Oncotarget

Research Papers: Immunology:

The sexist behaviour of immune checkpoint inhibitors in cancer therapy?

Andrea Botticelli, Concetta Elisa Onesti _, Ilaria Zizzari, Bruna Cerbelli, Paolo Sciattella, Mario Occhipinti, Michela Roberto, Francesca Di Pietro, Adriana Bonifacino, Michele Ghidini, Patrizia Vici, Laura Pizzuti, Chiara Napoletano, Lidia Strigari, Federica Mazzuca, Marianna Nuti and Paolo Marchetti

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Oncotarget. 2017; 8:99336-99346. https://doi.org/10.18632/oncotarget.22242

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Abstract

Andrea Botticelli1,2, Concetta Elisa Onesti1,2, Ilaria Zizzari3, Bruna Cerbelli4, Paolo Sciattella5, Mario Occhipinti1, Michela Roberto1,2, Francesca Di Pietro1,2, Adriana Bonifacino6, Michele Ghidini7, Patrizia Vici8, Laura Pizzuti8, Chiara Napoletano3, Lidia Strigari9, Giulia D’Amati4, Federica Mazzuca1,2, Marianna Nuti3 and Paolo Marchetti1,2

1Medical Oncology Department, Sant’Andrea Hospital, Rome, Italy

2Department of Clinical and Molecular Medicine, “Sapienza” University of Rome, Rome, Italy

3Department of Experimental Medicine, “Sapienza” University of Rome, Rome, Italy

4Department of Radiological Oncological and Pathological Sciences, “Sapienza” University of Rome, Rome, Italy

5Statistical Department, “Sapienza” University of Rome, Rome, Italy

6Breast Diagnosis and Treatment Unit, Sant’Andrea Hospital, “Sapienza” University of Rome, Rome, Italy

7Oncology Unit, ASST Cremona, Cremona, Italy

8Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy

9Laboratory of Medical Physics and Expert Systems, IRCCS Regina Elena National Cancer Institute, Rome, Italy

Correspondence to:

Concetta Elisa Onesti, email: [email protected]

Keywords: immune checkpoint inhibitors; anti-CTLA-4; anti-PD-1; sex differences; gender differences; Immunology

Received: July 28, 2017    Accepted: October 10, 2017    Published: November 01, 2017

ABSTRACT

Background: Immune checkpoint inhibitors, targeting the molecules CTLA-4, PD-1 and PD-L1, showed efficacy against several type of cancers and are currently used in clinical practice. An important biological variable that influences innate and adaptive immunity is the sex, acting through genetic, hormonal and environmental factors. The overall differences between sexes could be crucial to evaluate the response to ICIs.

Materials and methods: We performed a meta-analysis of Phase II-III Clinical Trials published up to June 2017 in which anti-CTLA-4, anti-PD-1 and anti-PD-L1 were studied. We extracted the OS and PFS HR differentiated by sex from subgroups analysis of each trial. We analyzed the three classes of drugs separately.

Results: We selected 36 Phase II-III Clinical Trials, 9 of which reported results for OS and 6 for PFS. We analyzed 2 Clinical Trials for OS with anti-CTLA-4, including 1178 patients, observing a benefit for males vs females (HR 0.65, 95% CI 0.55-0.77 vs HR 0.79, 95% CI 0.65-0.96, p 0.078).

Not statistically significant results were observed with anti-PD-1 neither for OS (males vs females: HR 0.72, 95% CI 0.64-0.83 vs HR 0.81, 95% CI 0.70-0.94, p 0.285) neither for PFS (males vs females: HR 0.66, 95% CI 0.52-0.82 vs HR 0.85, 95% CI 0.66-1.09, p 0.158). We cannot perform a meta-analysis for anti-PD-L1 due to the lack of data.

Conclusions: Different mechanisms could be involved in sex differences with regard to immunotherapy. These differences could be relevant to identify immunological targets in order to draw studies exploring novel combinations of immunotherapy agents.


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