Dataset Information

Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients.

ABSTRACT:

Background

While immune checkpoint blockade has greatly improved clinical outcomes in diseases such as melanoma, there remains a need for predictive biomarkers to determine who will likely benefit most from which therapy. To date, most biomarkers of response have been identified in the tumors themselves. Biomarkers that could be assessed from peripheral blood would be even more desirable, because of ease of access and reproducibility of sampling.

Methods

We used mass cytometry (CyTOF) to comprehensively profile peripheral blood of melanoma patients, in order to find predictive biomarkers of response to anti-CTLA-4 or anti-PD-1 therapy. Using a panel of ~ 40 surface and intracellular markers, we performed in-depth phenotypic and functional immune profiling to identify potential predictive biomarker candidates.

Results

Immune profiling of baseline peripheral blood samples using CyTOF revealed that anti-CTLA-4 and anti-PD-1 therapies have distinct sets of candidate biomarkers. The distribution of CD4⁺ and CD8⁺ memory/non-memory cells and other memory subsets was different between responders and non-responders to anti-CTLA-4 therapy. In anti-PD-1 (but not anti-CTLA-4) treated patients, we discovered differences in CD69 and MIP-1β expressing NK cells between responders and non-responders. Finally, multivariate analysis was used to develop a model for the prediction of response.

Conclusions

Our results indicate that anti-CTLA-4 and anti-PD-1 have distinct predictive biomarker candidates. CD4⁺ and CD8⁺ memory T cell subsets play an important role in response to anti-CTLA-4, and are potential biomarker candidates. For anti-PD-1 therapy, NK cell subsets (but not memory T cell subsets) correlated with clinical response to therapy. These functionally active NK cell subsets likely play a critical role in the anti-tumor response triggered by anti-PD-1.

SUBMITTER: Subrahmanyam PB

PROVIDER: S-EPMC5840795 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Publications

Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients.

Subrahmanyam Priyanka B PB Dong Zhiwan Z Gusenleitner Daniel D Giobbie-Hurder Anita A Severgnini Mariano M Zhou Jun J Manos Michael M Eastman Lauren M LM Maecker Holden T HT Hodi F Stephen FS

Journal for immunotherapy of cancer 20180306 1

<h4>Background</h4>While immune checkpoint blockade has greatly improved clinical outcomes in diseases such as melanoma, there remains a need for predictive biomarkers to determine who will likely benefit most from which therapy. To date, most biomarkers of response have been identified in the tumors themselves. Biomarkers that could be assessed from peripheral blood would be even more desirable, because of ease of access and reproducibility of sampling.<h4>Methods</h4>We used mass cytometry (Cy ...[more]

PMID: 29510697

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Project description:BACKGROUND:Uveal melanoma accounts for 85% of the ocular melanomas and has an increased risk of hematogenous spread, most commonly to the liver. After curative intent therapy like surgery and radiation, fifty percent of patients present with distant metastasis. Metastatic uveal melanoma (MUM) does not harbor typically targetable mutations, e.g., BRAF as in cutaneous melanoma. As a result, there is no proven therapy for MUM. Various chemotherapy and immunotherapy regimens have been tried and only partial response (PR) is the best that has been achieved in most of the cases. Here, we present a case of MUM treated with combination immune checkpoint therapy (ipilimumab and nivolumab) following the progression with single-agent nivolumab and demonstrating a durable response without recurrence more than 22 months from the last treatment. CASE PRESENTATION:A 72-year-old Caucasian man presented with ciliary body melanoma of the left eye and underwent curative-intent enucleation but six months later developed diffuse hepatic metastases. He initially was treated with nivolumab 3 mg/kg every two weeks for four cycles but restaging scan showed a significant progression of the disease with increasing LDH. With the FDA approval for the combination of nivolumab 1mg/kg with Ipilimumab 3 mg/kg every three weeks for metastatic melanoma, this combination was given for four cycles with continuous rise in LDH to 993 unit/L (110-220 unit/L) until finishing cycle four of the treatment. Three weeks later, maintainence nivolumab 3mg/kg was initiated but two weeks later, he developed grade 4 liver toxicity with ALT 1565 unit/L (0-55 unit/L). A presumptive diagnosis of autoimmune hepatitis was made, nivolumab was stopped and oral prednisone 1mg/kg was started with quick resolution of elevated transaminases. Restaging abdominal MRI one month after the first and last dose of maintenance nivolumab showed PR and continuous shrinkage of the metastatic lesions with no hypermetabolic activity even on PET/CT. He is 22 months' post-treatment and continues to do well without any evidence of active disease. CONCLUSION:Although, limited response has been shown to single agent immune checkpoint inhibitors and chemotherapy, our patient showed durable response with anti-CTLA-4 and anti-PD-1 combination therapy in MUM.

Dataset Information

Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients.

Background

Methods

Results

Conclusions

Publications

Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients.

Similar Datasets

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