Joana Felix1, Jérome Lambert2, Marie Roelens3, Eve Maubec4, Hélène Guermouche3, Cécile Pages5, Irina Sidina5, Debora J Cordeiro6, Guitta Maki7, François Chasset5, Raphaël Porcher8, Martine Bagot9, Anne Caignard3, Antoine Toubert6, Céleste Lebbé9, Hélène Moins-Teisserenc6. 1. INSERM, UMR-1160, Institut Universitaire d'Hématologie, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France. 2. Université Paris Diderot, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Saint-Louis, Service de Biostatistique et Informatique Médicale, Paris, France; INSERM, UMR 1153, Center de Recherche Epidémiologie et Statistique (CRESS), Paris, France. 3. INSERM, UMR-1160, Institut Universitaire d'Hématologie , Paris, France. 4. Service de Dermatologie, Hôpital Xavier Bichat , AP-HP , Paris, France. 5. Service de Dermatologie , AP-HP , Hôpital Saint Louis, Paris, France. 6. INSERM, UMR-1160, Institut Universitaire d'Hématologie, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Laboratoire d'Immunologie-Histocompatibilité, AP-HP, Hôpital Saint Louis, Paris, France. 7. Laboratoire d'Immunologie-Histocompatibilité , AP-HP , Hôpital Saint Louis, Paris, France. 8. INSERM, UMR 1153, Center de Recherche Epidémiologie et Statistique (CRESS), Paris, France; Centre d'Epidémiologie Clinique, Hôtel-Dieu, AP-HP, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 9. Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Service de Dermatologie, AP-HP, Hôpital Saint Louis, Paris, France; INSERM, UMR-976, Hôpital Saint-Louis, Paris, France.
Abstract
PURPOSE: Therapy targeting CTLA-4 immune checkpoint provides increased survival in patients with advanced melanoma. However, immunotherapy is frequently associated with delayed and heterogeneous clinical responses and it is important to identify prognostic immunological correlates of clinical endpoints. EXPERIMENTAL DESIGN: 77 patients with stage III/IV melanoma were treated with ipilimumab alone every 3 weeks, during 9 weeks. Blood samples were collected at the baseline and before each dose for in depth immune monitoring. RESULTS: The median follow-up was 28 mo with a median survival of 7 mo. Survival and clinical benefit were significantly improved when absolute lymphocyte count at the baseline was above 1 × 10(9)/L. Notably, ipilimumab had a global effect on memory T cells, with an early increase of central and effector subsets in patients with disease control. By contrast, percentages of stem cell memory T cells (TSCM) gradually decreased despite stable absolute counts and sustained proliferation, suggesting a process of differentiation. Higher proportions of eomes(+) and Ki-67(+) T cells were observed, with enhanced skin homing potential and induction of cytotoxic markers. CONCLUSION: These results suggest that CTLA-4 blockade is able to reshape the memory subset with the potential involvement of Eomes and memory subsets including TSCM.
PURPOSE: Therapy targeting CTLA-4 immune checkpoint provides increased survival in patients with advanced melanoma. However, immunotherapy is frequently associated with delayed and heterogeneous clinical responses and it is important to identify prognostic immunological correlates of clinical endpoints. EXPERIMENTAL DESIGN: 77 patients with stage III/IV melanoma were treated with ipilimumab alone every 3 weeks, during 9 weeks. Blood samples were collected at the baseline and before each dose for in depth immune monitoring. RESULTS: The median follow-up was 28 mo with a median survival of 7 mo. Survival and clinical benefit were significantly improved when absolute lymphocyte count at the baseline was above 1 × 10(9)/L. Notably, ipilimumab had a global effect on memory T cells, with an early increase of central and effector subsets in patients with disease control. By contrast, percentages of stem cell memory T cells (TSCM) gradually decreased despite stable absolute counts and sustained proliferation, suggesting a process of differentiation. Higher proportions of eomes(+) and Ki-67(+) T cells were observed, with enhanced skin homing potential and induction of cytotoxic markers. CONCLUSION: These results suggest that CTLA-4 blockade is able to reshape the memory subset with the potential involvement of Eomes and memory subsets including TSCM.
Entities:
Keywords:
CTLA-4; TSCM; immunotherapy; ipilimumab; melanoma; memory T cells
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