Antigen-specific active immunotherapy for ovarian cancer

Leffers, Ninke; Daemen, Toos; Helfrich, Wijnand; Boezen, H. Marike; Cohlen, Ben J; Melief, Kees; Nijman, Hans W.

doi:10.1002/14651858.cd007287.pub2

Cited by 15 publications

(12 citation statements)

References 64 publications

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“…Various targeted strategies have been evaluated for OC management [1, 4, 5] and many molecules are under investigation, among which agents to block growth factor receptors, such as monoclonal antibodies (MAbs), or tyrosine kinase inhibitors (TKIs), anti-angiogenetic molecules and DNA repair inhibitors, such as Poly(ADP-ribose) polymerase (PARP) inhibitors such olaparib (for review see [5]). However, these molecules only provide short-term survival improvement [6] and more effective treatments to address chemo-resistant recurrent OC are not available yet.…”

Section: Introductionmentioning

confidence: 99%

“…Finally, OC heterogeneity also complicates the targeted treatment strategies. The molecules evaluated in clinical trials do not seem to be clinically effective and with low toxicity in OCs [4]. Recently, in phase 2 trials, eight targeted drugs (gefitinib, imatinib, sorafenib, temsirolimus, mifepristone, enzastaurine, lapatinib and vorinostat) have produced objective response rates of less than 10% and stabilized the disease for six months in less than 25% of patients [11].…”

Section: Introductionmentioning

confidence: 99%

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The anti-tumor efficacy of 3C23K, a glyco-engineered humanized anti-MISRII antibody, in an ovarian cancer model is mainly mediated by engagement of immune effector cells

Estupina

Fontayne

Barret³

et al. 2017

Oncotarget

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Ovarian cancer is the leading cause of death in women with gynecological cancers and despite recent advances, new and more efficient therapies are crucially needed. Müllerian Inhibiting Substance type II Receptor (MISRII, also named AMHRII) is expressed in most ovarian cancer subtypes and is a novel potential target for ovarian cancer immunotherapy. We previously developed and tested 12G4, the first murine monoclonal antibody (MAb) against human MISRII. Here, we report the humanization, affinity maturation and glyco-engineering steps of 12G4 to generate the Fc-optimized 3C23K MAb, and the evaluation of its in vivo anti-tumor activity. The epitopes of 3C23K and 12G4 were strictly identical and 3C23K affinity for MISRII was enhanced by a factor of about 14 (KD = 5.5 × 10−11 M vs 7.9 × 10−10 M), while the use of the EMABling® platform allowed the production of a low-fucosylated 3C23K antibody with a 30-fold KD improvement of its affinity to FcγRIIIa. In COV434-MISRII tumor-bearing mice, 3C23K reduced tumor growth more efficiently than 12G4 and its combination with carboplatin was more efficient than each monotherapy with a mean tumor size of 500, 1100 and 100 mm3 at the end of treatment with 3C23K (10 mg/kg, Q3-4D12), carboplatin (60 mg/kg, Q7D4) and 3C23K+carboplatin, respectively. Conversely, 3C23K-FcKO, a 3C23K form without affinity for the FcγRIIIa receptor, did not display any anti-tumor effect in vivo. These results strongly suggested that 3C23K mechanisms of action are mainly Fc-related. In vitro, antibody-dependent cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP) were induced by 3C23K, as demonstrated with human effector cells. Using human NK cells, 50% of the maximal lysis was obtained with a 46-fold lower concentration of low-fucosylated 3C23K (2.9 ng/ml) than of 3C23K expressed in CHO cells (133.35 ng/ml). As 3C23K induced strong ADCC with human PBMC but almost none with murine PBMC, antibody-dependent cell phagocytosis (ADCP) was then investigated. 3C23K-dependent (100 ng/ml) ADCP was more active with murine than human macrophages (only 10% of living target cells vs. about 25%). These in vitro results suggest that the reduced ADCC with murine effectors could be partially balanced by ADCP activity in in vivo experiments. Taken together, these preclinical data indicate that 3C23K is a new promising therapeutic candidate for ovarian cancer immunotherapy and justify its recent introduction in a phase I clinical trial.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The anti-tumor efficacy of 3C23K, a glyco-engineered humanized anti-MISRII antibody, in an ovarian cancer model is mainly mediated by engagement of immune effector cells

Estupina

Fontayne

Barret³

et al. 2017

Oncotarget

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“…Although antibody approaches have been successful in other epithelial carcinomas, especially those of breast and colon, no such efficacy has yet been clearly demonstrated in OC. Nonetheless, the best evidence for immune efficacy in OC is with anti-CA- 125 antibodies, yet even in this approach, little clinical benefit is seen despite successful induction of significant immune responses [56].…”

Section: Anti-cd64mentioning

confidence: 99%

Immune Therapy for Ovarian Cancer: Promise and Pitfalls

Thibodeaux

Curiel

2011

International Reviews of Immunology

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“…Preclinical and preliminary clinical studies aimed at proving the immunotherapy concept in EOC were initiated by using monoclonal Ab (mAb), vaccinations or adoptive T-cell transferts [113-115]. The majority of these studies were uncontrolled phase I/II studies, with small sample sizes and heterogeneous inclusion criteria (recurrent or chemotherapy-refractory diseases) disrupting the comparisons and the identification of the best strategy.…”

Section: Introductionmentioning

confidence: 99%

“…All these mAb demonstrated adequate safety and tolerability but failed to demonstrate clear clinical benefits, even when an immunological response was evidenced [114,115]. Active immunotherapy by vaccination based on peptides or cellular approaches were also evaluated.…”

Section: Introductionmentioning

confidence: 99%

Immunity of human epithelial ovarian carcinoma: the paradigm of immune suppression in cancer

et al. 2013

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Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women, and there has been no substantial decrease in the death rates due to EOC in the last three decades. Thus, basic knowledge regarding ovarian tumor cell biology is urgently needed to allow the development of innovative treatments for EOC. Traditionally, EOC has not been considered an immunogenic tumor, but there is evidence of an immune response to EOC in patients. Clinical data demonstrate that an antitumor immune response and immune evasion mechanisms are correlated with a better and lower survival, respectively, providing evidence for the immunoediting hypothesis in EOC. This review focuses on the immune response and immune suppression in EOC. The immunological roles of chemotherapy and surgery in EOC are also described. Finally, we detail pilot data supporting the efficiency of immunotherapy in the treatment of EOC and the emerging concept that immunomodulation aimed at counteracting the immunosuppressive microenvironment must be associated with immunotherapy strategies.

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Antigen-specific active immunotherapy for ovarian cancer

Cited by 15 publications

References 64 publications

The anti-tumor efficacy of 3C23K, a glyco-engineered humanized anti-MISRII antibody, in an ovarian cancer model is mainly mediated by engagement of immune effector cells

The anti-tumor efficacy of 3C23K, a glyco-engineered humanized anti-MISRII antibody, in an ovarian cancer model is mainly mediated by engagement of immune effector cells

Immune Therapy for Ovarian Cancer: Promise and Pitfalls

Immunity of human epithelial ovarian carcinoma: the paradigm of immune suppression in cancer

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