Mechanism informs precision: In vivo determinants of response to anti-CTLA-4 antibodies (2018)

Background: Anti-CTLA-4 antibodies (mAbs) display impressive activity in mouse models relative to human subjects, yet this is rarely acknowledged. Translational efforts to date have focused principally on identifying mechanisms of response and resistance in humans, with little reference to pre-clinical models. Through parallel analysis of mouse and human tumours, we sought to characterise respective in vivo determinants of response to anti-CTLA-4 mAbs. Methods: Through multi-parametric flow-based profiling of blood, lymph node and tumour in mouse models and human cancers, we identified lymphocyte and innate effector cell subsets and compared expression of immune checkpoints and activatory/inhibitory Fc gamma receptors (FcγRs) required for ADCC. Thereafter, with use of a transgenic mouse model in which human FcγR expression is effectively recapitulated, we characterised in vivo mechanisms underlying the activity of anti-CTLA-4 mAbs. The translational relevance of such findings was confirmed through analysis of tumour exomes in patients with advanced melanoma treated with ipilimumab. Results: Antibodies of isotype equivalent to ipilimumab and tremelimumab exert their activity principally through depletion of intra-tumoural regulatory T cells (Treg) in vivo, increasing the CD8+ to Treg ratio and promoting tumour rejection. However, this activity only appears relevant in the context of inflamed tumour models. In this setting, engineered antibodies with improved FcγR binding profiles drive superior anti-tumour responses and survival in mouse models. In keeping with these observations, in patients with advanced melanoma, the presence of the germline CD16-V158F polymorphism, which confers a higher binding affinity to FcγRs, is associated with response to anti-CTLA-4 therapy, but only in tumours with high mutational or neoantigen burden. Conclusions: Treg depletion contributes to the activity of human anti-CTLA-4 mAbs but only in the context of inflamed tumours, explaining the modest response rates observed in the clinical setting relative to mouse models. The activity of anti-CTLA-4 mAbs in inflamed tumours may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumours will likely require combination approaches. Legal entity responsible for the study: The Royal Marsden NHS Foundation Trust, University College London Cancer Institute and The Francis Crick Institute. Funding: UCL/UCL Hospitals Biomedical Research Centre, the CRUK-UCL Centre (C416/A18088), CRUK’s Lung Cancer Centre of Excellence (C5759/A20465), the Comprehensive Cancer Imaging Centre (CCIC), the Cancer Immunotherapy Accelerator Award (CITA-CRUK) (C33499/A20265), CRUK’s TRACERx (led by C.S.) (C11496/A17786), the Sam Keen Foundation/UCL NIHR Biomedical Research Centre (A.J.S.F.), the UK MRC Skills Development Fellowship Award (K.L.), Bloodwise (formerly Leukaemia and Lymphoma Research) (08022/P4664), the Department of Health, and CRUK funding schemes for NIHR BRC and Experimental Cancer Medicine Centres. Disclosure: J. Larkin: Institutional research support: BMS, MSD, Novartis, Pfizer Consultancy: Eisai, BMS, MSD, GSK, Kymab, Pfizer, Novartis, Roche/Genentech, Secarna, Pierre Fabre, EUSA Pharma Support from NIHR RM/ICR Biomedical Research Centre for Cancer. C. Swanton: Grants: Pfizer, AstraZeneca Honoraria or consultant fees: Roche Ventana, Celgene, Pfizer, Novartis, Genentech, BMS Stock shareholder: GRAIL, Epic Biosciences, Apogen Biotech. Co-founder of Achilles Therapeutics. All other authors have declared no conflicts of interest.