Durable complete response to neoantigen-loaded dendritic-cell vaccine following anti-PD-1 therapy in metastatic gastric cancer

Zengqing Guo, Yuan Yuan, Chao Chen, Jing Lin, Qiwang Ma, Geng Liu, Yan Gao, Ying Huang, Ling Chen, Li-Zhu Chen, Yu-Fang Huang, Hailun Wang, Bo Li, Yu Chen, Xi Zhang, Zengqing Guo, Yuan Yuan, Chao Chen, Jing Lin, Qiwang Ma, Geng Liu, Yan Gao, Ying Huang, Ling Chen, Li-Zhu Chen, Yu-Fang Huang, Hailun Wang, Bo Li, Yu Chen, Xi Zhang

Abstract

Neoantigens are ideal targets for dendritic cell (DC) vaccines. So far, only a few neoantigen-based DC vaccines have been investigated in clinical trials. Here, we reported a case of a patient with metastatic gastric cancer who received personalized neoantigen-loaded monocyte-derived dendritic cell (Neo-MoDC) vaccines followed by combination therapy of the Neo-MoDC and immune checkpoint inhibitor (ICI). The patient developed T cell responses against neoantigens after receiving the Neo-MoDC vaccine alone. The following combination therapy triggered a stronger immune response and mediated complete regression of all tumors for over 25 months till October, 2021. Peripheral blood mononuclear cells recognized seven of the eight vaccine neoantigens. And the frequency of neoantigen-specific T cell clones increased obviously after vaccination. Overall, this report describing a complete tumor regression in a gastric cancer patient mediated by Neo-MoDC vaccine in combination with ICI, and suggesting a promising treatment for patients with metastatic gastric cancer.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. The combination immunotherapy of Neo-MoDC…
Fig. 1. The combination immunotherapy of Neo-MoDC vaccine and nivolumab mediated rapid complete regression.
a Treatment schema. Cyclophosphamide (CTX) 300 mg/m2 was administrated two days before the first dose of Neo-MoDC vaccine. b The changes of tumor marker CA125 during the treatment. c Tumor lesions shrank during treatment and the follow-ups. Two vertical dotted lines denote day 126 (lymph node < 10 mm) and day 231 (tumor complete regression by PET/CT). d PET/CT image of right ovary (Left panels, yellow circles) and PET image (right panel) show complete regression on day 231. e Representative images of targeted tumor lesions during treatment. Yellow arrows represent targeted tumor lesions. Blue arrows denote complete regressed tumor lesions.
Fig. 2. Neoantigen-specific immunological monitoring.
Fig. 2. Neoantigen-specific immunological monitoring.
a Scans of ELISPOT (left panel) and quantification (right panel) results showed day62 PBLs (after DC vaccination, before ICI treatment) and day245 PBLs (after the combination treatment) generated more IFN-γ spots than day-6 PBLs (before vaccination) when induced by ASP pools 1 or 2. ASP pool 1, 15mer assay mutant peptides pool of TMEM38B F251V, TIGD3 V118M, ZZEF1 R898H, and URB1 R421W; ASP pool 2, 15mer assay mutant peptide pool of DLEC1 R331C, TMTC1 C313Y, MTA2 R92W, and TDP1 K112Rfs.101. The positive control for ELISPOT was PMA/ionomycin at the concentration of 1 ng/mL PMA and 500 ng/mL ionomycin. The control is media only. b Mapping of CD8+ T cells response to each 15mer peptide. Each 27mer mutant peptide was cutting into four 15mer peptides (denoted by blue, red, black, and orange bars) whose start and end positions in the 27mer peptide are 1-to-15, 5-to-19, 9-to-23, and 13-to-27 (also shown in Supplementary Fig. 3). Dotted line, 2 folds of mock (media only); *, mutant epitope with SFC number > 2 folds than that of mock. c ELISPOT assays showed that 5 out of 6 tested mutant peptides, but not their corresponding WT peptides, specifically activated CD8+ T cells. Data shown here were the mean value of two replicates. d Total frequency of neoantigen-specific TCRB clones increased during vaccination. e Neoantigen-specific TCRB clones, whose frequencies were in top 10 in tumor tissue, changed in PBLs during vaccination.

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