Combination immunotherapy induces distinct T-cell repertoire responses when administered to patients with different malignancies.

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.

• Authors: Jason Cham, Li Zhang, Serena Kwek, Alan Paciorek, Tao He, Grant Fong, David Y Oh, Lawrence Fong
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 8 Issue 1 (05 2020) ISSN: 2051-1426 [Electronic] England
• PMID: 32376721 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• CTLA-4 Antigen
• CTLA4 protein, human
• Ipilimumab
• Receptors, Antigen, T-Cell
• Recombinant Proteins
• sargramostim
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Adult
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• CD8-Positive T-Lymphocytes (drug effects, immunology, metabolism)
• CTLA-4 Antigen (antagonists & inhibitors, immunology)
• Granulocyte-Macrophage Colony-Stimulating Factor (administration & dosage, adverse effects)
• High-Throughput Nucleotide Sequencing
• Humans
• Ipilimumab (administration & dosage, adverse effects)
• Male
• Melanoma (blood, drug therapy, immunology, secondary)
• Middle Aged
• Prostatic Neoplasms, Castration-Resistant (blood, drug therapy, immunology, pathology)
• Receptors, Antigen, T-Cell (genetics, metabolism)
• Recombinant Proteins (administration & dosage, adverse effects)
• Skin Neoplasms (blood, drug therapy, immunology, pathology)
• Treatment Outcome