Investigation of the impact of sex hormones on cancer immunotherapy outcome

Although the introduction of immune checkpoint inhibitors (ICI), which block tumor-elicited inhibitory signals on CD8+ cytotoxic T cells, has revolutionized treatment of patients with many cancer types, cancer still is one of the major causes of death worldwide. So far, only a minority of cancer patients have long-term control of their disease via immunotherapies. In this context, data from clinical trials suggest that there might be fundamental differences in the way that male and female cancer patients respond to immunotherapy. In line with those results, we could show that in mouse models of colorectal and lung cancer, male mice benefited much more from immunotherapies with so-called immune checkpoint inhibitors. Our preliminary results indicate that the better immunotherapy response in males is related to the higher testosterone levels in males, which may influence the tumor microenvironment and the activity of important immune cells. In the next years, we will work on understanding how exactly testosterone influences responses to cancer immunotherapy, and whether there are other mechanisms that have to be taken into account as well, both using mouse models and patient samples.

In addition, we are currently in the process of setting up a Phase 3 clinical trial together with patient experts to investigate if the smaller benefit of females from anti-PD1 blockade can be overcome by additional chemotherapy. This trial is potentially practice-changing and represents the first ever sex-specific lung cancer clinical trial. In addition, the design process is a successful example of patient involvement, which is still underdeveloped in Germany.

Enrollment is planned to start summer 2025.

Ben-Batalla, I., M. E. Vargas-Delgado, M. Janning, G. Von Amsberg, and S. Loges. (2020)
Influence of androgens in immunity to self and foreign: Effects on immunity and cancer.
Frontiers in Immunology I 11:1184

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Ben-Batalla, I., M. E. Vargas-Delgado, L. Meier, and S. Loges. (2019)
Sexual dimorphism in solidand hematological malignancies.
Semin Immunopathol I 41:251-263

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Bauer, R., F. Udonta, M. Wroblewski, I. Ben-Batalla, I. M. Santos, F. Taverna, M. Kuhlencord, V. Gensch, S. Pasler, S. Vinckier, J. M. Brandner, K. Pantel, C. Bokemeyer, T. Vogl, J. Roth, P. Carmeliet, and S. Loges. (2018)
Blockade of Myeloid-Derived Suppressor Cell Expansion with All-Trans Retinoic Acid Increases the Efficacy of Antiangiogenic Therapy.
Cancer Res I 78:3220-3232

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Wroblewski, M., R. Bauer, M. Cubas Cordova, F. Udonta, I. Ben-Batalla, K. Legler, C. Hauser, J. Egberts, M. Janning, J. Velthaus, C. Schulze, K. Pantel, C. Bokemeyer, and S. Loges. (2017)
Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B.
Nat Commun I 8:269

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Ben-Batalla, I., R. Erdmann, H. Jorgensen, R. Mitchell, T. Ernst, G. von Amsberg, P. Schafhausen, J. L. Velthaus, S. Rankin, R. E. Clark, S. Koschmieder, A. Schultze, S. Mitra, P. Vandenberghe, T. H. Brummendorf, P. Carmeliet, A. Hochhaus, K. Pantel, C. Bokemeyer, G. V. Helgason, T. L. Holyoake, and S. Loges. (2017)
Axl Blockade by BGB324 Inhibits BCRABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia.
Clin Cancer Res I 23:2289-2300

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