Research programs in the Section for Studies on Host-Immune Response consist of elucidation of the molecular basis of immune responses against cancer and the development of gene and cell therapy for solid cancers. In particular, the Section has focused on the fundamental studies of immune gene therapy and cell therapy and development of novel cancer targeting vectors. The Section has been collaborating with the Genetics Division and the Central RI Laboratory.

The type I interferon (IFN) protein is a cytokine with pleiotropic biological functions, including suppression of cell growth, induction of apoptosis, inhibition of angiogenesis and immunomodulation. The Section examined the integrated antitumor activity of local IFN-a gene therapy using a syngeneic pancreatic cancer model in a hamster. When a hamster IFN-a adenovirus vector was injected into syngeneic subcutaneous tumors of hamster pancreatic cancer cells (PGHAM-1) in the Syrian hamster, tumor growth was significantly suppressed due to cell death and T cell- and NK cell-mediated antitumor immunity. Moreover, in this case, tumor regression was observed not only for the injected subcutaneous tumors but also for the untreated tumors both in the peritoneal cavity and at distant sites. No significant systemic toxicity was observed in the treated hamsters. The subcutaneous rechallenge of PGHAM-1 cells was rejected in 3 of 4 cured hamsters from the initial tumor challenge. The results showed that a local IFN-a gene therapy is a promising therapeutic strategy for pancreatic cancer, due to its multiple mechanisms of antitumor activities and lack of significant toxicity ⁽¹¹⁹⁾.

In autologous hematopoietic stem cell transplantation (HSCT), lymphopenia-induced homeostatic proliferation (HP) of T cells is driven by the recognition of self antigens, and there is an opportunity to skew the T-cell repertoire during the T cell recovery by engaging tumor-associated antigens (TAAs), leading to a break of tolerance against tumors. However, it has been reported that the HP-driven antitumor responses decline rapidly in association with tumor growth. The Section hypothesized that a tumor-specific immune response induced by allogeneic MHC (alloMHC) gene transfer could enhance and sustain HP-induced antitumor immunity following autologous HSCT. First, lethally irradiated lymphopenic mice transfused with syngeneic bone marrow plus T cells showed significant tumor growth inhibition of syngeneic colon cancer cells within a period of 35 days; however, the tumor then resumed rapid growth and the survival of the mice was not prolonged. In contrast, when the alloMHC gene-expressing plasmid was intratumorally injected in the early phase of the immune reconstitution following syngeneic HSCT, the established tumors were markedly regressed and the survival of the recipient mice was prolonged without significant toxicities, whereas no survival advantage was recognized in recipient mice injected with a control plasmid. This tumor suppression was evident even in the other tumors that were not injected with the alloMHC plasmid. The antitumor response was characterized by the development of tumor specific T cell- and NK cell-mediated cytotoxicities. The results suggested the efficacy and safety of integrating intratumoral alloMHC gene transfer with an autologous HSCT for the treatment of solid cancers ⁽¹²⁰⁾.

Targeting of gene transfer at the level of cell entry is one of the most attractive challenges in vector development. However, attempts to redirect adenovirus vectors to alternative receptors by engineering the capsid-coding region have shown limited success, because proper targeting ligand-receptor systems on the cells of interest are generally unknown. Systematic approaches to generate adenovirus vectors targeting any given cell type need to be developed to achieve this goal. The Section constructed an adenovirus library which was generated by a Cre-lox mediated in vitro recombination between an adenoviral fiber-modified plasmid library and genomic DNA to display random peptides on a fiber knob. As proof-of-concept, the Section screened the adenovirus display library on a glioma cell line and observed selection of several particular peptide sequences. The targeted vector carrying the most frequently isolated peptide significantly enhanced gene transduction in the glioma cell line but not in many other cell lines. Because the insertion of a pre-selected peptide into a fiber knob often fails to generate an adenovirus vector, the selection of targeting peptides is highly useful in the context of the adenoviral capsid. The results showed that this vector screening system could facilitate the development of a targeted adenovirus vector for a variety of applications in medicine ⁽¹²¹⁾.