5IL-2/anti-IL-2complexIL-2Cx(S4B6)Memorization & maintenanceNKscmIM-NKTM-NKSemi-NKNK cellTumor antigenα-GalCerCD1dexpansionexpansionnNKNKTnCD8TactivationaAVCvaccineCD8TcellIL-2/anti-IL-2 complexIL-2Cx(S4B6)Memorization & maintenanceTEFTscmTCMTM-TEFFor the first time, IMS researchers demonstrate that a combination vaccine therapy induces immune cells with stem-like properties, providing long-lasting, targeted protection against cancer.Drugs that act to boost the natural defenses of our im-mune system – known as immunotherapies – are revolu-tionizing cancer treatment. Immunotherapies can act in a variety of ways: by enhancing the non-specific killing actions of our innate immune system, the targeted destruc-tion of tumors by our adaptive immune system, or both.One immunotherapy that falls into the latter category is the artificial adjuvant vector cell (aAVC) vaccine developed by Shin-Ichiro Fujii, Team Leader of the Laboratory for Immunotherapy at IMS. In mice, this first-of-its-kind cel-lular vaccine system simultaneously engages natural killer (NK) cells of the innate immune system and killer T cells of the adaptive immune system for up to one year. The aAVC vaccine is showing similar favorable immune activity in human patients with relapse and refractory acute myeloid leukemia in a Phase 1 clinical trial.Nevertheless, Fujii and his team aspired to further boost the vaccine’s efficacy. Specifically, they wanted to increase the length of protection provided by the treatment, which, if successful, could translate to not only a more powerful option for patients with cancer but could also reduce the need for regular boosters.To achieve their goal, the researchers focused on ampli-fying the T and NK cell response. “We wanted to enhance the T cell response by 2 or 3-fold,” Fujii said. “We hypothe-sized that if we could somehow stimulate NK cells for a long time, we might see long-term protection against cancer.”One natural activator of T and NK cells is the cytokine IL-2. However, because IL-2 alone can cause serious side effects, in their study published in the Journal for Immuno-Therapy of Cancer, the researchers used IL-2 in a complex with IL-2 monoclonal antibodies (IL-2Cx). Specifically, they tested an IL-2Cx targeted to killer T cells by biasing the complex to the CD122 antigen.When administered together with the aAVC vaccine in a mouse model of advanced-stage leukemia, the research-ers were surprised to find that the CD122-biased IL-2Cx resulted in 100% survival for up to 120 days. In contrast, survival dropped to around 10-20% in under 50 days with the aAVC vaccine alone.At the cellular level, the team confirmed that the supe-rior survival effects of the combination therapy were due to its strong influence on NK and killer T cells. In fact, the treatment engaged many more killer T cells and prolonged activation of NK cells and memory killer T cells than the aAVC vaccine alone.Astonishingly, in-depth characterization of the activated NK and T cell populations revealed that the combination therapy induced and maintained large numbers of NK and killer T cells with stem cell-like properties.“No other vaccine has been capable of spontaneously inducing stem-like T and NK cells,” remarked Fujii, who explained that these cells have high specificity against can-cer. How these stem-like T and NK cells are induced by the combination therapy is a mystery the team is now endeav-oring to solve.The researchers are also working to translate their prom-ising findings to the clinic. To do this, they will carefully examine the treatment’s safety and identify the patients and diseases that will most benefit from the treatment.Figure: Combining the artificial adjuvant vector cell (aAVC) vaccine with an interleukin (IL)-2/anti-IL-2 complex biased to the CD122 antigen (also known as IL-2Cx (S4B6)) enhances protection against cancer compared to the aAVC aloneThe aAVC system alone activated and expanded killer (CD8) T cells, natural killer (NK) cells, and memory killer T cells. In contrast, when the aAVC was administered alongside the IL-2Cx (S4B6), the combination treatment activated and expanded a larger variety of NK cells and killer T cells, including NK memory stem cells (NKscm) and T memory stem cells (Tscm), to provide prolonged, targeted protection against cancer.Original paper:Shimizu K, Ueda S, Kawamura M, Aoshima H, Satoh M, Nakabayashi J, Fujii S. Combination of cancer vaccine with CD122-biased IL-2/anti-IL-2 Ab complex shapes the stem-like effector NK and CD8+ T cells against tumor. J Immunother Cancer 11, e006409 (2023)Shin-ichiro FujiiTrialing a complex combination for cancer
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