↗
PubMed2026

Biological Parts in Yeast Synthetic Biology: From Regulatory Elements to Predictive Design Platforms.

Yeasts, particularly Saccharomyces cerevisiae, are important eukaryotic chassis for synthetic biology because of their tractable genetics, versatile toolkits, and broad utility in metabolic engineering and functional genomics. Progress in this field has been driven by biological parts that enable programmable control of gene expression and cellular behavior. Early efforts focused mainly on promoters, terminators, and other regulatory elements for tuning individual genes. However, as engineering expanded to multigene pathways, genetic circuits, and dynamic regulatory systems, the limits of part-centric design became clear. Part performance is often shaped by genomic context, chromatin state, host physiology, and interactions with other components, which restricts modularity and predictability. In response, yeast synthetic biology is shifting toward integrated design frameworks combining multilayer regulation, standardized assembly, automated experimentation, and computational modeling. This review provides an integrated perspective on the evolution of biological parts across DNA-, RNA-, and protein-level regulation, connecting these advances with assembly frameworks, biofoundries, and machine learning to trace the trajectory from part-centric engineering toward predictive, system-level design in yeast synthetic biology.

Biofoundry↗