Ipilimumab with stereotactic ablative radiation therapy : Phase I results and immunologic correlates from peripheral T-cells
Mené sur 35 patients présentant une ou plusieurs métastases au niveau du foie ou des poumons, cet essai de phase I évalue la dose limitante toxique de l'ipilimumab en combinaison avec une radiothérapie stéréotaxique ablative, puis analyse la réponse antitumorale des cellules du système immunitaire
Purpose : Little prospective data is available on clinical outcomes and immune correlates from combination radiation and immunotherapy. We conducted a phase I trial (NCT02239900) testing stereotactic ablative radiation therapy (SABR) with ipilimumab. Experimental Design : SABR was given either concurrently (1 day after the first dose) or sequentially (1 week after the second dose) with ipilimumab (3 mg/kg every 3 weeks for 4 doses) to 5 treatment groups: concurrent 50 Gy (in 4 fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and sequential 60 Gy (in 10 fractions) to lung or liver. Maximum tolerated dose was determined with a 3+3 dose de-escalation design. Immune marker expression was assessed by flow cytometry. Results : Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the radiation field was assessable in 31 patients. Three patients (10%) exhibited partial response and 7 (23%) experienced clinical benefit (defined as partial response or stable disease lasting {greater than or equal to}6 months). Clinical benefit was associated with increases in peripheral CD8+ T-cells; CD8+/CD4+ T-cell ratio; and proportion of CD8+ T-cells expressing 4-1BB and PD1. Liver (vs. lung) irradiation produced greater T-cell activation, reflected as increases in the proportions of peripheral T-cells expressing ICOS, GITR, and 4-1BB. Conclusions : Combining SABR and ipilimumab was safe with signs of efficacy; peripheral T-cell markers may predict clinical benefit; and systemic immune activation was greater after liver irradiation.