Abstract CT100: A new therapeutic cancer vaccine inducing multifunctional immunity, artificial adjuvant vector cells
Authors: Fujii Shin-ichiro , Kawamata Toyotaka , Shimizu Kanako , Nakabayashi Jun , Yamasaki Satoru , Iyoda Tomonori , Shinga Jun Jun , Hidaka Michihiro , Nojima Masanori , Nagamura Fumitaka , Tojo Arinobu 
Published: April 2023

Abstract
Background: Cancer immunotherapy is an effective way of battling cancer, and is based on artificial stimulation of the immune system to attack cancer cells. Although several strategies show successful results, it remains to prevent the subsequent cancer escape from the immune surveillance. The further success depends on a variety of functional effector cell types involved and their sustenance following activation. For this purpose, simultaneous induction of innate and adaptive immunity should be one of ideal strategies. We focus on DCs, which play a pivotal role in determining the quality and magnitude of innate and adaptive immunity. To effectively utilize the DC in situ, we have developed a system using allogeneic cells as artificial adjuvant vector cells (aAVCs), comprised of a CD1d-NKT ligand complex on the cell surface and containing tumor antigen inside of the cells. This approach induces adjuvant effects by combining NKT cell activation with delivery of tumor antigen to DCs in vivo. In addition to linking innate and adaptive immunity, aAVC therapy can lead to efficient trafficking of specific anti-tumor CD8+ T cells to the tumor site and also the formation of long-term memory T cells. This novel design of aAVC therapy is a platform and allows for a replacement of any cancer antigens as the therapeutic package. After completion of the regulatory science consultation for discussing the pharmaceutical quality and the design of a clinical study with PMDA in Japan, we developed the WT1-expressing aAVC (aAVC-WT1) for the clinical application.
Methods: This first-in-human, open label, single-center trial involves a bifurcated 3+3 design with aAVC-WT1 dose escalations (1 × 106, 1 × 107, and 1 × 108 per body). The three patients in each cohort had not received any chemotherapy during more than 2 weeks before the therapy and had received aAVC-WT1 intravenously twice in a 4-week interval. Nine of the ten enrolled patients with relapsed and refractory AML underwent complete analysis per-protocol set and were evaluated in our phase I dose-escalation trial of aAVC-WT1.
Results: No dose-limiting toxicities were observed, whereas activation of NKT and/or NK cells was observed in all patients. Five patients experienced objective leukemic regression, which correlated with WT1-specific T-cell responses. Paired single-cell RNA and TCR sequencing demonstrated effector CD8+ T cell clones in the bone marrow. Some bone marrow CD8+ T cells underwent transition from pre-existing precursor exhausted T cells to functional T cells or emerged as newly activated T cells, some of which were maintained long-term. These demonstrate the feasibility and safety of aAVC-WT1 therapy and the capacity of this platform to activate both innate and adaptive immunity in humans.
Conclusion: aAVC-WT1 therapy showed an acceptable safety profile at doses tested and encouraging signs of clinical response. These data support further development of aAVC-WT1 for patients with AML. Clinical trial registry number: UMIN 000028083.
Citation Format: Shin-ichiro Fujii, Toyotaka Kawamata, Kanako Shimizu, Jun Nakabayashi, Satoru Yamasaki, Tomonori Iyoda, Jun Jun Shinga, Michihiro Hidaka, Masanori Nojima, Fumitaka Nagamura, Arinobu Tojo. A new therapeutic cancer vaccine inducing multifunctional immunity, artificial adjuvant vector cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT100.