Dataset Information

Phenotypic and Genomic Determinants of Immunotherapy Response Associated with Squamousness.

ABSTRACT: Advanced and metastatic squamous cell carcinomas (SCC) are common and difficult-to-treat malignancies. We assessed 75 immunotherapy-treated patients with SCC from a clinically annotated database of 2,651 patients, as well as 9,407 patients from a deidentified database for molecular features that might influence checkpoint blockade response. SCCs had higher tumor mutational burdens (TMB) than non-SCCs (P < 0.0001). Cutaneous SCCs had the highest TMB (P < 0.0001), with 41.3% demonstrating a very high TMB (?50 mutations/Mb). In immunotherapy-treated patients with SCC, higher TMB (?12 mutations/Mb) correlated with a trend to higher clinical benefit rate [stable disease ? 6 months or partial/complete remission; 60% vs. 29%; (high vs. low TMB); P = 0.06] and significantly longer median time-to-treatment failure (TTF; 9.9 vs. 4.4 months; P = 0.0058). Cutaneous SCCs had the highest clinical benefit [11/15 patients (73%) vs. 20/60 (33%) non-cutaneous (P = 0.008)], TTF (P = 0.0015), and overall survival (P = 0.06) with immunotherapy treatment. In conclusion, among a diverse set of SCCs, higher TMB and cutaneous disease associated with better immunotherapy outcome.

SUBMITTER: Goodman AM

PROVIDER: S-EPMC6548620 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Phenotypic and Genomic Determinants of Immunotherapy Response Associated with Squamousness.

Goodman Aaron M AM Kato Shumei S Chattopadhyay Ranajoy R Okamura Ryosuke R Saunders Ila M IM Montesion Meagan M Frampton Garrett M GM Miller Vincent A VA Daniels Gregory A GA Kurzrock Razelle R

Cancer immunology research 20190419 6

Advanced and metastatic squamous cell carcinomas (SCC) are common and difficult-to-treat malignancies. We assessed 75 immunotherapy-treated patients with SCC from a clinically annotated database of 2,651 patients, as well as 9,407 patients from a deidentified database for molecular features that might influence checkpoint blockade response. SCCs had higher tumor mutational burdens (TMB) than non-SCCs (<i>P</i> < 0.0001). Cutaneous SCCs had the highest TMB (<i>P</i> < 0.0001), with 41.3% demonstr ...[more]

PMID: 31003990

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Project description:Targeting the PD-1/PD-L1 pathway has changed the landscape of cancer immunotherapy, revolutionizing the treatment of many cancers. Somatic tumor mutational burden (TMB) and T-cell–inflamed gene expression profile (GEP) are clinically validated pan-tumor genomic biomarkers that predict responsiveness to anti-PD-1/anti-PD-L1 monotherapy in a variety of tumor types. Here we analyze the association between these biomarkers and efficacy in 11 commonly used preclinical murine syngeneic models using a rodent surrogate antibody (muDX400) of pembrolizumab, a humanized monoclonal antibody against PD-1. Response to muDX400 treatment was broadly classified in these models into 3 categories: highly responsive, partially responsive, and intrinsically resistant to therapy. Molecular and cellular profiling validated differences in immune-cell infiltration and activation in the tumor microenvironment of muDX400 responsive tumors. Baseline and post-treatment genomic analysis showed an association between murine-GEP and TMB and response to muDX400 treatment. To better understand the limitations, predictive nature and role of these models in guiding treatment options at the bedside, we extended our analysis to investigate a canonical set of cancer and immune biology-related gene expression signatures, including signatures of angiogenesis, monocytic myeloid derived suppressor cell (mMDSC) and stromal/EMT/TGF-β biology previously shown to have potential negative impact on immunotherapy efficacy in the clinic. Finally, reverse translation studies were performed to evaluate the association between murine-GEP and preclinical efficacy with standard of care and anti-angiogenic combinations with muDX400 which show promising clinical activity. These efforts begin to elucidate which biological mechanisms can and cannot be appropriately and productively tested in these preclinical models to facilitate the development of rational orthogonal combination strategies with checkpoint blockade as well as the evaluation of underlying biological mechanisms associated with response in the clinic

Dataset Information

Phenotypic and Genomic Determinants of Immunotherapy Response Associated with Squamousness.

Publications

Phenotypic and Genomic Determinants of Immunotherapy Response Associated with Squamousness.

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