Chemokine gene modification of human dendritic cell-based tumor vaccines using a recombinant adenoviral vector

Abstract

Previous animal studies conducted in our laboratory have shown that tumor antigen-pulsed dendritic cells (TP-DC) can mediate antitumor effects in vivo. However, durable and complete regression of established tumors has been difficult to achieve through the administration of TP-DC alone. To better augment immune priming to tumors in vivo, we have hypothesized that it is necessary to achieve an increased number of host-derived, naïve T cells at the site of TP-DC vaccine injections. To accomplish this goal, we have embarked on a series of studies that utilize defined chemokines. One of these molecules, secondary lymphoid tissue chemokine (SLC), has been shown to be uniquely chemoattractant for naïve T cells and dendritic cells. We propose that gene modification of DC-based tumor vaccines to produce human SLC will enhance T-cell recruitment and immune priming to tumorassociated antigens, and thereby translate into improved antitumor vaccine efficacy in vivo. Utilizing an E1-, E3-deleted adenoviral vector containing the gene for human SLC, we have been able to transduce human DC to produce biologically active human SLC that chemoattracts human T cells in vitro. SLC production by transduced DC was markedly enhanced upon DC maturation. Additionally, these SLC-secreting DC were found to be viable to a large extent despite the cytopathic effect inherent in adenoviral gene transfer and, most importantly, functional as determined by their ability to prime autologous T cells to a known melanomaassociated antigen, MART-1. Based on these encouraging results, we plan to initiate Phase I clinical studies utilizing DC-SLC to treat patients with advanced solid tumors.

Loss of New Chemokine CXCL14 in Tumor Tissue Is Associated with Low Infiltration by Dendritic Cells (DC), while Restoration of Human CXCL14 Expression in Tumor Cells Causes Attraction of DC Both In Vitro and In Vivo

“…enhance T cell recruitment and immune priming to tumor-associated Ags (38). In fact, injection of recombinant secondary lymphoid tissue chemokine in the axillary lymph node region in mice with bilateral multifocal pulmonary adenocarcinomas led to a marked reduction in tumor burden with extensive lymphocytic and DC infiltration of the tumors and enhanced survival (39).…”

Therapeutic Use of Dendritic Cells to Promote the Extranodal Priming of Anti-Tumor Immunity

“…DC genetically engineered to secrete high-levels of CCL21 (DC.CCL21) and injected directly into B16 murine melanomas promote strong extranodal T cell cross-priming/recruitment into the TME, even in LTα −/− mice that lack SLO (8, 68). The superiority of DC.CCL21 in enhancing the cross-priming of protective Type-1 anti-tumor T cell responses has also been confirmed in alternate murine models (76, 77). …”

Chemokines as Cancer Vaccine Adjuvants

“…These preclinical investigations lead researchers to successfully transduce CCL21-expressing human DCs [72], setting the ground work for future clinical trial development. A recently closed Phase I clinical trial in melanoma applied intradermal injections of adenovirus-CCL21 transduced class I peptide-pulsed DCs [55].…”