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Combination of pembrolizumab and pelareorep promotes anti-tumour immunity in advanced pancreatic adenocarcinoma (PDAC)

British Journal of Cancer volume 129, pages 782–790 (2023)Cite this article

Subjects

Abstract

Background

We previously reported activity of pelareorep, pembrolizumab and chemotherapy. Patients developed new T-cell clones and increased peripheral T-cell clonality, leading to an inflamed tumour. To evaluate a chemotherapy-free regimen, this study assesses if pelareorep and pembrolizumab has efficacy by inducing anti-tumour immunological changes (NCT03723915).

Methods

PDAC patients who progressed after first-line therapy, received iv pelareorep induction with pembrolizumab every 21-days. Primary objective is overall response rate. Secondary objectives included evaluation of immunological changes within tumour and blood.

Results

Clinical benefit rate (CBR) was 42% amongst 12 patients. One patient achieved partial response (PR) and four stable disease (SD). Seven progressed, deemed non-responders (NR). VDAC1 expression in peripheral CD8+ T cells was higher at baseline in CBR than NR but decreased in CBR upon treatment. On-treatment peripheral CD4+ Treg levels decreased in CBR but not in NR. Analysis of tumour demonstrated PD-L1+ cells touching CD8+ T cells, and NK cells were more abundant post-treatment vs. baseline. A higher intensity of PD-L1 in tumour infiltrates at baseline, particularly in CBR vs. NR. Finally, higher levels of soluble (s)IDO, sLag3, sPD-1 observed at baseline among NR vs. CBR.

Conclusion

Pelareorep and pembrolizumab showed modest efficacy in unselected patients, although potential immune and metabolic biomarkers were identified to warrant further evaluation.

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Fig. 1: Study design and clinical efficacy analysis.
Fig. 2: Identification of differences in immune cell populations between CBR and NR using spectral flow cytometry (CyTEK).
Fig. 3: Distinct features of peripheral CD8+ T cells between CBR and NR.
Fig. 4: Distinct features of tumour-infiltrating leucocytes (TILs) between CBR and NR.
Fig. 5: Plasma levels of soluble immune checkpoints between NR and CBR.

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Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The study received Pembrolizumab from Merck (MISP 55500). The study received Reolysin and research funding from Oncolytics Biotech.

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Author notes

  1. These authors contributed equally: Siqi Chen, Ping Xie.

Authors and Affiliations

  1. Robert H. Lurie Comprehensive Cancer Center, Division of Hematology & Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Devalingam Mahalingam, Siqi Chen, Ping Xie, Aparna Kalyan, Sheetal Kircher, Victoria Maurer, Mary Mulcahy, Al- Benson & Bin Zhang

  2. Oncolytics Biotech, Calgary, AB, Canada

    Houra Loghmani, Thomas Heineman & Matt Coffey

  3. Quantitative Data Sciences Core, Department of Preventative Medicine, Biostatistics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Irene B. Helenowski & Xinlei Mi

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Contributions

Conceptualisation and design: DM, BZ. Data acquisition: DM, SC, PX, AK, SC, VC, MM, AB, BZ. Data analysis: DM, SC, PX, HL, TH, AK, SC, IBH, XM, MC, MM, AB, BZ. Manuscript writing: DM, SC, PX, HL, TH, BZ. Manuscript revisions and approval of final version: All authors. Accountability of work: all authors.

Corresponding authors

Correspondence to Devalingam Mahalingam or Bin Zhang.

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Competing interests

DM received research funding Oncolytics Biotech and drug support from Merck. HL, TH and MC are employees of Oncolytics Biotech.

Ethics approval and consent to participate

This study was conducted upon approval of the Institutional Review Board (IRB) at Northwestern University, Chicago, IL on 5/02/2018 (IRB number: STU00207577) and in accordance with current U.S. Food and Drug Administration (FDA) regulations, the International Conference on Harmonisation (ICH), Good Clinical Practices (GCPs), the Declaration of Helsinki, and local ethical and legal requirements. All patients signed a written informed consent before the conduct of any study procedures and after a full explanation of the study to the patient by the study investigator.

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Mahalingam, D., Chen, S., Xie, P. et al. Combination of pembrolizumab and pelareorep promotes anti-tumour immunity in advanced pancreatic adenocarcinoma (PDAC). Br J Cancer 129, 782–790 (2023). https://doi.org/10.1038/s41416-023-02344-5

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