Impact of Preexisting and Induced Humoral and Cellular Immune Responses in an Adenovirus-Based Gene Therapy Phase I Clinical Trial for Localized Mesothelioma

Molnar-Kimber, Katherine L.; Sterman, Daniel H.; Chang, Michael Y.; Kang, Eugen H.; ElBash, Mohammed; Lanuti, Michael; Elshami, Ashraf A.; Gelfand, Karen; Wilson, James M.; Kaiser, Larry R.; Albelda, Steven Μ.

doi:10.1089/hum.1998.9.14-2121

Cited by 183 publications

(112 citation statements)

References 35 publications

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“…In this respect, a recent study has demonstrated that pre-existing humoral immune responses did not preclude gene transfer. 30 Our strategy to date in human trials is to include all patients in trials, irrespective of in vitro measures of pre-existing immunity, and to develop correlations between the in vitro assays and efficiency of in vivo gene therapy.…”

Section: Figure 4 Cytokine Secretion Patterns Induced By Adenovirus mentioning

confidence: 99%

Immune responses to adenovirus and adeno-associated virus in humans

et al. 1999

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Vectors based on human adenovirus (Ad) and adenovirus (NAB). Approximately two of three patients demonassociated virus (AAV) are being evaluated for human strated CD4 + T cells that proliferated to Ad antigens of gene therapy. The response of the host to the vector, in which most were of the TH 1 subset, based on cytokine terms of antigen-specific immunity, will play a substantial secretion. A substantially different pattern of immune role in clinical outcome. We have surveyed cohorts of norresponses was observed to AAV2. Although virtually all mal subjects and cystic fibrosis patients for pre-existing patients had Ig to AAV2, most of these antibodies were immunity to these viruses, caused by naturally acquired not neutralizing (32% NAB) and only 5% of patients had infections. A number of humoral and cellular assays to peripheral blood lymphocytes that proliferated in response adenovirus serotype 5 (Ad5) and adeno-associated virus to AAV2 antigens. These studies demonstrate marked hetserotype 2 (AAV2) were performed from serum and peripherogeneity in pre-existing immunity to Ad5 and AAV2 in eral blood mononuclear cells. Virtually all subjects had Ig human populations. The impact of these findings on outto Ad5 although only 55% of these antibodies neutralized come following gene therapy will require further study.

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Section: Figure 4 Cytokine Secretion Patterns Induced By Adenovirus mentioning

confidence: 99%

Immune responses to adenovirus and adeno-associated virus in humans

et al. 1999

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“…The presence of vector-specific neutralizing antibodies inhibits vector readministration, especially when administered systemically, for example, in liver or lungs. 72 Interestingly, the blocking effects of neutralizing antibodies for vector readministration have less influence in the muscle, eyes or brain, primarily because of the physical barriers of lymphoid fluids in these organs. 73,74 Studies in rhesus monkeys have demonstrated that AAV and adenovirus vector elicit markedly different immunoglobulin isotypes.…”

Section: Immunity To Viral Vectors K Jooss and N Chirmulementioning

confidence: 99%

Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy

2003

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“…A major concern for the future clinical application of Ad vectors is the possibility that preexisting immunity to an adenovirus of the same or cross-reactive serotype may strongly limit vector efficacy. This holds particularly true for adenovirus type 5, because of a high seroprevalence in the adult human population (21,22). We therefore determined how a preexisting anti-adenovirus type 5 immunity can affect i.m.…”

Section: Intramuscular Injection Of C4afo-mepo Ad Vector Overcomes Prmentioning

confidence: 99%

An improved helper-dependent adenoviral vector allows persistent gene expression after intramuscular delivery and overcomes preexisting immunity to adenovirus

Maione

Rocca

Giannetti

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Helper-dependent adenoviral vectors deleted of all viral coding sequences have shown an excellent gene expression profile in a variety of animal models, as well as a reduced toxicity after systemic delivery. What is still unclear is whether long-term expression and therapeutic dosages of these vectors can be obtained also in the presence of a preexisting immunity to adenovirus, a condition found in a high proportion of the adult human population. In this study we performed intramuscular delivery of helper-dependent vectors carrying mouse erythropoietin as a marker transgene. We found that low doses of helper-dependent adenoviral vectors can direct long-lasting gene expression in the muscles of fully immunocompetent mice. The best performance-i.e., 100% of treated animals showing sustained expression after 4 months-was achieved with the latest generation helper-dependent backbones, which replicate and package at high efficiency during vector propagation. Moreover, efficient and prolonged transgene expression after intramuscular injection was observed with limited vector load also in animals previously immunized against the same adenovirus serotype. These data suggest that human gene therapy by intramuscular delivery of helper-dependent adenoviral vectors is feasible. R eplication-deficient adenoviral (Ad) vectors deleted of one or more early genes (first-and second-generation Ad vectors) are among the most efficient vehicles for in vivo gene delivery, but their utilization for therapeutic purposes is limited by the transient nature of transgene expression and the systemic toxicity, which are both due to inflammatory and immune responses triggered by the residual expression of viral proteins (1-5). The development of Ad vectors deleted of all viral coding sequences offers the prospect of a safer and more efficient way to deliver genes (6). Production of fully deleted Ad vectors, also called helper-dependent (HD) Ad vectors, is possible thanks to the supply in trans of the viral proteins required for replication and packaging by a helper first-generation virus (7).Previous studies by several laboratories have shown improved performances of HD vs. first-generation vectors after intravenous (i.v.) injection as to efficacy of transduction, longevity of transgene expression, and systemic toxicity (8-11). These studies strongly suggested that latest generation adenoviruses may be useful for human applications. However, delivery of Ad vectors (including HD vectors) to human recipients may be rendered particularly difficult when a preexisting immunity against an adenovirus serotype identical to, or cross-reactive with, the one used for gene transfer has previously developed as a consequence of a natural infection. This interfering effect is expected to be particularly pronounced in the case of i.v. delivery, because transducing vector particles will be exposed to circulating neutralizing antibodies before reaching the main target organ, the liver. It is therefore important to evaluate performance, therapeutic efficacy, an...

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Impact of Preexisting and Induced Humoral and Cellular Immune Responses in an Adenovirus-Based Gene Therapy Phase I Clinical Trial for Localized Mesothelioma

Cited by 183 publications

References 35 publications

Immune responses to adenovirus and adeno-associated virus in humans

Immune responses to adenovirus and adeno-associated virus in humans

Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy

An improved helper-dependent adenoviral vector allows persistent gene expression after intramuscular delivery and overcomes preexisting immunity to adenovirus

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