Novel combination immunotherapy with MUC1 vaccination and immune checkpoint blockade in ovarian cancer

AbstractCARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

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Novel therapeutics: response and resistance in ovarian cancer

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2019-000456 ◽

2019 ◽

Vol 29 (Suppl 2) ◽

pp. s16-s21 ◽

Cited By ~ 2

Author(s):

Dmitriy Zamarin

Keyword(s):

Ovarian Cancer ◽

Cancer Research ◽

Immune Checkpoint ◽

Parp Inhibitors ◽

Immune Checkpoint Blockade ◽

Cell Cycle Checkpoint ◽

Checkpoint Blockade ◽

The Novel ◽

Novel Therapeutics ◽

Dna Damaging Agents

Here we review the latest pre-clinical and clinical developments for treatment of ovarian cancer, presented at the American Association of Cancer Research/Rivkin Center Ovarian Cancer Research Symposium held at the University of Washington in September 2018. Abstracts and presentations pertaining to the 'Novel Therapeutics' session were reviewed and are summarized here. The session featured a keynote presentation from Dr Ursula Matulonis, who summarized the current state of the art of treatment of ovarian cancer, including recent clinical trials incorporating the use of novel agents, including poly-ADP-ribose polymerase (PARP) inhibitors, other DNA-damaging agents, vascular endothelial growth factor receptor inhibitors, mirvetuximab soravtansine, and immune checkpoint blockade. Dr Jung-Min Lee then summarized the rationale and the results of early studies for targeting cell cycle checkpoint kinases for anti-cancer therapy. Eight submissions were selected for oral presentations, and 36 abstracts were presented as posters. The topics covered a range of clinical and pre-clinical strategies and biomarkers, including immunotherapy, mechanisms of chemotherapy, and PARP inhibitor resistance, DNA-damaging agents, and other novel therapeutic strategies. Key studies have highlighted that resistance to chemotherapy and PARP inhibitors remain a major challenge in therapy of ovarian cancer. Cancer stem cells represent an important mechanism of chemoresistance and strategies to target these cells may be a pathway to prevention of ovarian cancer relapse. Advancement of novel therapeutics targeting DNA damage, cell metabolism, and endoplasmic reticulum present some of the novel strategies in the pipeline. Emerging compelling pre-clinical data with novel antibody-drug conjugates targeting various surface receptors in ovarian cancer alone and in combination with immune checkpoint blockade generate a strong enthusiasm for rapid translation of these strategies to clinic.

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