Immune biomarker evaluation of sequential tyrosine kinase inhibitor and nivolumab monotherapies in renal cell carcinoma: the phase I TRIBE trial

K S Shohdy; M Pillai; K S Abbas; J Allison; T Waddell; E Darlington; S Mohammad; S Hood; S Atkinson; K Simpson; D Morgan; P Nathan; E Kilgour; C Dive; F Thistlethwaite

doi:10.1016/j.iotech.2024.100712

Immune biomarker evaluation of sequential tyrosine kinase inhibitor and nivolumab monotherapies in renal cell carcinoma: the phase I TRIBE trial

Immunooncol Technol. 2024 Mar 18:22:100712. doi: 10.1016/j.iotech.2024.100712. eCollection 2024 Jun.

Authors

K S Shohdy^{1

2}, M Pillai¹, K S Abbas³, J Allison¹, T Waddell¹, E Darlington¹, S Mohammad⁴, S Hood⁴, S Atkinson⁴, K Simpson⁴, D Morgan⁴, P Nathan⁵, E Kilgour⁴, C Dive⁴, F Thistlethwaite^{1

2}

Affiliations

¹ The Christie NHS Foundation Trust, Manchester, UK.
² Division of Cancer Sciences, The University of Manchester, Manchester, UK.
³ Faculty of Medicine, Alexandria University, Alexandria, Egypt.
⁴ Cancer Biomarker Centre, Cancer Research UK Manchester Institute, Manchester, UK.
⁵ Mount Vernon Cancer Centre - East and North Herts NHS Trust, Northwood, Middlesex, UK.

Abstract

Background: Predictive biomarkers for immune checkpoint blockade in the second-line treatment of metastatic renal cell carcinoma (mRCC) are lacking.

Materials and methods: Patients with histologically confirmed RCC who started nivolumab after at least 4 months of tyrosine kinase inhibitors (TKIs) were recruited for this study. Serial tissue and blood samples were collected for immune biomarker evaluation. The primary endpoint was to determine the association of specific T-cell subsets with clinical outcomes tested using Wilcoxon rank sum for clinical benefit rate (CBR) and log-rank test for progression-free survival (PFS).

Results: Twenty patients were included in this trial with a median age of 64 years and followed-up for a median of 12 months. The median PFS for patients who received TKI was 13.8 months, while for those subsequently treated with nivolumab following TKI therapy, the median PFS was 2.6 months. CBR of nivolumab was 20% with two partial responses. Functionally active programmed cell death protein 1+ CD4+ T cells were enriched in non-responders (q = 0.003) and associated with worse PFS on nivolumab (P = 0.04). Responders showed a significant reduction in the effector CD4+T-cell (T_EF) fraction compared to non-responders at 3 months on nivolumab (0.40 versus 0.80, P = 0.0005). CD127+CD4+ T cells were enriched in patients who developed immune-related adverse effects (q = 0.003). Using in-house validated multiplex immunohistochemistry for six markers, we measured tumour-associated immune cell densities in tissue samples. Responders to nivolumab showed a significantly higher mean of immune cell densities in tissue samples compared to non-responders (346 versus 87 cells/mm², P = 0.04).

Conclusions: In this small study, analysis of tissue-based and peripheral blood immune cell subsets predicted clinical outcomes of nivolumab. Further studies are warranted with larger populations to validate these observations.

Keywords: clinical benefit rate; immune checkpoint blockade; metastatic renal cell carcinoma; nivolumab; predictive biomarkers; progression-free survival.