Strengthened tumor antigen immune recognition by inclusion of a recombinant Eimeria antigen in therapeutic cancer vaccination

Abstract

The need for novel, effective adjuvants that are capable of eliciting stronger cellular and humoral adaptive immune responses to antigenic targets is well understood in the vaccine development field. Unfortunately, many adjuvants investigated thus far are either too toxic for human application or too weak to induce a substantial response against difficult antigens, such as tumor-associated antigens (TAAs). In spite of this trend, clinical investigations of recombinant Eimeria antigen (rEA) have revealed this protein to be a non-toxic immunogenic agent with the ability to trigger a Th1-predominant response in both murine and human subjects. Our past studies have shown that injection of an rEA-encoding adenovirus (rAd5-rEA) alongside an HIV antigen-encoding adenovirus greatly improves the adaptive immune response against this pathogen-derived transgene. In this report, we investigated if rAd5-rEA could promote and/or alter cytotoxic memory responses towards carcinoembryonic antigen (CEA), a colorectal cancer-related TAA. We found that the addition of rAd5-rEA to an Ad-based CEA vaccine (rAd5-CEA) induced a dose-dependent increase in several anti-CEA T and B cell responses. Moreover, inclusion of rAd5-rEA increased the number of CEA-derived antigenic epitopes that elicited significant cell-mediated and IgG-mediated recognition. These enhanced anti-CEA immune responses also translated into superior CEA-targeted cell killing, as evaluated by an in vivo cytotoxic T lymphocyte assay. Overall, these results suggest that co-administration of rAd5-rEA with a tumor antigen vaccine can substantially boost and broaden the TAA-specific adaptive memory response, thereby validating the potential of rAd5-rEA to be a beneficial adjuvant during therapeutic cancer vaccination.

An Open-Label Study of Subcutaneous CpG Oligodeoxynucleotide (PF03512676) in Combination with Trastuzumab in Patients with Metastatic HER2+ Breast Cancer

“…TLR activation can promote a robust innate immune response and produce anti-tumor responses. For example, TLR agonists can increase tumor antigen-specific cytotoxic T cell killing, 14 - 16 lead to anti-tumor Th1 polarization, 17 , 18 and boost anti-PD-1 adaptive immunity. 19 , 20 There has been considerable interest in TLR9, a receptor that recognizes unmethylated CpG oligodeoxynucleotides (ODN) commonly found in bacterial and viral genomes.…”

Comparison of three different methods of transfection for production of recombinant adenovirus vector expressing human carcinoembryonic antigen (CEA) gene

“…Indeed, TAAs are overexpressed in tumor cells but often fail to induce sufficient immune responses. Thus, one of the main purpose in the cancer vaccine fields is to enhance TAA-specific cellular immune responses via allowing the delivery of different TAAs that can be able to stimulate the effective antitumor immunity (3,4). Many researches have confirmed that the infiltration of T cells into tumor microenvironment is associated with increase survival without recurrence in patients.…”

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

“…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).…”