Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance

Abstract

Immune checkpoint blockade produces clinical benefit in many patients. However better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1), and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T-cell receptor sequencing (TCR-seq) and whole exome sequencing (WES) within the same cohort, and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of copy number alterations identified a higher burden of copy number loss in non-responders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was non-redundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.

781 Melanoma subtypes demonstrate distinct PD-L1 expression profiles

“…More recent studies have identified chromosomal alterations as contributing genetic factors of resistance to immunotherapy. 46,47 The relationship of these alterations to PD-L1 expression or specific melanoma subtypes has yet to be defined.…”

“…More recent studies have identified chromosomal alterations as contributing genetic factors of resistance to immunotherapy. 46,47 The relationship of these alterations to PD-L1 expression or specific melanoma subtypes has yet to be defined.Pure desmoplastic melanomas tend to be characterized by the presence of lymphoid aggregates. Such intratumoral lymphoid aggregates have both prognostic and therapeutic value, as they facilitate lymphocyte recruitment and help maintain both T-cell and B-cell antitumor responses.…”

Predictors of response and resistance to checkpoint inhibitors in solid tumors

“…Of an initial cohort of 56 patients, 54 were treated with CTLA-4 inhibitor, and 7 of them responded (1). The non-responders were then treated with the PD-1 inhibitor, and 14 (28%) responded (1).…”

“…Of an initial cohort of 56 patients, 54 were treated with CTLA-4 inhibitor, and 7 of them responded (1). The non-responders were then treated with the PD-1 inhibitor, and 14 (28%) responded (1). Using serial biopsies, the authors identified several tumor factors that favor response and resistance (1).…”

“…The non-responders were then treated with the PD-1 inhibitor, and 14 (28%) responded (1). Using serial biopsies, the authors identified several tumor factors that favor response and resistance (1). Of note, their definition of response is either radiographic partial or complete remission or stable disease lasting at least 6 months (1).…”