Transcutaneous vaccination is an attractive strategy that delivers antigen molecules topically into the skin to induce protective or therapeutic immune responses. In the last two decades, the skin has been regarded as a potential administration site for vaccines due to the abundant antigen presenting cells in the skin such as Langerhans cells and dermal dendritic cells, which are found in the epidermis or dermis. To create an efficient transcutaneous vaccine, the antigen needs to be penetrated across the stratum corneum, which is the outermost layer of the skin and possesses a high barrier function. To overcome this issue, various types of drug delivery systems have been proposed such as ultrasound, jet immunization and microneedles as physical methods, and penetration peptides, liposomes and nanoparticles as chemical methods. In this review, a solid-in-oil (S/O） nanodispersion, which is an oil-based drug carrier for proteins and peptides, and its application for transcutaneous protein delivery and vaccination are summarized. Along with comparing the S/O nanodispersion with the other oil-based drug carriers, the transdermal delivery of proteins such as insulin is introduced. Finally, basic immunological responses via transcutaneous administration with the S/O nanodispersion containing a model antigen, and researches on protect and therapeutic applications are summarized.

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Adoptive immunotherapy transferring cancer cell-specific cytotoxic T lymphocytes (CTLs） is expected as an ideal cancer treatment strategy that is effective not only for the regression of primary cancer but also for the suppression of metastasis and recurrence. However, the inability to prepare CTLs quantitatively and qualitatively enough for treatment and the poor accumulation of transferred CTLs in tumor limit the clinical application. Developed as a breakthrough measure is the next-generation adoptive immunotherapy using chimeric antigen receptor (CAR）-expressing T cells, and the research and development for practical use are accelerated by several reports about the dramatic clinical efficacy of CAR-T cell therapy against hematological cancers. Herein, we outline the trends and problems of research on CAR-T cell therapy and introduce our tumor vessel-injuring CAR-T cell therapy.

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Cancer immunotherapy is an approach to treatment to effectively induce anti-tumor immunity to tumor tissues. Recent implementation of cancer immunotherapy approach to cancer treatment has been employed. In this study, we have attempted to develop a DC vaccine therapy using TECs isolated from solid tumor tissue as vaccine antigens. As a result, immunotherapy targeting tumor blood vessels showed the efficacy for tumor growth and metastases. However, vaccination using DCs pulsed with TECs did not inhibit physiological angiogenesis. Additionally, DC vaccination using TECs derived not only from the same tumor tissue but from a different type of tumor also suppressed metastasis. These results thus show that cancer vaccine therapy targeting TECs is an effective therapy against angiogenesis in several types of cancer, but does not affect normal blood vessel growth.

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Complement system is one of the central part of innate immunity partly responsible for recognition and removal of foreign materials, not only pathogens but also artificial nanoparticles. Complement system composed of more than 30 proteins causes cascade enzymatic activation, produces various bioactive substances, and finally induces inflammation and phagocytosis of foreign materials. It is well known that artificial nanoparticles activate complement system and physicochemical properties of nanoparticles affect level of complement activation, resulting in unexpected pharmacokinetics change of nanoparticles and toxicity. Hence, it is important to understand the mechanism behind complement activation by nanoparticles. In addition, intrinsic role of complement system in immune response is useful for development of vaccine. In this review, we introduce the negative and positive aspect of complement activation against nanoparticles.

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Cancer is still a formidable disease with high rates of morbidity and mortality, although a number of anti-cancer drug have been developed. Much attention has been paid on drug delivery system (DDS) and nanoparticles have been developed based on liposomes and polymeric micelles for target delivery of anti-cancer drugs to tumor tissue. However, chemotherapeutic reagents and molecular-targeting drugs have limitations. One of the limitations is that cancer cells which receive those molecules are killed but others are still alive. Another limitation is that cancer cells resistant to those drugs are frequently emerging. Disease recurrence is the most difficult problem in cancer treatment. To suppress the growth of residual or inoperable tumors, cancer immunotherapy has been developed, but it was not successful. By analyzing the mechanism of immunological tolerance in cancer, it is revealed that cancer can escape from host immune surveillance by suppressing effector immune cells using a variety of approaches. Recently, cancer immunotherapy is revived by the development of immune-checkpoint inhibitory therapy. In DDS field, activation of anti-tumor immunity is also considered to be absolutely necessary for cancer treatment. It is reported recently that systemic administration of liposomes incorporating tumor-antigen RNA is effective for cancer treatment because the liposomes can target antigen-presenting cells but not cancer cells. We discovered that inactivated Sendai virus (Hemagglutinating virus of Japan) particle (HVJ envelope; HVJ-E) has multiple anti-cancer activities including activation of anti-tumor immunity and cancer selective killing. The anti-tumor activities of HVJ-E mainly depends on retinoic acid-inducible gene-I (RIG-I) signaling pathway, which is a novel approach in the field of cancer therapy. Clinical trials to treat cancers using HVJ-E itself are ongoing. HVJ-E can convert DDS by incorporating therapeutic molecules inside the particle. Therapeutic molecules are directly introduced inside the various cells both in vitro and in vivo via membrane fusion. We are investigating the possibility of HVJ-E vector incorporating therapeutic molecules for next generation cancer therapy.

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