Irreversible electroporation of localised prostate cancer downregulates immune suppression and induces systemic anti-tumour T-cell activation - IRE-IMMUNO study

Bart Geboers; Matthijs J Scheltema; Jason Jung; Joyce Bakker; Florentine E F Timmer; Xanthe Cerutti; Athos Katelaris; Paul Doan; William Gondoputro; Alexandar Blazevski; Shikha Agrawal; Jayne Matthews; Anne-Maree Haynes; Tim Robertson; James E Thompson; Martijn R Meijerink; Susan J Clark; Tanja D de Gruijl; Phillip D Stricker

doi:10.1111/bju.16496

Irreversible electroporation of localised prostate cancer downregulates immune suppression and induces systemic anti-tumour T-cell activation - IRE-IMMUNO study

BJU Int. 2024 Aug 5. doi: 10.1111/bju.16496. Online ahead of print.

Authors

Bart Geboers^{1

2

3

4

5}, Matthijs J Scheltema^{1

2

6}, Jason Jung^{1

2}, Joyce Bakker^{7

5

8}, Florentine E F Timmer^{4

5}, Xanthe Cerutti^{1

2}, Athos Katelaris^{1

2}, Paul Doan^{1

2}, William Gondoputro^{1

2}, Alexandar Blazevski^{1

2}, Shikha Agrawal^{1

2}, Jayne Matthews^{2

3}, Anne-Maree Haynes¹, Tim Robertson⁹, James E Thompson^{1

2}, Martijn R Meijerink^{4

5}, Susan J Clark¹, Tanja D de Gruijl^{7

5

8}, Phillip D Stricker^{2

3}

Affiliations

¹ Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, New South Wales, Australia.
² St. Vincent's Prostate Cancer Research Centre, Sydney, New South Wales, Australia.
³ Department of Urology, St. Vincent's Private Clinic, Sydney, New South Wales, Australia.
⁴ Department of Radiology and Nuclear Medicine, Amsterdam UMC, Location Vrije Universiteit, Amsterdam, The Netherlands.
⁵ Cancer Centre Amsterdam, Amsterdam, The Netherlands.
⁶ Department of Urology, St. Antonius Hospital, Utrecht, The Netherlands.
⁷ Department of Medical Oncology, Amsterdam UMC, Location Vrije Universiteit, Amsterdam, The Netherlands.
⁸ Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands.
⁹ Department of Anesthesiology, St. Vincent's Private Clinic, Sydney, New South Wales, Australia.

PMID: 39101639
DOI: 10.1111/bju.16496

Abstract

Objectives: To prospectively compare systemic anti-tumour immune responses induced by irreversible electroporation (IRE) and robot-assisted radical prostatectomy (RARP) in patients with localised intermediate-risk prostate cancer (PCa).

Patients and methods: Between February 2021 and June 2022, before and after treatment (at 5, 14 and 30 days) peripheral blood samples of 30 patients with localised PCa were prospectively collected. Patient inclusion criteria were: International Society of Urological Pathologists Grade 2-3, clinical cancer stage ≤T2c, prostate-specific antigen level <20 ng/mL). Patients were treated with IRE (n = 20) or RARP (n = 10). Frequency and activation status of lymphocytic and myeloid immune cell subsets were determined using flow cytometry. PCa-specific T-cell responses to prostatic acid phosphatase (PSAP) and cancer testis antigen (New York oesophageal squamous cell carcinoma 1 [NY-ESO-1]) were determined by interferon-γ enzyme-linked immunospot assay (ELISpot). Repeated-measures analysis of variance and two-sided Student's t-tests were used to compare immune responses over time and between treatment cohorts.

Results: Patient and tumour characteristics were similar between the cohorts except for age (median 68 years [IRE] and 62 years [RARP], P = 0.01). IRE induced depletion of systemic regulatory T cells (P = 0.0001) and a simultaneous increase in activated cytotoxic T-lymphocyte antigen 4 (CTLA-4)⁺ cluster of differentiation (CD)4⁺ (P < 0.001) and CD8⁺ (P = 0.032) T cells, consistent with reduction of systemic immune suppression allowing for effector T-cell activation, peaking 14 days after IRE. Effects were positively correlated with tumour volume/ablation size. Accordingly, IRE induced expansion of PSAP and/or NY-ESO-1 specific T-cell responses in four of the eight immune competent patients. Temporarily increased activated myeloid derived suppressor cell frequencies (P = 0.047) were consistent with transient immunosuppression after RARP.

Conclusions: Irreversible electroporation induces a PCa-specific systemic immune response in patients with localised PCa, aiding conversion of the tumour microenvironment into a more immune permissive state. Therapeutic efficacy might be further enhanced by combination with CTLA-4 checkpoint inhibition, potentially opening up a new synergistic treatment paradigm for high-risk localised or (oligo)metastatic disease.

Keywords: ablation; abscopal effect; focal therapy; immune response; immunotherapy; irreversible electroporation; prostate cancer.

Abstract

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