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Oncolytic reovirus sensitizes multiple myeloma cells to anti-PD-L1 therapy

Leukemia volume 32, pages 230–233 (2018)Cite this article

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Adaptive resistance mediated by inhibitory ligands such as PD-L1 has emerged as an important mechanism of malignant cell survival and spurred the development of new agents that disrupt the PD-L1/PD-1 immune checkpoint.1 Analysis of patient specimens from clinical trials of novel immune checkpoint inhibitors indicates that high basal expression of PD-L1 on tumor cells may predict sensitivity to and be necessary to elicit significant clinical benefit from this drug class.2, 3 These data suggest that strategies that increase PD-L1 levels could potentially prime malignant cells with low PD-L1 expression and render them sensitive to anti-PD-1/PD-L1 blockade. To investigate this possibility, we first conducted an analysis of basal PD-L1 transcript levels in multiple myeloma (MM) patients (n=351) from the total therapy 2 trial. These analyses demonstrated that expression is very heterogeneous among MM patients and that MM patients as a group do not significantly overexpress PD-L1 compared with normal plasma cells (Supplementary Figure 1). Consistent with the low basal PD-L1 expression we identified, significant clinical responses were not observed in any MM patients in a phase I study of nivolumab in patients with relapsed/refractory lymphoid malignancies.4

Preliminary results of a phase I study of nivolumab as a single agent in patients with relapsed/refractory lymphoid malignancies did not demonstrate significant efficacy in patients with MM.4 However, preclinical and phase 1 studies targeting PD-1 in combination with lenalidomide have shown significant activity.9, 10, 11, 12 These findings suggest that immune checkpoint blockade in MM may be most effective in combination with agents that increase MM tumor immunogenicity. Measurement of the levels of PD-L1 in MM patients has produced varied results with some studies finding significant expression and others finding low levels.13, 14, 15 In our study, we found that PD-L1 was expressed on MM cells, but was not significantly upregulated compared with normal plasma cells, albeit with considerable variability among patients. Since PD-L1 expression has been identified as a potential predictive biomarker of PD-L1/PD-1 therapy, many MM patients with low PD-L1 expression may not benefit from targeting the PD-L1/PD-1 axis with monotherapy.

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Acknowledgements

This project was supported by grants from the National Cancer Institute (R01CA190789 to STN and R01CA172443 to JSC) and the University of Arizona Cancer Center Support Grant P30CA023074.

Author contributions

KRK performed experiments, analyzed and interpreted data, and wrote the manuscript. CME, WZ, KW and CMC performed experiments, analyzed and interpreted data, and participated in manuscript preparation. FA, VV and JSC contributed to data interpretation and manuscript preparation. STN designed the study, analyzed and interpreted data, performed experiments and wrote the manuscript. All authors approved the manuscript before submission.

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Authors and Affiliations

  1. Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    K R Kelly & K Wu

  2. Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    C M Espitia & W Zhao

  3. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    V Visconte

  4. Division of Hematology and Oncology, University of Arizona, Tucson, AZ, USA

    F Anwer

  5. Division of Translational and Regenerative Medicine, Department of Medicine and The University of Arizona Comprehensive Cancer Center, Tucson, AZ, USA

    C M Calton, J S Carew & S T Nawrocki

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  1. K R Kelly
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Corresponding author

Correspondence to S T Nawrocki.

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Kelly, K., Espitia, C., Zhao, W. et al. Oncolytic reovirus sensitizes multiple myeloma cells to anti-PD-L1 therapy. Leukemia 32, 230–233 (2018). https://doi.org/10.1038/leu.2017.272

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