Immune checkpoint inhibitors1 result in impressive clinical responses2-5 but optimal results will require combination with each other6 and other therapies.,This raises fundamental questions about mechanisms of non-redundancy and resistance.,Here, we report major tumor regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation (RT) and reproduced this effect in mouse models.,Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common.,Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T cell exhaustion.,Accordingly, optimal response in melanoma and other cancer types requires RT, anti-CTLA4, and anti-PD-L1/PD-1.,Anti-CTLA4 predominantly inhibits T regulatory cells (Tregs) to increase the CD8 T cell to Treg (CD8/Treg) ratio.,RT enhances the diversity of the T cell receptor (TCR) repertoire of intratumoral T cells.,Together, anti-CTLA4 promotes expansion of T cells, while RT shapes the TCR repertoire of the expanded peripheral clones.,Addition of PD-L1 blockade reverses T cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligo-clonal T cell expansion.,Similar to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed.,Thus, PD-L1 on melanoma cells allows tumors to escape anti-CTLA4-based therapy, and the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response and immunity through distinct mechanisms.
Historically, melanoma with brain metastases has a poor prognosis.,In this retrospective medical record review, we report the outcome of patients with stage IV melanoma with brain metastases treated with ipilimumab and brain stereotactic radiosurgery (SRS).,All patients with metastatic melanoma treated with ipilimumab from June 2010 to September 2012 were identified and stratified by presence (A) or absence (B) of brain metastases at the time of ipilimumab administration.,All patients with brain metastases received SRS.,Overall survival (OS) was defined as time from the date of stage IV diagnosis and the time of ipilimumab administration to death or last follow-up.,Survival curves were estimated using the Kaplan-Meier method, and Cox proportional hazards model was employed to compute the hazard ratios (HR).,Results: Five out of 10 patients in Cohort A and 10 out of 21 patients in Cohort B died as of last follow-up.,In Cohort A, median number of lesions treated with SRS was 3.,Median survivals from date of stage IV for Cohorts A and B were 29.3 and 33.1 months, respectively (HR = 0.93, P = 0.896).,Median survival from cycle 1 ipilimumab was 16.5 and 24.5 months for Cohort A and B, respectively (HR = 1.05, P = 0.931).,The 3-year survival rates from the date of cycle one of ipilimumab administration for Cohort A and B were 50% (95% CI: 27-93%) and 39% (95% CI: 19-81%), respectively.,Eight of 10 patients in Cohort A maintained a good PS.,Survival of patients with melanoma brain metastases treated with ipilimumab combined with SRS may be comparable to patients without brain metastases.