Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients

Abstract

First generation, E1-deleted Adenovirus subtype 5 (Ad5)-based vectors, although promising platforms for use as cancer vaccines, are impeded in activity by naturally occurring or induced Ad-specific neutralizing antibodies. Ad5-based vectors with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), the latter encoding the DNA polymerase and the pre-terminal protein, by virtue of diminished late phase viral protein expression, were hypothesized to avoid immunological clearance and induce more potent immune responses against the encoded tumor antigen transgene in Ad-immune hosts. Indeed, multiple homologous immunizations with Ad5 [E1-, E2b-]-CEA(6D), encoding the tumor antigen CEA, induced CEA-specific cell-mediated immune (CMI) responses with antitumor activity in mice despite the presence of pre-existing or induced Ad5-neutralizing antibody. In the present phase I/II study, cohorts of patients with advanced colorectal cancer were immunized with escalating doses of Ad5 [E1-, E2b-]-CEA(6D). CEA-specific CMI responses were observed despite the presence of pre-existing Ad5 immunity in a majority (61.3%) of patients. Importantly, there was minimal toxicity, and overall patient survival (48% at 12 months) was similar regardless of pre-existing Ad5 neutralizing antibody titers. The results demonstrate that, in cancer patients, the novel Ad5 [E1-, E2b-] gene delivery platform generates significant CMI responses to the tumor antigen CEA in the setting of both naturally acquired and immunization-induced Ad5-specific immunity.

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes

“…by engineered adenoviruses, which are capable of safely vaccinating and re-vaccinating against hundreds of neoepitopes and tumor-associated antigens despite pre-existing immunity against adenovirus [47]. Remarkable results have thus far been published demonstrating the delivery of tumor-associated antigens by this engineered adenovirus in a cohort of late-stage colorectal cancer patients [48].…”

Decreased Vector Gene Expression from E2b Gene-Deleted Adenovirus Serotype 5 Vaccines Intensifies Proinflammatory Immune Responses

“…While this may serve as a partial contributor toward these divergent responses, multiple recombinant Ad5 studies have shown that anti-Ad5 immunity alone is not predictive of a recombinant Ad5-based vaccine's efficacy (11,14,47).…”

“…Conventional Ad5[E1Ϫ] vaccines possess the ability to promote strong immunologic responses against their expressed transgenes, but the same properties also trigger host antiviral responses, which can lead to increased toxicity, limited persistence, and decreased efficacy in the face of preexisting anti-Ad5 immunity (7,28,29,34,46 (28,34), and remain therapeutically efficacious in hosts harboring substantial preexisting anti-Ad5 immunity (5,(14)(15)(16)30).…”

“…Ad5-based vaccines are attractive for a multitude of reasons, including their broad human cell tropism, relative ease of manufacturing for scaled production, and low potential for adverse side effects (1). Additionally, numerous studies have demonstrated the tremendous ability of Ad5-based vaccines to create robust, transgene-specific cell-mediated immunity against antigens derived from pathogens, such as HIV (2)(3)(4)(5)(6)(7)(8), the malaria parasite (9,10), and Mycobacterium tuberculosis (11,12), as well as many tumor-associated antigens (13)(14)(15)(16)(17). Although the advantages of these vaccines are abundant, there has been some hesitation toward their practical use due to the high prevalence of preexisting Ad5 immunity in the human population (18)(19)(20).…”

Novel cancer antigens for personalized immunotherapies: latest evidence and clinical potential

“…Clinically, CEA has been investigated extensively as an immunotherapeutic target for colorectal and various other cancers [Turriziani et al 2012]. In a phase I/II clinical trial, treatment with an adenoviral gene delivery platform encoding the CEA antigen produced cell-mediated immunity in 61% of patients with advanced CRC and a 48% OS rate at 12 months [Morse et al 2013a]. A phase II study in CRC patients who were disease-free following metastasectomy and perioperative chemotherapy compared the effectiveness of autologous dendritic cells modified with PANVAC™, a poxvector encoding both CEA and MUC1, to the PANVAC™ poxvector administered in combination with GM-CSF.…”