Combination immunotherapy induces distinct T-cell repertoire responses when administered to patients with different malignancies
Year: 2020
Type: article
Abstract: BACKGROUND: CTLA-4 blockade with ipilimumab is Food and Drug Administration-approved for melanoma as a monotherapy and has been shown to modulate the circulating T-cell repertoire. We have previously reported clinical trials combining CTLA-4 blockade with granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic melanoma patients and in metastatic castration resistant prostate cancer (mCRPC) patients. Here, we investigate the effect that cancer type has on circulating T cells in metastatic melanoma and mCRPC patients, treated with ipilimumab and GM-CSF. METHODS: We used next-generation sequencing of T-cell receptors (TCR) to compare the circulating T cells of melanoma and mCRPC patients receiving the same treatment with ipilimumab and GM-CSF by Wilcoxon rank sum test. Flow cytometry was utilized to investigate specific T-cell populations. TCR sequencing results were correlated with each T-cell subpopulation by Spearman's rank correlation coefficient. Of note, 14 metastatic melanoma patients had samples available for TCR sequencing and 21 had samples available for flow cytometry analysis; 37 mCRPC patients had samples available for sequencing of whom 22 have TCR data available at both timepoints; 20 of these patients had samples available for flow cytometry analysis and 16 had data available at both timepoints. RESULTS: While melanoma and mCRPC patients had similar pretreatment circulating T-cell counts, treatment induces greater expansion of circulating T cells in melanoma patients. Metastatic melanoma patients have a higher proportion of clones that increased more than fourfold after the treatment compared with mCRPC patients (18.9% vs 11.0%, p=0.017). Additionally, melanoma patients compared with mCRPC patients had a higher ratio of convergent frequency (1.22 vs 0.60, p=0.012). Decreases in clonality induced by treatment are associated with baseline CD8+ T-cell counts in both patient groups, but are more pronounced in the melanoma patients (r=-0.81, p<0.001 vs r=-0.59, p=0.02). TRIAL REGISTRATION NUMBERS: NCT00064129; NCT01363206.
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
Funders: Foundation for the National Institutes of Health, Prostate Cancer Foundation, Conquer Cancer Foundation, San Francisco State University, Peter Michael Foundation, Bladder Cancer Advocacy Network, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, Department of Medicine, University of California, San Francisco
Awards: Determinants of prostate cancer sensitivity to PD-1 blockade, G2943536239, G3197809554, G4264431182, G6209186452, Molecular and immune drivers of immunotherapy responsiveness in prostate cancer, Molecular Pathology of Cancer, Identification of circulating and tissue-specific autoimmune responses in checkpoint inhibitor-induced immune-related adverse events
OpenAlex ID: W3022229928