journal contribution
posted on 2024-01-17, 08:21 authored by Joseph C. Murray, Lavanya Sivapalan, Karlijn Hummelink, Archana Balan, James R. White, Noushin Niknafs, Lamia Rhymee, Gavin Pereira, Nisha Rao, Benny Weksler, Nathan Bahary, Jillian Phallen, Alessandro Leal, David L. Bartlett, Kristen A. Marrone, Jarushka Naidoo, Akul Goel, Benjamin Levy, Samuel Rosner, Christine L. Hann, Susan C. Scott, Josephine Feliciano, Vincent K. Lam, David S. Ettinger, Qing Kay Li, Peter B. Illei, Kim Monkhorst, Robert B. Scharpf, Julie R. Brahmer, Victor E. Velculescu, Ali H. Zaidi, Patrick M. Forde, Valsamo Anagnostou Supplementary Fig.S8 Overview of peripheral blood TCR dynamics in patients with immunotherapy-related pneumonitis. (A) Swimmer plot showing treatment duration for 17 patients with immune-related
toxicity and paired baseline and on-treatment blood samples available for analysis. The time to identification of significant TCR clonotypic expansions and regressions in first on-treatment blood samples is
shown alongside the time to clinical diagnosis of toxicity. Overall, TCR clonotype dynamics were identified on average 20 weeks prior to the clinical presentation of immune-related toxicity in these patients.
(B-E) Logo plots showing global TCR clusters identified using GLIPH2 that were significantly expanded in
on-therapy peripheral blood samples from patients who developed pneumonitis compared to individuals
who developed other immune-related adverse events (irAEs) and individuals who did not develop
immune-related toxicity. The size of each cluster, defined by the number of distinct CDR3 member
sequences, is indicated alongside each panel. Enriched clusters with a minimum motif length of 5 are
shown. (F-G) Boxplots showing the differential abundance of TCR clusters shown in (C-E) from baseline
to on-treatment samples across patient groups.
Funding
National Institutes of Health (NIH)
Emerson Collective (Emerson)
V Foundation for Cancer Research (VFCR)
LUNGevity Foundation (LUNGevity)
Conquer Cancer Foundation (CCF)
International Association for the Study of Lung Cancer (IASLC)
History
ARTICLE ABSTRACT
Although immunotherapy is the mainstay of therapy for advanced non–small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect—especially in the setting of stable disease—calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE).
We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles.
Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE.
Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.
