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Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC) [scRNA-Seq]

ABSTRACT: This study demonstrates two fundamental tenets of immunotherapy: vaccines targeting any tumor antigen will not be as effective as those targeting true oncogenic drivers and neither the stimulation of tumor-specific T-cells nor the blockade of a key immune checkpoint is enough to overcome the layers of immune suppression by itself. It provides single cell genetic evidence that vaccination alone generates a population of CD8 T-cells incapable of long-term tumor control due to the activation of numerous immune dysfunction pathways within the tumor. These promising studies have led to the initiation of a Phase II clinical trial testing a novel HER2 vaccine in combination with Pembrolizumab (NCT03632941) to determine if this combination can elicit effective anti-tumor immunity while minimizing off-target immune responses in patients with advanced HER2+ BC.

ORGANISM(S): Mus musculus

PROVIDER: GSE148480 | GEO | 2020/04/11

REPOSITORIES: GEO

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Project description:Background: Anti-PD-1 therapy has become a cornerstone of tumor immunotherapy. Over a dozen of anti-PD-1/PD-L1 antibodies have currently been marketed. However, these agents exhibit notable disparities in their characteristics and clinical performance. For instance, in the field of small cell lung cancer (SCLC) where the majority of anti-PD-1 antibodies yielded limited success, Serplulimab produced impressive survival improvements and has been approved by NMPA. The marketing authorization application has also been validated by EMA. Nevertheless, the molecular mechanism underpinning Serplulimab’s superiority over its competitors remains elusive. Methods: We characterized the difference of Serplulimab with approved PD-1/PD-L1 inhibitors such as Pembrolizumab and Nivolumab on their antibody binding features and funcations in vitro and anti-tumor activity in vivo. We also investigated the potential cellular pathways underlying the efficacy of Serplulimab in combination with other immune checkpoint inhibitors. Results: In comparison to competitors, Serplulimab robustly induces PD-1 receptor endocytosis while fostering weaker PD-1-CD28 cis interactions. This phenomenon could mitigate the dephosphorylation of CD28 by SHP2, thereby facilitating sustained and robust T cell activation. Notably, Serplulimab and Pembrolizumab exhibited similar performance in both in vitro Mixed Lymphocyte Reaction assays and in vivo efficacy studies. However, upon co-administration with anti-TIGIT or anti-LAG3, the Serplulimab-containing combination consistently demonstrated superior tumor killing efficacy compared to the Pembrolizumab-based combination. Moreover, our mechanistic investigations have unveiled that the Serplulimab combination effectively reduces tumor microenvironment Treg cell populations, augments effector and memory T cell populations, and more potently modulates genes associated with diverse facets of the immune system, surpassing the effects of the Pembrolizumab combination. Conclusions: In summary, our data underscore Serplulimab as a highly differentiated PD-1 monoclonal antibody with best-in-class therapeutic potential

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Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC) [scRNA-Seq]

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