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. 2020 Dec;1(1-4):58-70.
doi: 10.1002/aac2.12012. Epub 2020 Sep 17.

Impact of age-related T cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: a prospective cohort study

Jason E Galloway  1   2 , Andrea M Holderbaum  1   2 , Namrata Arya  1   2 , Suohui Zhang  1   2 , Michael S Bodnar  1   2 , Ruthann Norman  3 , William E Carson  3 , Lianbo Yu  4 , Kari L Kendra  5 , Christin E Burd  1   2
Affiliations

Impact of age-related T cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: a prospective cohort study

Jason E Galloway et al. Aging Cancer. 2020 Dec.

Abstract

Background: The impact of biologic aging on immune checkpoint inhibitor (ICI) toxicity and efficacy is underexplored in metastatic melanoma (MM). In peripheral blood T-lymphocytes (PBTLs), biologic aging is characterized by changes in T-cell composition and cellular senescence. Whether indicators of PBTL biologic aging vary in MM patients or can be used to predict premature ICI discontinuation (pID) is unknown.

Methods: We prospectively collected PBTLs from 117 cancer-free controls and 46 MM patients scheduled to begin pembrolizumab or nivolumab monotherapy. 74 mRNAs indicative of T-cell subsets, activation, co-stimuation/inhibition and cellular senescence were measured by Nanostring. Relationships between each mRNA and chronologic age were assessed in patients and controls. Candidate biomarkers were identified by calculating the hazard ratio (HR) for pID in patients divided into low and high groups based on log-transformed mRNA levels or the magnitude by which each mRNA measurement deviated from the control trend (Δage). Area under the curve (AUC) analyses explored the ability of each biomarker to discriminate between patients with and without pID at 6 months and 1 year.

Results: Fifteen mRNAs correlated with chronologic age in controls, including markers of T-cell subsets, differentiation, cytokine production and co-stimulation/inhibition. None of these mRNAs remained correlated with age in patients. Median follow-up was 94.8 (1.6-195.7) weeks and 35 of 46 patients discontinued therapy (23 progression, 7 toxicity, 5 comorbidity/patient preference). Elevated pre-therapy CD8A (HR 2.2[1.1-4.9]), CD45RB (HR 2.9[1.4-5.8]) and TNFRSF14 (HR 2.2[1.1-4.5]) levels predicted pID independent of Δage-correction. CD3ε, CD27 and FOXO1 predicted pID only after Δage-correction (HR 2.5[1.3-5.1]; 3.7[1.8-7.8]; 2.1[1.1-4.3]). AUC analysis identified Δage-CD3ε and -CD27 as candidate predictors of pID (AUC=0.73; 0.75).

Conclusions: Correlations between transcriptional markers of PBTL composition and chronologic age are disrupted in MM. Correcting for normal, age-related trends in biomarker expression unveils new biomarker candidates predictive of ICI outcomes.

Keywords: Aging biomarker; CD27; T cell; aging; anti-PD-1; biomarker; checkpoint inhibitor; melanoma; senescence.

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Conflict of interest statement

Conflict of interest statement: The authors declare no potential conflicts of interest. Competing interests The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Patient flow and event diagrams.
A, Study flow diagram showing the progression of all enrolled patients. All enrolled patients completed analysis with an average follow-up of 94.8 weeks. B, Kaplan-Meier curve of patient discontinuation events. Discontinuation events are enumerated after initial follow-up (12 weeks) and every 24 weeks thereafter.
Figure 2.
Figure 2.. Hazard ratios for OSU_Senescense mRNAs predictive of premature ICI discontinuation.
OSU_Senescence mRNAs for which the risk of premature ICI discontinuation differs between the high and low expression groups. Data are shown for levels of each mRNA (mRNA) and for the magnitude by which patient mRNA level differs from cancer-free controls (Δage mRNA). Whiskers represent 95% confidence intervals. Positive hazard ratios indicate risks associated with high pre-therapy transcript expression.
Figure 3.
Figure 3.. Kaplan-Meier analysis of OSU_Senescense mRNAs predictive of ICI discontinuation.
A-D, Comparison of ICI discontinuation rates in the indicated mRNA high and low groups. The cumulative number of patients that discontinued therapy due to disease progression and toxicity is shown at initial follow-up (12 weeks) and every 24 weeks thereafter. P-values were determined using log-rank tests to compare the high and low groups.
Figure 4.
Figure 4.. Kaplan-Meier analysis of OSU_Senescense mRNAs predictive of premature ICI discontinuation only after Δage-correction.
A-F, Comparison of ICI discontinuation rates in the indicated mRNA high and low groups before (A, C, E) and after (B, D, F) Δage-correction. The cumulative number of patients that discontinued therapy due to disease progression and toxicity is shown at initial follow-up (12 weeks) and every 24 weeks thereafter. P-values were determined using log-rank tests.
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