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Functional precision oncology for follicular lymphoma with patient-derived xenograft in avian embryos

Leukemia volume 38, pages 430–434 (2024)Cite this article

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The standard of care of follicular lymphoma (FL) combines an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) with chemotherapy (such as cyclophosphamide, hydroxyadriamycine, vincristine and prednisone (CHOP) or bendamustine) followed by maintenance with anti-CD20 [1]. Despite impressive results achieved with these treatments, around 20% of patients experience disease progression during the 24 months following immunochemotherapy (POD24) and have a dismal prognosis [2]. Prospective identification of these patients is an unmet need, which could be achieved by measuring the response of primary cancer cells to perturbations, following the concept of functional precision oncology [3]. However, this type of analysis is limited in FL due to the lack of an adequate model, as primary FL cells cannot be grown in vitro [4]. Only a few patient-derived xenografts (PDX) have been established in mice, but these models are time consuming and not suitable for drug testing in multiple replicates [5]. The avian embryo has recently been demonstrated as a promising host for primary cancer cells [6, 7], and presents many interesting features: i/it requires a low number of cells, which enables multiple replicas with the same sample, ii/it allows intravenous drug injection to assess drug sensitivity, iii/tumor volume can be measured using light sheet microscopy and iv/ tumor cells can be collected back for detailed analyses such as single cell RNA sequencing (scRNAseq). Here we explored the ability of this model to host primary FL cells (FL-AVI-PDX).

Next, we tested whether the FL-AVI-PDX model can capture interpatient heterogeneity of therapeutic response. We engrafted cells from twenty patients treated with RCHOP and rituximab maintenance, including 9 poor responders with FL progression during the first 24 months (POD24) and 11 good responders with long progression free survival (Supplementary Table 1). Twenty-four hours after engraftment, FL-bearing avian embryos were randomly treated by intravenous injection of excipient or RCHOP at the maximal tolerated dose (MTD), used with the same stoichiometry between each drug as in clinics (Supplementary Table 4, Supplementary Fig. 1E, F). The embryos were harvested after an additional 24 h for measurement of tumor volumes based on CFSE fluorescence using light sheet microscopy (Supplementary Fig. 1G). Analyses of tumor volumes showed that RCHOP consistently reduced the mean tumor volume in FL-AVI-PDX from good responder patients but not in FL-AVI-PDX from poor responder patients (mean tumor volume reduction 35% vs. −2%, p = 0.0001) (Fig. 1E, F, Supplementary Table 2). Multivariate analysis showed that tumor volume reduction is an independent prognostic predictor of progression free survival in this cohort (hazard ratio 0.32, range 0.15–0.67, p = 0.003) (Fig. 1G, Supplementary Fig. 1H). Altogether, these data show that clinically relevant information correlates with functional testing in the FL-AVI-PDX model. As almost all FL patients achieve complete clinical response after RCHOP, the observation of a significant difference of response to RCHOP in ovo was unexpected. A possible hypothesis is that this differential effect on bulk tumor reduction is due to the low drug concentrations delivered in avian embryos, which may reveal subtle differences in chemosensitivity. Of note, further characterization of the FL-AVI-PDX model would be required to assess its value to model response to R-bendamustine, another widely used first line treatment for FL.

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Fig. 1: Establishment of the FL-AVI-PDX model that captures the clinical heterogeneity of response to RCHOP.
Fig. 2: The FL-AVI-PDX reveals a transcriptomic signature of response to RCHOP in primary FL cells which can be targeted in vitro and in vivo.

Data availability

The single-cell RNA-seq data generated during the current study is available in the Gene Expression Omnibus database under accession code GSE231523. Computer code used to generate these results is available on GitHub at https://github.com/Lipinski-B/Flinovo.

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Acknowledgements

The authors thank the Institut Carnot Calym for having provoked the scientific collaboration and provided access to the CeVi_Collection. The authors also thank the Centre de Ressources Biologiques CRB-Sud from Hospices Civils de Lyon, Lyon Sud hospital pharmacy department for having provided RCHOP compounds. We thank Yann Guillermin for his help in data collection. We thank Sabrina Baaklini, Pierre Milpied, Bertrand Nadel, Jerome Tamburini, and Bruno Tesson for helpful scientific discussions. We acknowledge the contribution of SFR Biosciences (UAR3444/CNRS, US8/Inserm, ENS de Lyon, UCBL) lentivectors production facility (Gerland) and cytometry facility (Lyon Sud).

Funding

This work was supported by grants from the Agence Nationale de la Recherche (ANR-19-CE17-005-01) and financial support from the Hospices Civils de Lyon.

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Author notes

  1. These authors contributed equally: Boris Lipinski, Clélia Costechareyre, Loraine Jarrosson.

Authors and Affiliations

  1. Centre International de Recherche en Infectiologie (CIRI, INSERM U1111, CNRS UMR 5308, École Normale supérieure de Lyon), Lymphoma ImmunoBiology team, Faculté de Médecine Lyon sud, Université Claude Bernard Lyon 1, 69007, Lyon, France

    Manon Zala, Boris Lipinski, Edith Julia, Aurélie Verney, Alexandra Traverse-Glehen, Emmanuel Bachy, Sarah Huet, Laurent Genestier & Pierre Sujobert

  2. OncoFactory, an ERBC company, Faculté de Médecine et de Pharmacie, 8 avenue Rockefeller, 69008, Lyon, France

    Clélia Costechareyre, Loraine Jarrosson, Romain Teinturier & Marjorie Lacourrège

  3. Hospices Civils de Lyon, Hôpital Lyon Sud, Service de biochimie, 69310, Pierre Bénite, France

    Jérôme Guitton

  4. Hospices Civils de Lyon, Hôpital Lyon Sud, Service d’Anatomopathologie, 69310, Pierre Bénite, France

    Alexandra Traverse-Glehen

  5. Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Gilles Salles

  6. Hospices Civils de Lyon, Hôpital Lyon Sud, Service d’hématologie biologique, 69310, Pierre Bénite, France

    Sarah Huet & Pierre Sujobert

  7. University of Lyon, University Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, NeuroMyoGene Institute, 69008, Lyon, France

    Valérie Castellani & Céline Delloye-Bourgeois

  8. Cancer Research Center of Lyon (CRCL, INSERM U1052-CNRS UMR5286, University of Lyon), University Claude Bernard Lyon 1, Centre Léon Bérard, 69008, Lyon, France

    Céline Delloye-Bourgeois

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  1. Manon Zala
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Contributions

MZ, LG, VC, CD-B, and PS conceptualized the study and acquired fundings; MZ, BL, CC, LJ, RT, ML, AV, and JG, performed the investigations; MZ, BL, CC, LJ, RT, EJ, ML, VC, CD-B, and PS designed the methodology; AT-G, EB, GS, SH, PS provided resources; MZ, RT, VC, CD-B, and PS supervised the study; MZ and PS wrote the original draft.

Corresponding author

Correspondence to Pierre Sujobert.

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Competing interests

CC, LJ, ML and RT are employed by Oncofactory, an ERBC company. VC and CDB are co-founders of Oncofactory SAS.

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Declaration of generative AI and AI-assisted technologies in the writing process. During the preparation of this work the authors used ChatGPT in order to improve English editing and readability. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

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Zala, M., Lipinski, B., Costechareyre, C. et al. Functional precision oncology for follicular lymphoma with patient-derived xenograft in avian embryos. Leukemia 38, 430–434 (2024). https://doi.org/10.1038/s41375-024-02150-9

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