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It is increasingly understood that cancers can be recognized by the immune system and inflammation relates to response. Combining stereotactic radiotherapy (SBRT), to increase release of cancer cell antigens, with an anti-CTLA-4 and PD-L1 inhibitor may lead to increased response rates. No solid biomarker in predicting treatment response is available. We set out to study feasibility of combined durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) with SBRT on the primary tumor. The extend of tumor-infiltrating cells has shown to correlate to improved prognosis using checkpoint inhibitor (CPI) treatment of various cancers. We hypothesized that the peripheral blood T-cell activation status may be a predictor of response, progression free survival (PFS) and overall survival (OS). Methods: Three immunotherapy regimes were combined with SBRT in sequential cohorts as ≥2nd line in CPI naïve patients with NSCLC stage IIIB/IV. One week after the 1st dose of CPI, patients were irradiated on the primary tumor (1x 20Gy on 9cc). The 1st cohort (n=3) received durvalumab, the 2nd and 3rd cohort (both n=6) a combination of durvalumab and tremelimumab, followed by durvalumab monotherapy. Exploratory endpoint was the correlation of response with T-cell function. T-cell function was assessed using flow cytometric analysis of peripheral blood T-cells and compared to simultaneously included healthy controls. In short, whole blood was activated ex vivo using Staphylococcal enterotoxin B (SEB) after which the T-cell activation status was assesses by expression of CD69 and cytokines (IL-2, IFN-γ, TNF-α). Patients were divided in above (responders, R) and below median PFS (non-responders, NR). We compared intracellular cytokine production in both CD4+ and CD8+ T-lymphocytes between both groups and with healthy controls (HC) using the Mann-Whitney U test. Findings: Fifteen patients were included as described above. Median PFS was 2 months, OS 10 months (immature). Baseline characteristics of both groups were comparable. T-cell function was assessed in 14 patients and HC at baseline. Data are shown as median (P-value) for R vs NR below. R had a significant higher percentage activated CD8+ T-cells upon SEB stimulation than NR: CD8+CD69+ 15.8 vs 3.5 (0.008) and IL-2+CD8+CD69+ 8.8 vs 2.9 (0.02). There was a trend in TNF-α+CD8+CD69+ 19.8 vs 8.0 (0.11) and IFN-ɣ+CD8+CD69+ 21.4 vs 5.5 (0.22). These differences were all significant for R compared to HC (p0.66). Interpretation: With a mild antigen independent stimulus (SEB), the CD8+ T-cells of responders were significantly more activated at baseline compared to non-responders and healthy controls. This suggests an elevated pre-treatment T-cell activation status in patients that responded to the treatment and the possibility to use this as a potential biomarker to predict the response to CPI treatment. Disclosure: This study was sponsored by a research grant from AstraZeneca. Citation Format: Hanneke Kievit, M. Benthe Muntinghe-Wagenaar, Lucie B.M. Hijmering-Kappelle, Birgitta I. Hiddinga, J Fred Ubbels, Robin Wijsman, Bart-Jan Kroesen, Marcel J. van der Leij, A. Rutgers, Harry J. Groen, Huib A. Kerstjens, Anthonie J. van de Wekken, T Jeroen Hiltermann. Baseline T-cell function predicts response to SBRT and immunotherapy in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1984. |
