In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 3001-3001
Abstract:
3001 Background: PD-L1, which is highly expressed on tumors, is a ligand of PD-1, an inhibitory receptor present on activated T cells. PD-L1 expression is regulated by intrinsic (mutations) and adaptive (tumor infiltrating T cells) mechanisms. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: A Ph I study was conducted with MPDL3280A administered IV q3w in pts with locally advanced or metastatic solid tumors. The expansion cohort required available tumor tissue. In addition, the study included a serial biopsy cohort with tumor sampling prior to and during treatment. Tumor samples were analyzed by IHC and a Genentech immunochip measuring ≈90 immune-related genes to characterize the tumor immune microenvironment at baseline (BL) and/or during MPDL3280A treatment. Further, blood-based biomarkers and circulating immune cell subsets were serially measured. Results: Pretreatment tumor samples were available for IHC from 112 pts and for immunochip from 96 pts.In addition, 23 pts had paired BL and on-treatment samples. Blood-based biomarkers were evaluated in 76 pts. Elevated BL PD-L1 expression by IHC was associated with response to MPDL3280A, and coordinated expression of PD-L1 and CD8+ T-cells was observed. Furthermore, a T-cell gene signature (including CD8, IFNg and Granzyme-A) was associated with treatment response. On treatment, responding tumors showed increasing PD-L1 expression and a Th1-dominant immune infiltrate, providing evidence for adaptive PD-L1 upregulation. Nonresponders showed minimal tumor CD8+ T-cell infiltration and an absence of T-cell activation (measured by Granzyme-A and Perforin expression). Additionally, a subpopulation of pts exhibited changes in circulating cytokines (IFNg) and activated T-cell subsets (HLADR+Ki67+). Conclusions: PD-L1 tumor expression and T-cell gene signature correlate with response to MPDL3280A. MPDL3280A therapy led to T-cell reactivation and restored antitumor immunity. These data provide mechanistic insights into immunotherapy and support pt selection for treatment with MPDL3280A monotherapy. Clinical trial information: NCT01375842.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2013.31.15_suppl.3001
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2013
detail.hit.zdb_id:
2005181-5
Permalink