Antigen-specific Immunotherapy in Ovarian Cancer and p53 as Tumor Antigen

Vermeij, Renee; Leffers, Ninke; Melief, Cornelis J.M.; Daemen, Toos; Nijman, Hans W.

doi:10.2174/138161212802002805

Cited by 12 publications

(11 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Firstly, OC cells express many tumor-associated antigens against which specific immune responses have been detected [6]–[10]. Secondly, the studies pioneered by Coukos and colleagues indicate tumor immune response is a critical determinant of clinical outcomes of patients with OC supported by the close correlation between survival of these patients and tumor infiltration with CD3 + T cells in the large annotated clinical samples [11].…”

Section: Introductionmentioning

confidence: 99%

PD-1 Blockade and OX40 Triggering Synergistically Protects against Tumor Growth in a Murine Model of Ovarian Cancer

et al. 2014

View full text Add to dashboard Cite

The co-inhibitory receptor Programmed Death-1 (PD-1) curtails immune responses and prevent autoimmunity, however, tumors exploit this pathway to escape from immune destruction. The co-stimulatory receptor OX40 is upregulated on T cells following activation and increases their clonal expansion, survival and cytokine production when engaged. Although antagonistic anti-PD-1 or agonistic anti-OX40 antibodies can promote the rejection of several murine tumors, some poorly immunogenic tumors were refractory to this treatment. In the present study, we evaluated the antitumor effects and mechanisms of combinatorial PD-1 blockade and OX40 triggering in a murine ID8 ovarian cancer model. Although individual anti-PD-1 or OX40 mAb treatment was ineffective in tumor protection against 10-day established ID8 tumor, combined anti-PD-1/OX40 mAb treatment markedly inhibited tumor outgrowth with 60% of mice tumor free 90 days after tumor inoculation. Tumor protection was associated with a systemic immune response with memory and antigen specificity and required CD4+ cells and CD8+ T cells. The anti-PD-1/OX40 mAb treatment increased CD4+ and CD8+ cells and decreased immunosuppressive CD4+FoxP3+ regulatory T (Treg) cells and CD11b+Gr-1+ myeloid suppressor cells (MDSC), giving rise to significantly higher ratios of both effector CD4+ and CD8+ cells to Treg and MDSC in peritoneal cavity; Quantitative RT-PCR data further demonstrated the induction of a local immunostimulatory milieu by anti-PD-1/OX40 mAb treatment. The splenic CD8+ T cells from combined mAb treated mice produced high levels of IFN-γ upon tumor antigen stimulation and exhibited antigen-specific cytolytic activity. To our knowledge, this is the first study testing the antitumor effects of combined anti-PD-1/OX40 mAb in a murine ovarian cancer model, and our results provide a rationale for clinical trials evaluating ovarian cancer immunotherapy using this combination of mAb.

show abstract

Section: Introductionmentioning

confidence: 99%

PD-1 Blockade and OX40 Triggering Synergistically Protects against Tumor Growth in a Murine Model of Ovarian Cancer

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Thus identification of common oncogene mutations in premalignant lesions could provide mutated epitopes against which a very safe and likely very strong immune response could be generated with a vaccine. Vaccines based on mutated oncogens such as H-ras, K-ras and p53 have been tested in animal models and in clinical trials in advanced cancer with marginal successes similar to vaccines based on non-mutated antigens [33–35]. Testing of vaccines based on these antigens in the prophylactic setting has not yet been tried in the clinic.…”

Section: Candidate Antigens For Preventative Vaccinesmentioning

confidence: 99%

Cancer immunoprevention

Finn

Beatty

2016

Current Opinion in Immunology

View full text Add to dashboard Cite

Cancer immunotherapy is now a reality. The results are phenomenal but the cost is outrageous. Even if the cost eventually comes down and immunotherapy becomes more broadly available, using the knowledge derived from immunotherapy to apply to immunoprevention would be a good strategy. The most likely approach to cancer immunoprevention is cancer vaccines. To date, cancer vaccines have been tested mostly in the setting of advanced disease. Numerous immunosuppressive mechanisms have been identified in the tumor microenvironment as well as systemically that compromise the ability of cancer patients to respond to the vaccines. Multiple approaches are being tested to improve therapeutic cancer vaccine efficacy, including combinations with other immunotherapies. An alternative approach is to administer the vaccines to individuals without cancer but at high risk for cancer. Data in support of this approach and immunoprevention in general is accumulating and clinical testing has started.

