Dataset Information

Enfortumab Vedotin Induces Immunogenic Cell Death and Shows Enhanced Preclinical Antitumor Activity When Combined With a PD-1 Inhibitor

ABSTRACT: Enfortumab vedotin is a Nectin-4-directed antibody–drug conjugate designed to deliver the microtubule-disrupting agent monomethyl auristatin E (MMAE) in tumor cells. Using preclinical models of urothelial cancer (UC), we expand the understanding of the multifaceted mechanism of action for enfortumab vedotin that includes direct cytotoxicity on Nectin-4–positive tumor cells, indirect bystander effect on neighboring Nectin-4–negative tumor cells, and MMAE-mediated induction of immunogenic cell death (ICD) and associated increase in activated immune cells in the tumor microenvironment. Importantly, vaccination with enfortumab vedotin-treated tumor cells drives antitumor immunity and provides protection against rechallenge in mice. MMAE-mediated ICD induction modulates the tumor microenvironment in a complementary manner to immune checkpoint inhibition. Accordingly, enfortumab vedotin plus PD-1 inhibitor shows enhanced antitumor activity in vivo. These preclinical results demonstrate the underlying mechanisms consistent with the significantly improved clinical outcomes observed for enfortumab vedotin plus pembrolizumab relative to chemotherapy in the first-line treatment of la/mUC.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE264352 | GEO | 2024/04/19

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described; whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets taking advantage from well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers: the combination of retinoic acid (RA) and interferon-alpha (IFN-a) and doxorubicin, and to non ICD inducers like gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells subjected to ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). In this sense, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for a proper immune system antitumor response activation. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression validated the inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and the inhibitory co-receptor LAG-3 on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of Class I and II MHC pathway, whose implication in ICD was demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.

Project description:Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types. However, evidence illustrates that targeting FAK is most effective in combination therapy rather than in monotherapy. Here, we demonstrated that the FAK inhibitor, IN10018, and pegylated liposome doxorubicin (PLD) exerted effective antitumor activity preclinically and clinically (clinical trial ID: CTR20200913). The clinical study is a phase Ib trial which includes dose confirmation and expansion sections. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. As of the data cutoff date (30 November 2022), a total of 61 platinum-resistant ovarian cancer (PROC) patients were enrolled and no IN10018-related grade 4 or 5 adverse effects (AEs) were reported. The ORR was 46.3% (95% confidence interval (CI): 32.6%, 60.4%) and the DCR was 83.3% (95% CI: 70.7%, 92.1%). The median PFS was 7.26 months (95% CI: 5.16 - 8.02 months), and the median duration of response (DoR) was 6.93 months (95% CI: 4.17 - 9.13 months). The primary and secondary endpoints were met. The median OS was not reached, and still maturing. Notably, the regimen exhibited response latency and long-lasting effects in the clinical trial, outcomes frequently observed in immunotherapy. Our preclinical study revealed that the 2-drug combination can maximize the immunogenic cell death (ICD) of cancer cells, boosting the maturation of dendritic cells (DCs) and stimulating CD8 T cells to strengthen the antitumor effects. At present, immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of immunogenic niche. Our work confirmed that IN10018 in combination with PLD can prime the tumor microenvironment, supplementing it with sufficient tumor-infiltrating lymphocytes (TILs) to activate antitumor immunity. Correspondingly, animal studies validated that the antitumor effects of ICB can be significantly enhanced by this doublet regimen. The preclinical results warrant further clinical exploration for the triplet regimen with IN10018, PLD, and ICB.

Dataset Information

Enfortumab Vedotin Induces Immunogenic Cell Death and Shows Enhanced Preclinical Antitumor Activity When Combined With a PD-1 Inhibitor

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets