Abstract 5015: TCR usage analysis in blood reveals different mechanisms of action of CTLA-4 and PD-1 blockade in patients

Abstract

Abstract Immune-checkpoint blockade therapies are providing long-lasting responses in a subset of patients with malignant metastatic melanoma. In an effort to better understand the underlying mechanism, the T-cell population in peripheral blood mononuclear cells (PBMCs) was characterized. The complementarity determining region 3 (CDR3) of the rearranged T cell receptor variable ß chain genes (TCR Vß) was sequenced. This was performed using gDNA extracted from the PBMCs of twenty-one patients that were treated with antibody to Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) (tremelimumab) and seven patients that were treated with antibody to the Programmed Death-1 (PD-1) blockade (MK-3475) at baseline and at day 30-60 post first treatment. Four healthy donors were also sequenced as controls. Control PBMCs displayed random distribution with three patients showing a decrease and one showing an increase in the number of unique productive sequences (UPS) from baseline to the time after first cycle. In PBMCs from patients receiving the CTLA-4 antibody, two out of 21 samples showed a decrease in total number of UPS, while 19 out of 21samples experienced an increase. In PBMCs from patients receiving PD-1 antibody, the reponse was more similar to healthy donors as 5 out of 7 (71%) displayed a decrease and 2 out 7 (29%) an increase in total UPS from the pre to post timepoint. There was an increase in the absolute lymphocyte count (ALC) after CTLA-4 blockade therapy (p=0.03), but not in the samples from patients treated with PD-1 antibody (p=0.53). A direct correlation between ALC increase and increase in UPS for CTLA-4 blockade was ruled out (p=0.1 Spearman Correlation). When analyzing according to clinical response status, all responders to CTLA-4 blockade (4 out of 19) experienced an increase in the number of circulating clones. However, samples from clinical responders to PD-1 blockade showed an increase (2 out of 5) or decrease (1 out of 2) in the circulating pool. Considering the concerning toxicity profile for CTLA-4-blockade versus the mild toxicity for PD-1 antibodies, this data supports a model where CTLA-4 blockade induces a non-specific systemic expansion of T cells, while PD-1 blockade may have more specific effects directly in the tumor. Citation Format: Lidia Robert, Christina L. Harview, Ryan Emerson, Stephen Mok, Blanca Homet, Begonya Comin-Anduix, Richard C. Koya, Harlan Robins, Paul C. Tumeh, Antoni Ribas. TCR usage analysis in blood reveals different mechanisms of action of CTLA-4 and PD-1 blockade in patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5015. doi:10.1158/1538-7445.AM2014-5015