Abstract 5650
Background
Up to 44% of patients receiving combination ipilimumab and nivolumab develop checkpoint-inhibitor-(CI) colitis, however its molecular pathogenesis is poorly understood. We aimed to characterise peripheral blood and gut mononuclear cells (PBMC; GMNC) in patients with CI-colitis and controls to gain insights into disease aetiology. We were particularly interested in activated, memory, gut-homing CD8+ T-cells and also the innate-like mucosal-associated invariant T (MAIT) cells that play important roles in mucosal immunity.
Methods
In Cohort I PBMC from patients with CI-colitis (N = 9) were compared with those from patients who received CI with no adverse-events (CI-controls; N = 11), patients with active ulcerative colitis (UC; N = 6) and Healthy Volunteers (N = 16). PBMC findings were tested in a second cohort (Cohort II; IN-Colitis N = 15; IN-NAE=9). GMNC were isolated in Cohort III (IN-colitis N = 5; IN-controls N = 5; UC N = 6; Healthy Volunteers N = 6). Flow-cytometric analysis was used throughout.
Results
CI-colitis patients had low circulating MAIT cells compared with CI-controls at baseline in Cohort I. Low levels of circulating MAIT cells in both CI-colitis and CI-controls (compared to Healthy Volunteers) were found in Cohort II. CI-treated patients had high levels of activated-memory T-cells in peripheral blood (CD8 + >CD4+) that included a gut-homing population, regardless of the development of colitis. However, activation of circulating MAIT cells was not evident. In gut tissue there was elevation of activated, granzyme-B+ MAIT cells in CI-colitis compared with CI-controls. CI-colitis was characterised by an activated-memory CD8+ lymphocytosis.
Conclusions
Melanoma patients can have low baseline circulating MAIT cells. In one cohort this associated with CI-colitis. In tissue, activated MAIT cells were elevated in CI-colitis. Further work is needed to determine which immune populations are useful for the prediction and prognostication of CI-colitis, and if MAIT cells contribute to tissue damage or repair.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Celgene.
Disclosure
S.C. Sasson: Research grant / Funding (institution): Celgene. V.T.F. Cheung: Speaker Bureau / Expert testimony: Janssen. G.V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Mass-Array; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche. M.R. Middleton: Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Advisory / Consultancy: Eisai; Advisory / Consultancy: Lilli; Advisory / Consultancy: Merck; Advisory / Consultancy: Millenium; Advisory / Consultancy: Novartis; Advisory / Consultancy: Physiomics; Advisory / Consultancy: Rignotec; Advisory / Consultancy: Roche. O. Brain: Speaker Bureau / Expert testimony: BMS; Research grant / Funding (institution): Celgene. All other authors have declared no conflicts of interest.
Resources from the same session
2664 - Phase (Ph) II study of MBG453 + spartalizumab in patients (pts) with non-small cell lung cancer (NSCLC) and melanoma pretreated with anti–PD-1/L1 therapy
Presenter: Nicholas Mach
Session: Poster Display session 3
Resources:
Abstract
1285 - Preliminary results of STELLAR-001, a dose escalation phase I study of the anti-C5aR, IPH5401, in combination with durvalumab in advanced solid tumors.
Presenter: Christophe Massard
Session: Poster Display session 3
Resources:
Abstract
3808 - GOLFIG chemo-immunotherapy in metastatic colorectal cancer (mCRC) patients: A fifteen year retrospective analysis
Presenter: Pierpaolo Correale
Session: Poster Display session 3
Resources:
Abstract
5677 - Immune correlates in peripheral blood samples in a preoperative window of opportunity randomized trial of nivolumab with or without tadalafil in resectable squamous cell carcinoma of the head and neck (SCCHN)
Presenter: Larry Harshyne
Session: Poster Display session 3
Resources:
Abstract
4854 - Phase 1 evaluation of AB928, a novel dual adenosine receptor antagonist, combined with chemotherapy or AB122 (anti-PD-1) in patients (pts) with advanced malignancies
Presenter: John Powderly
Session: Poster Display session 3
Resources:
Abstract
4344 - Phase 1 Trial of CV301 in Combination with Anti-PD-1 Therapy in Non-squamous NSCLC
Presenter: Arun Rajan
Session: Poster Display session 3
Resources:
Abstract
4555 - Safety and efficacy results of the combination of DPX-Survivac, pembrolizumab and intermittent low dose cyclophosphamide (CPA) in subjects with advanced and metastatic solid tumors: preliminary results from the hepatocellular carcinoma (HCC), NSCLC, bladder cancer, & MSI-H cohorts
Presenter: Henry Conter
Session: Poster Display session 3
Resources:
Abstract
3012 - Excellent CBR and Prolonged PFS in Non-Squamous NSCLC with Oral CA-170, an Inhibitor of VISTA and PD-L1
Presenter: Vivek Radhakrishnan
Session: Poster Display session 3
Resources:
Abstract
2536 - Phase Ib/II trial of TG4001 (Tipapkinogene sovacivec), a therapeutic HPV-vaccine, and Avelumab in patients with recurrent/metastatic (R/M) HPV-16+ cancers
Presenter: Christophe Le Tourneau
Session: Poster Display session 3
Resources:
Abstract
1845 - Induction of tumor-infiltrating functional CD8 positive cells and PD-L1 expression in esophageal cancer by S-588410
Presenter: Takashi Kojima
Session: Poster Display session 3
Resources:
Abstract