Immune Response to Adenoviral Based Vectors in Humans

Host immune response can play a significant role in the outcome of in vivo gene therapy. Experiments with adenoviral vectors clearly demonstrate the development of neutralizing antibodies that block readministration and cellular responses that extinguish gene expression. However, most of the work described in this field relates to animal models that are naive to the virus. This will not be the case in humans, many of whom have been exposed to Ad due to a naturally acquired infection. A study performed by Chirmule et al. [147] surveyed normal subjects and cystic fibrosis patients to demonstrate the relevance of pre-existing immunity to Ad to the outcome of in vivo gene therapy. They found that antibodies reactive to Ad capsid proteins were present in 97% of individuals; however, serum from only 55% of subjects actually neutralized Ad infection in vitro. Due to this discrepancy between seropositivity and neutralization of virus in vitro, the authors suggest that human trials should include all patients irrespective of in vitro measurements of preexisting immunity. This conclusion is also based on results from a Phase 1 gene therapy clinical trial for localized mesothelioma where it was shown that preexisting humoral immune responses did not preclude gene transfer [148].

Similarly, in human clinical trials where an adenovirus vector encoding hCFTR was repeatedly administered to the nasal epithelium of patients with cystic fibrosis [149], a complex immune response ensued which varied from patient to patient. Importantly, the pattern of the immune response did not differentiate patients with either large or absent correction of the CF defect following exposure to an Ad/CFTR vector [149].

Thus, what are the strengths and the limits of using experimental animals to predict human responses to gene transfer vectors? The intensity and the nature of the anti-Ad humoral immune response in experimental animals is dependent on the dose and on the route of administration of the vector. But is this the case in humans? To address this question a study was designed to determine the variability of human systemic humoral immune responses to adenovirus administered to different organs [150]. The study aimed to determine (a) if the administration of Ad vectors to humans always produced systemic anti-Ad neutralizing antibodies, (b) if the extent of the neutralizing antibody response depended on the route of administration, (c) if the systemic anti-Ad humoral response was dose dependent, and (d) how much preexisting anti-Ad antibodies influence the subsequent humoral response to Ad vector administrations.

Vectors were administered to the airway epithelium of individuals with cystic fibrosis, or individuals with liver metastatic tumors from colon cancer, or the skin of healthy normal individuals or the myocardium of individuals with coronary artery disease. Interestingly, the administration of the Ad vector to the bronchial epithelium of CF patients yielded the lowest antibody response, while direct injection of the Ad vector to colon carcinoma metastases in the liver resulted in the most vigorous antibody response. For those individuals that received Ad vector intradermally or intramyocardially there was a varying response, with some individuals having no increase in anti-Ad neutralizing antibody titer with others having a robust response. The most significant observation was the strong correlation between preexisting neutralizing antibodies and the likelihood that an individual would mount a higher titer following vector administration. Irrespective of route of administration and underlying disease state individuals with higher baseline anti-Ad neutralizing antibodies mounted a higher neutralizing antibody response after exposure to an Ad vector.

How much does disease state modify the systemic humoral host response to Ad vectors? In the case of individuals with CF they yielded the lowest antibody response following intrabronchial administration of an Ad vector. The authors suggest that the minimal responses to bronchial administration of Ad in CF patients could be due to the fact that the airway epithelium of these individuals is covered by mucus, which can preclude efficient Ad vector infection of the airway epithelial cells.

To address this concern the same authors have just recently reported the results of a clinical trial using an El-E3-deleted Ad vector, which was repeatedly administered to the lung airway of six normal individuals [151]. There were minimal to no systemic or local (epithelial lining fluid) anti-Ad neutralizing antibodies in the normal individuals following vector administration. This is a significant observation as in this situation there are no adverse conditions in the normal lung unlike the CF lung, that might affect host immune responses. Thus, in contrast to experimental animals where it has been shown that there is a robust anti-Ad response following repeated vector administration to the lung, it appears that for Ad-based vectors for use in human lung gene therapy this maybe less of a problem.

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