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Immune Checkpoint Blockers and Ovarian Cancer.

ABSTRACT: Although the idea, called "cancer immunotherapy," is very appealing and has previously been shown to work in several mouse models of cancer, it has in general been very difficult to translate cancer immunotherapy approaches to humans. Because of this frustration, by the 1990s, many scientists and biotechnology companies had given up on the idea of cancer immunotherapy. After few years, first detection T-cell suppression of effect of cytotoxic T-lymphocyte antigen-4 (CTLA4) molecule was established. Antibody (Ab) to CTLA4 could increase T-cell starting a completely new age of tumor immunology. Immune checkpoints are new ways in manipulation of immunological control over malignant tumors. It has lent an important measure to manage, especially recurrent and refractory cancers and those cancer where there is an unmet need like recurrent melanoma, renal cell carcinoma, and recurrent ovarian cancer. As a new development, this subject is experiencing rapid progress, and multiple avenues are opening up. Although there are many hurdles to overcome this needs constant updating, especially for students of ovarian cancer who are looking at it with much hope.

SUBMITTER: Bose CK

PROVIDER: S-EPMC5582557 | biostudies-literature | 2017 Apr-Jun

REPOSITORIES: biostudies-literature

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Immune Checkpoint Blockers and Ovarian Cancer.

Bose Chinmoy K CK

Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology 20170401 2

Although the idea, called "cancer immunotherapy," is very appealing and has previously been shown to work in several mouse models of cancer, it has in general been very difficult to translate cancer immunotherapy approaches to humans. Because of this frustration, by the 1990s, many scientists and biotechnology companies had given up on the idea of cancer immunotherapy. After few years, first detection T-cell suppression of effect of cytotoxic T-lymphocyte antigen-4 (CTLA4) molecule was establish ...[more]

PMID: 28900328

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Project description:BACKGROUND:Oxazaphosphorines (cyclophosphamide (CPA), ifosfamide (IFO)) are major alkylating agents of polychemotherapy protocols but limiting their toxicity and increasing their efficacy could be of major interest. Oxazaphosphorines are prodrugs that require an activation by cytochrome P450 (CYP). CPA is mainly metabolized (>80%) to phosphoramide mustard while only 10%-50% of IFO is transformed in the alkylating entity, isophosphoramide mustard and 50%-90% of IFO release chloroacetaldehyde, a nephrotoxic and neurotoxic metabolite. Geranyloxy-IFO (G-IFO) was reported as a preactivated IFO to circumvent the toxic pathway giving directly the isophosphoramide mustard without CYP metabolization. The similarity in structure of CPA and IFO and the similarity in metabolic balance of CPA and G-IFO have led us to explore immunomodulatory effect of these components in mice and to investigate the combination of these oxazaphosphorines with immune checkpoint blockers (ICB). METHODS:The investigation of the immunomodulatory properties of IFO and G-IFO compared with CPA has been conducted through immune cell phenotyping by flow cytometry and analysis of the cytokine profile of T cells after ex-vivo restimulation. T cell-mediated antitumor efficacy was confirmed in CD4+ and CD8+ T cell-depleted mice. A combination of oxazaphosphorines with an anti-programmed cell death 1 (PD-1) antibody has been studied in MCA205 tumor-bearing mice. RESULTS:Studies on a MCA205 mouse model have demonstrated a dose-dependent effect of IFO and G-IFO on T cell immunity. These components in particular favored Th1 polarization when used at low dose (150 and eq. 100 mg/kg, respectively). Antitumor activity at low dose was abolished in mice depleted in CD4+ and CD8+ T cells. G-IFO at low dose (eq. 100 mg/kg) in combination with anti-PD-1 antidody showed high synergistic antitumor efficacy compared with IFO. CONCLUSION:Oxazaphosphorines are characterized by a dual mechanism of antitumor action; low-dose schedules should be preferred in combination with ICB, and dose escalation was found to have better utility in polychemotherapy protocols where a conventional direct cytotoxic anticancer effect is needed. G-IFO, the novel oxazaphosphorine drug, has shown a better metabolic index compared with IFO as its metabolization gives mainly the alkylating mustard as CPA (and not IFO) and a best potential in combination with ICB.

Dataset Information

Immune Checkpoint Blockers and Ovarian Cancer.

Publications

Immune Checkpoint Blockers and Ovarian Cancer.

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