title: 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.
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Subudhi
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Ana
authors.initials: A
authors.lastname: Aparicio
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Amado J
authors.initials: AJ
authors.lastname: Zurita
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: John C
authors.initials: JC
authors.lastname: Araujo
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Salahaldin A
authors.initials: SA
authors.lastname: Tahir
authors.affiliation: Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Brinda R
authors.initials: BR
authors.lastname: Korivi
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Slack
authors.affiliation: Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Luis
authors.initials: L
authors.lastname: Vence
authors.affiliation: Adaptive Biotechnologies, Seattle, WA 98102.
authors.forename: Ryan O
authors.initials: RO
authors.lastname: Emerson
authors.affiliation: Adaptive Biotechnologies, Seattle, WA 98102.
authors.forename: Erik
authors.initials: E
authors.lastname: Yusko
authors.affiliation: Adaptive Biotechnologies, Seattle, WA 98102.
authors.forename: Marissa
authors.initials: M
authors.lastname: Vignali
authors.affiliation: Adaptive Biotechnologies, Seattle, WA 98102; Fred Hutchinson Cancer Research Center, Seattle, WA 98102.
authors.forename: Harlan S
authors.initials: HS
authors.lastname: Robins
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 padsharma@mdanderson.org jallison@mdanderson.org.
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 padsharma@mdanderson.org jallison@mdanderson.org.
authors.forename: Padmanee
authors.initials: P
authors.lastname: Sharma
mesh_terms: D000074322:Antineoplastic Agents, Immunological / Q000009:adverse effects* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D060965:Clonal Evolution / Q000276:immunology*; D004198:Disease Susceptibility; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000209:etiology*; D006801:Humans; D000074324:Ipilimumab / Q000009:adverse effects* / Q000627:therapeutic use; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D000074324:Ipilimumab
keywords: CD8; T cells; ipilimumab; prostate cancer; toxicities