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Background Ipi 10 mg/kg (every 3 weeks for 4 doses) combined with a 3 + 3 dose-escalation design of RT at week 4 (W4) seemed to have antitumor activity in the 19 pts treated in the phase I study Mel-Ipi-Rx from August 2011 to July 2015 (ESMO 2016, 1117P). This ancillary study assesses the impact of ipi + RT on SIAR and TGR variation (ΔTGR) of irradiated (TGRirr) and non-irradiated (TGRnon-irr) lesions. Methods Blood samples were collected at baseline (W0), W4 (before 2nd ipi injection) and W6 (after ipi + RT) to phenotype T cells. TGR, defined as an increase in tumor volume during 1 month, was computed for TGRirr, and TGRnon-irr in 2 periods: (i) Reference-TGR (REF-TGR) on W0, and (ii) Experimental-TGR (EXP-TGR) between W0 and 1st evaluation. The ΔTGR between REF-TGR and EXP-TGR was used to assess the treatment (TRT) effect. A negative value reflected a slowdown of disease progression (DP). Results Ipi alone was associated with increased effector T cells (TEM), Treg and ICOS+ CD4+ T cells at W4. At W6, only TEM and ICOS+ CD4+ T cells significantly increased, suggesting that RT + ipi could increase activated memory CD4+ T cells rather than Treg cells. CD8+ T cells did not increase at W4 while central memory T cells (TCM) and terminally differentiated (TEMRA) increased between W4 and W6, suggesting that RT + ipi could boost these CD8+ T populations. Increased CD8 from W0 to W4 was significantly correlated to progession-free survival (PFS) (p = 0.0163). Increased CD8 tended to be positively correlated to overall survival (OS) from W0 to W6 (p = 0.0786). Interestingly, a higher effect of RT + ipi seemed to be associated with a deeper ΔTGRnon-irr than ΔTGRirr, although insignificant. The EXP-TGRnon-irr was significantly associated with DP. Conclusions RT + ipi was associated with increased CD4+ and CD8+ ICOS+ T cells. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation. The ΔTGRnon-irr lesions could be more important than ΔTGRirr lesions in responding pts and may be related to an abscopal effect. Updated PFS and OS will be presented. Clinical trial identification EUDRACT 2010-020317-93 NCT01557114. Legal entity responsible for the study Eric Deutsch and Caroline Robert are both corresponding authors and contributed equally to the work. Funding Has not received any funding. Disclosure C. Boutros: Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Speaker Bureau / Expert testimony: Merck. N. Chaput: Research grant / Funding (self): Cytune Pharma; Research grant / Funding (self): BMS; Research grant / Funding (self): Sanofi; Research grant / Funding (institution): GSK; Honoraria (self), Advisory / Consultancy: AstraZeneca. C. Mateus: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck. E. Routier: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pierre Fabre. C. Massard: Honoraria (self), Advisory / Consultancy: AMGEN; Honoraria (self), Advisory / Consultancy: ASTELLAS; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: BeiGene; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Celgene; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Merck; Non-remunerated activity/ies: AstraZeneca; Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: BMS; Non-remunerated activity/ies: Johnson and Johnson; Non-remunerated activity/ies: Lilly; Non-remunerated activity/ies: MedImmune; Non-remunerated activity/ies: Merck. C. Caramella: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: MSK; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Amgen. J. Soria: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Astex; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: GSK; Honoraria (self), Advisory / Consultancy: GammaMabs; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Roche/genentech; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Takeda; Full / Part-time employment, Full time employee since 2017: MedImmune; Shareholder / Stockholder / Stock options: AstraZeneca; Shareholder / Stockholder / Stock options: Gristso. C. Robert: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: MSD. E. Deutsch: Honoraria (self), Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Boehringer; Honoraria (self), Advisory / Consultancy: MedImmune; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy: Accuray; Honoraria (self), Speaker Bureau / Expert testimony: MSD. All other authors have declared no conflicts of interest.