The recent progress in cancer immunotherapy has been remarkable, and the immune checkpoint inhibitors have brought about a paradigm shift in cancer treatment. Chimeric antigen receptor (CAR)-T-cell therapy has shown excellent anti-tumor effects in hematological malignancies, and CAR-T cell therapy (tisagenlecleucel) has already been approved in Japan for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and relapsed or refractory diffuse large B-cell lymphoma (DLBCL). On the other hand, several CAR-T cell therapies have not been successful in clinical trials for solid tumors. The reason may be the ability of CAR-T cells to reach solid tumors, and the physical and immunological barriers surrounding solid tumors. The development of CAR-T cell therapy for brain tumors, which are solid tumors, faces the same problem, but in addition, there are concerns about diffi culties due to problems specifi c to the central nervous system. In this review, we discuss the major challenges facing CAR-T cell therapy in malignant brain tumors. These include neuroanatomical considerations, obstacles to effector T cell traffi cking, immunosuppression in the tumor microenvironment, antigen heterogeneity, and off-tumor toxicity. This will be followed by an update on the current clinical status of CAR T-cell therapy for malignant brain tumors.

Almost 40 years after the discovery of HIV-1/AIDS, combination anti-retroviral therapy (cART) has dramatically improved the prognosis of people living with HIV (PLWH), and AIDS has become a treatable chronic infection from a fatal disease. Recently, new effective and safe anti-HIV drugs have been developed one after another, and UNAIDS aims to end the AIDS epidemic by 2030. On the other hand, although cART can reduce the viral production in the PLWH's body below the detection limit, it can not eliminate the HIV provirus integrated into the gene in the host cells. Therefore, the virus will be produced again after discontinuation of cART. Under such circumstances, research for the cure (or remission) of HIV has been widely carried out. In this review, we focus on the drug development targeting HIV latently infected cells and overview the progress including our current studies.

Oncolytic virus therapy has been emerging as an important modality of cancer immunotherapy. Oncolytic viruses exert an antitumor effect through two mechanisms: direct oncolytic and indirect immune-mediated mechanisms. Recombinant herpes simplex virus type 1 (HSV-1) has been leading the fi eld of oncolytic virus therapy, and has been approved for the treatment of advanced melanoma in the United States and Europe and of glioblastoma in Japan. Human hematopoietic cells are resistant to HSV-1 replication and thus oncolytic HSV-1 has been considered unsuitable to treat hematological malignancies. However, we showed that more than half of human hematological tumor cell lines and primary tumor cells derived from various lineages were susceptible to oncolytic HSV-1. The expression of an HSV-1 receptor, nectin-1, was critical to the susceptibility. In an immunocompetent mouse model, intratumoral injection of HSV-1 into lymphoma induced regression of injected, as well as non-injected, contralateral tumors accompanied by abundant infi ltration of antigen-specifi c CD8+ T cells. In addition, HSV-1 exerted an anti-myeloma effect in vitro through direct oncolysis and immune activation governed by plasmacytoid dendritic cells and NK cells. Lenalidomide augmented the anti-myeloma effect of HSV-1. These data suggest that intratumoral injection of oncolytic HSV-1 may be applicable to systemic hematological malignancies. Combination with other treatments, particularly immune checkpoint blockade, and further elucidation of antitumor mechanisms of oncolytic virus therapy are expected to advance the effi cacy of this promising modality of cancer immunotherapy.