Biomarkers on melanoma patient T Cells associated with ipilimumab treatment

Abstract

BackgroundIpilimumab induces long-lasting clinical responses in a minority of patients with metastatic melanoma. To better understand the mechanism(s) of action and to identify novel biomarkers associated with the clinical benefit and toxicity of ipilimumab, baseline characteristics and changes in CD4+ and CD8+ T cells from melanoma patients receiving ipilimumab were characterized by gene profiling and flow cytometry.MethodsMicroarray analysis of flow-cytometry purified CD4+ and CD8+ T cells was employed to assess gene profiling changes induced by ipilimumab. Selected molecules were further investigated by flow cytometry on pre, 3-month and 6-month post-treatment specimens.ResultsIpilimumab up-regulated Ki67 and ICOS on CD4+ and CD8+ cells at both 3- and 6-month post ipilimumab (p ≤ 0.001), decreased CCR7 and CD25 on CD8+ at 3-month post ipilimumab (p ≤ 0.02), and increased Gata3 in CD4+ and CD8+ cells at 6-month post ipilimumab (p ≤ 0.001). Increased EOMES+CD8+, GranzymeB+EOMES+CD8+ and decreased Ki67+EOMES+CD4+ T cells at 6 months were significantly associated with relapse (all p ≤ 0.03). Decreased Ki67+CD8+ T cells were significantly associated with the development of irAE (p = 0.02). At baseline, low Ki67+EOMES+CD8+ T cells were associated with relapse (p ≤ 0.001), and low Ki67+EOMES+CD4+ T cells were associated with irAE (p ≤ 0.008).ConclusionsUp-regulation of proliferation and activation signals in CD4+ and CD8+ T cells were pharmacodynamic markers for ipilimumab. Ki67+EOMES+CD8+ and Ki67+EOMES+CD4+T cells at baseline merit further testing as biomarkers associated with outcome and irAEs, respectively.

Clinical Significance of Circulating CD33+CD11b+HLA-DR− Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab

“…Our observation is further supported by a recently published study (20), showing that ipilimumab treatment has no effect on the frequencies of circulating monocytic like Lin À CD14 þ HLA-DR À MDSCs. These observations in conjunction with previous studies showing that CD4 þ and CD8 þ T cells are affected by this treatment (37) suggest that most probably, activated T cells and Tregs that constantly express high levels of CTLA-4 on their cell surface (38) are the most promising candidates to be directly targeted upon ipilimumab treatment. Indeed, it has been shown that ipilimumab therapy in melanoma mediates both in vivo and ex vivo depletion of Foxp3 þ Treg cells (39).…”

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

“…10 This observation is in line with previous reports showing that this T cell subpopulation was upregulated both in the peripheral blood and at tumor site of MM patients following IPI treatment. 19,22,23,28,[30][31] The evidence that IPI treatment of MM patients can upregulate the frequency in the periphery of memory/activated T cell subsets was also observed in our study. [24][25][26][27][28] Taken together these observations corroborate the hypothesis that changes of the frequency of circulating T cell subsets from patients enrolled in the NIBIT-M1 study resulted from the activity of the checkpoint blockade agent and were not affected by chemotherapy.…”

Biomarkers for Immunostimulatory Monoclonal Antibodies in Combination Strategies for Melanoma and Other Tumor Types

“…Some authors show that there is no relationship between irAEs and ipilimumab activity (44,45), whereas others have described that patients having an irAE are more likely to achieve clinical benefit (46). It was recently found that ipilimumab is able to upregulate Ki67 and ICOS on CD4 þ and CD8 þ cells (47). Interestingly, the baseline low level of circulating Ki67…”