show abstract

“…Previous studies show that EOC cells express many tumor-associated antigens against which specific immune responses can be detected [5-9]. The pioneer studies by Coukos and colleagues further indicate immune response in tumor tissue is associated with clinical outcome of patients with EOC as evidenced by the close correlation between patient survival and tumor infiltration with CD3 + T cells in the large annotated clinical samples [10].…”

Section: Introductionmentioning

confidence: 99%

Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs

Lü¹,

Xü

Zhang³

et al. 2014

J Transl Med

154

125

View full text Add to dashboard Cite

BackgroundThe coinhibitory receptor Programmed Death-1 (PD-1) inhibits effector functions of activated T cells and prevents autoimmunity, however, cancer hijack this pathway to escape from immune attack. The costimulatory receptor glucocorticoid-induced TNFR related protein (GITR) is up-regulated on activated T cells and increases their proliferation, activation and cytokine production. We hypothesize that concomitant PD-1 blockade and GITR triggering would synergistically improve the effector functions of tumor-infiltrating T cells and increase the antitumor immunity. In present study, we evaluated the antitumor effects and mechanisms of combined PD-1 blockade and GITR triggering in a clinically highly relevant murine ID8 ovarian cancer model.MethodsMice with 7 days-established peritoneal ID8 ovarian cancer were treated intraperitoneally (i.p.) with either control, anti-PD-1, anti-GITR or anti-PD-1/GITR monoclonal antibody (mAb) and their survival was evaluated; the phenotype and function of tumor-associated immune cells in peritoneal cavity of treated mice was analyzed by flow cytometry, and systemic antigen-specific immune response was evaluated by ELISA and cytotoxicity assay.ResultsCombined anti-PD-1/GITR mAb treatment remarkably inhibited peritoneal ID8 tumor growth with 20% of mice tumor free 90 days after tumor challenge while treatment with either anti-PD-1 or anti-GITR mAb alone exhibited little antitumor effect. The durable antitumor effect was associated with a memory immune response and conferred by CD4+ cells and CD8+ T cells. The treatment of anti-PD-1/GITR mAb increased the frequencies of interferon-γ-producing effector T cells and decreased immunosuppressive regulatory T cells and myeloid-derived suppressor cells, shifting an immunosuppressive tumor milieu to an immunostimulatory state in peritoneal cavity. In addition, combined treatment of anti-PD-1/GITR mAb mounted an antigen-specific immune response as evidenced by antigen-specific IFN-γ production and cytolytic activity of spleen cells from treated mice. More importantly, combined treatment of anti-PD-1/GITR mAb and chemotherapeutic drugs (cisplatin or paclitaxel) further increased the antitumor efficacy with 80% of mice obtaining tumor-free long-term survival in murine ID8 ovarian cancer and 4 T1 breast cancer models.ConclusionsCombined anti-PD-1/GITR mAb treatment induces a potent antitumor immunity, which can be further promoted by chemotherapeutic drugs. A combined strategy of anti-PD-1/GITR mAb plus cisplatin or paclitaxel should be considered translation into clinic.

show abstract

Antigen-specific Immunotherapy in Ovarian Cancer and p53 as Tumor Antigen

Cited by 12 publications

References 0 publications

PD-1 Blockade and OX40 Triggering Synergistically Protects against Tumor Growth in a Murine Model of Ovarian Cancer

PD-1 Blockade and OX40 Triggering Synergistically Protects against Tumor Growth in a Murine Model of Ovarian Cancer

Cancer immunoprevention

Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs

Contact Info

Product

Resources

About