Background Tertiary lymphoid structures (TLS) may develop in non-lymphoid tissues in response to a variety of different stimuli and can serve as foci for generating anti-tumor immunity.1 TLS formation is emerging as a strong prognostic and predictive biomarker2 associated with patient survival benefits in NSCLC.3,4Pulsed Electric Fields (PEF) have been reported to induce an immunogenic form of cell death and thus may enhance adaptive immunity in the setting of cancer. The treat-and-resect INCITE ES study enrolled adults with suspected or confirmed NSCLC stage IA2-IB (>1 to ≤4 cm) and without a history of treatment for cancer within the previous two years.
Methods The INCITE ES study design includes both control and treatment groups with 8 enrolled control group subjects and 30 enrolled treatment group subjects. Treatment group subjects received PEF (AliyaTM System, GTI-00018 investigational device; Galvanize Therapeutics, San Carlos, CA) either percutaneously or endoscopically at time of biopsy prior to surgical resection. Blood, bronchoalveolar lavage (BAL) when applicable, and tissue samples were collected over the course of the study for appropriate pre- and post-PEF comparison.
Serial histologic sections were obtained from an initial cohort of 12 patients (n=1 control, n=11 treatment group) on the day of surgery 17-21 days post-PEF delivery, stained for standard H&E as well as duplex stained for pan-cytokeratin (panCK) and CD20, and reviewed by an independent pathologist.
Results TLS were identified and characterized according to their maturity and localization within or adjacent to the tumor (see criteria in Table 1). Intratumor TLS were observed admixed among tumor cells or within the invasive margin (figures 1 to 5), including within the cellular depletion zone induced by PEF (figures 6 and 7). Independent of tumor morphology, a significant quantity of 49.8 ± 55.8 TLS per tumor was observed post-PEF (n=11, average ± S.D.). TLS across treated tumors showed varying proportions of mature vs. immature TLS, using the criteria in Table 1. No TLS were identified in the available pre-PEF biopsy specimens (figures 2 and 8). TLS density was greater in PEF specimens compared to the non-treated control, where only three immature TLS were observed (figure 9).
Conclusions This initial cohort suggests that PEF may induce the formation of TLS within the tumor, including proximal to the PEF delivery zone. The observed density and detection of mature TLS may suggest ongoing immune activity. As such, PEF has the potential to induce or enhance an immune response irrespective of tumor morphology.
Trial Registration The study is registered on clinicaltrials.gov (NCT04732520).
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Ethics Approval This abstract discusses the INCITE ES clinical study. Participants gave informed consent before taking part in the study. The study obtained ethics approval from the Ethics Committee for Research with Drugs (CEIm) of the Salamanca Health Area (Salamanca, Spain, reference 20/1615 (E.C.P.S.), Committee on Research Involving Human Subjects (CMO) of Radboud University Medical Center (Nijmegen, the Netherlands, NL76406.091.21), and the Joint Chinese University of Hong Kong – New Territories East Cluster Research Ethics Committee (Hong Kong SAR, reference 2021.294-T).
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