Induced pluripotent stem cell‐derived myeloid cells expressing OX40 ligand amplify antigen‐specific T cells in advanced melanoma

• Published in: Pigment cell and melanoma research Vol. 33; no. 5; pp. 744 - 755
• Main Authors: Kimura, Toshihiro, Fukushima, Satoshi, Okada, Etsuko, Kuriyama, Haruka, Kanemaru, Hisashi, Kadohisa‐Tsuruta, Mina, Kubo, Yosuke, Nakahara, Satoshi, Tokuzumi, Aki, Kajihara, Ikko, Makino, Katsunari, Miyashita, Azusa, Aoi, Jun, Makino, Takamitsu, Tsukamoto, Hirotake, Nishimura, Yasuharu, Inozume, Takashi, Zhang, Rong, Uemura, Yasushi, Senju, Satoru, Ihn, Hironobu
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.09.2020
• Subjects: antigen specificity; Antigens; Cancer immunotherapy; CD8 antigen; Cell therapy; Effector cells; Flow cytometry; Immune checkpoint inhibitors; Immune system; Immunological memory; Immunoregulation; Immunotherapy; In vivo methods and tests; iPS‐ML; Lymphocytes; Lymphocytes T; Melanoma; Memory cells; Myeloid cells; Ovalbumin; OX40; Ox40L protein; Peptides; Pluripotency; Spleen; Stem cell transplantation; Stem cells; Suicide; Suicide genes; Survival; Syngeneic grafts; Tumor necrosis factor; Tumors; OX40; melanoma; iPS-ML; antigen specificity; cancer immunotherapy
• ISSN: 1755-1471; 1755-148X
• DOI: 10.1111/pcmr.12887

Immune checkpoint inhibitors improved the survival rate of patients with unresectable melanoma. However, some patients do not respond, and variable immune‐related adverse events have been reported. Therefore, more effective and antigen‐specific immune therapies are urgently needed. We previously reported the efficacy of an immune cell therapy with immortalized myeloid cells derived from induced pluripotent stem cells (iPS‐ML). In this study, we generated OX40L‐overexpressing iPS‐ML (iPS‐ML‐Zsgreen‐OX40L) and investigated their characteristics and in vivo efficacy against mouse melanoma. We found that iPS‐ML‐Zsgreen‐OX40L suppressed the progression of B16‐BL6 melanoma, and prolonged survival of mice with ovalbumin (OVA)‐expressing B16 melanoma (MO4). The number of antigen‐specific CD8+ T cells was higher in spleen cells treated with OVA peptide‐pulsed iPS‐ML‐Zsgreen‐OX40L than in those without OX40L. The OVA peptide‐pulsed iPS‐ML‐Zsgreen‐OX40L significantly increased the number of tumor‐infiltrating T lymphocytes (TILs) in MO4 tumor. Flow cytometry showed decreased regulatory T cells but increased effector and effector memory T cells among the TILs. Although we plan to use allogeneic iPS‐ML in the clinical applications, iPS‐ML showed the tumorgenicity in the syngeneic mice model. Incorporating the suicide gene is necessary to ensure the safety in the future study. Collectively, these results indicate that iPS‐ML‐Zsgreen‐OX40L therapy might be a new method for antigen‐specific cancer immunotherapy.