Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities

Abstract

Immune checkpoint therapies, such as ipilimumab, induce dramatic antitumor responses in a subset of patients with advanced malignancies, but they may also induce inflammatory responses and toxicities termed immune-related adverse events (irAEs). These irAEs are often low grade and manageable, but severe irAEs may lead to prolonged hospitalizations or fatalities. Early intervention is necessary to minimize morbidities that occur with severe irAEs. However, correlative biomarkers are currently lacking. In a phase II clinical trial that treated 27 patients with metastatic prostate cancer, we aimed to test the safety and efficacy of androgen deprivation therapy plus ipilimumab. In this study, we observed grade 3 toxicities in >40% of treated patients, which led to early closure of the study. Because ipilimumab enhances T-cell responses, we hypothesized that increased clonal T-cell responses in the systemic circulation may contribute to irAEs. Sequencing of the T-cell receptor β-chains in purified T cells revealed clonal expansion of CD8 T cells, which occurred in blood samples collected before the onset of grade 2–3 irAEs. These initial results suggested that expansion of ≥55 CD8 T-cell clones preceded the development of severe irAEs. We further evaluated available blood samples from a second trial and determined that patients who experienced grade 2–3 irAEs also had expansion of ≥55 CD8 T-cell clones in blood samples collected before the onset of irAEs. We propose that CD8 T-cell clonal expansion may be a correlative biomarker to enable close monitoring and early intervention for patients receiving ipilimumab.

Immune checkpoint inhibitor‐associated pituitary‐adrenal dysfunction: A systematic review and meta‐analysis

“…In addition, 38 clinical trials with results from https://ClinicalTrials.gov were identified and included. Overall, we included a total of 160 clinical trials involving 40 432 patients in the meta‐analysis (Figure , Table ) . The trials include 37 phase 3 studies with 25 084 patients; 1 phase 2/3 study with 1033 patients; 66 phase 2 studies with 8529 patients; 11 phase 1/2 studies with 1263 patients; and 45 phase 1 studies with 4523 patients.…”

VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer

“…However, prostate cancer has proven poorly responsive to immune checkpoint monotherapy 3–5 . To better understand the immune profile within prostate tumors and potential compensatory immune inhibitory pathways that may arise in the setting of immune checkpoint monotherapy, we conducted a clinical trial (NCT01194271) with ipilimumab plus androgen deprivation therapy (ADT) prior to surgery in patients with localized prostate cancer (Supplementary Fig.…”

T‐cell receptor and B‐cell receptor repertoire profiling in adaptive immunity

“…For example, higher intra‐tumoral TCR clonality has been observed in responders to anti‐PD1 antibody treatment at both pre‐treatment and during‐treatment timepoints, whereas no such effect was observed for CTLA4 blockade therapy . In contrast, higher TCR repertoire diversity in the peripheral blood after CTLA4 blockade was correlated with drug‐related toxicities in prostate cancer and metastatic melanoma .…”