Human IL-6 fosters long-term engraftment of patient-derived disease-driving myeloma cells in immunodeficient mice
Zainul S. Hasanali, Alfred L. Garfall, Lisa Burzenski, Leonard D. Shultz, Yan Tang, Siddhant Kadu, Neil C. Sheppard, Wei Liu, Derek Dopkin, Dan T. Vogl, Adam D. Cohen, Adam J. Waxman, Sandra P. Susanibar-Adaniya, Martin Carroll, Edward A. Stadtmauer, David Allman
Zainul S. Hasanali, Alfred L. Garfall, Lisa Burzenski, Leonard D. Shultz, Yan Tang, Siddhant Kadu, Neil C. Sheppard, Wei Liu, Derek Dopkin, Dan T. Vogl, Adam D. Cohen, Adam J. Waxman, Sandra P. Susanibar-Adaniya, Martin Carroll, Edward A. Stadtmauer, David Allman
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Resource and Technical Advance Hematology

Human IL-6 fosters long-term engraftment of patient-derived disease-driving myeloma cells in immunodeficient mice

Abstract

Multiple myeloma is a largely incurable and life-threatening malignancy of antibody-secreting plasma cells. An effective and widely available animal model that recapitulates human myeloma and related plasma cell disorders is lacking. We show that busulfan-conditioned human IL-6–transgenic (hIL-6–transgenic) NSG (NSG+hIL6) mice reliably support the engraftment of malignant and premalignant human plasma cells, including from patients diagnosed with monoclonal gammopathy of undetermined significance, pre- and postrelapse myeloma, plasma cell leukemia, and amyloid light chain amyloidosis. Consistent with human disease, NSG+hIL6 mice engrafted with patient-derived myeloma cells developed serum M spikes, and a majority developed anemia, hypercalcemia, and/or bone lesions. Single-cell RNA sequencing showed nonmalignant and malignant cell engraftment, the latter expressing a wide array of mRNAs associated with myeloma cell survival and proliferation. Myeloma-engrafted mice given CAR T cells targeting plasma cells or bortezomib experienced reduced tumor burden. Our results establish NSG+hIL6 mice as an effective patient-derived xenograft model for study and preclinical drug development of multiple myeloma and related plasma cell disorders.

Authors

Zainul S. Hasanali, Alfred L. Garfall, Lisa Burzenski, Leonard D. Shultz, Yan Tang, Siddhant Kadu, Neil C. Sheppard, Wei Liu, Derek Dopkin, Dan T. Vogl, Adam D. Cohen, Adam J. Waxman, Sandra P. Susanibar-Adaniya, Martin Carroll, Edward A. Stadtmauer, David Allman

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Figure 8

Responses to BCMA-CART or bortezomib.

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Responses to BCMA-CART or bortezomib. (A–G) NSG+hIL6 mice were implanted...
(A–G) NSG+hIL6 mice were implanted with BM cells from an untreated newly diagnosed Igκ+ MM patient. Fourteen weeks later (week zero), serum Ig+ mice were given a single dose of human BCMA-CART cells (pink, n = 6) or untransduced T cells (UTD) from the same normal donor (black, n = 5). Sera were analyzed by ELISA for human Ig weekly over 6 weeks (A–C). Shown are total Ig levels (A), fold change over time (B), and aggregate fold change data for each group (C). *P < 0.05, **P < 0.005. For A and B, each line derives from an individual host. (D and E) Representative flow cytometric plots on week 6 for Igκ+ (D) or CD4+ and CD8+ T cells (E) among BM cells in recipients of UTD or BCMA-CART cells as indicated. Igκ-versus-FSC plots are pregated on viable CD19– and CD3– events; CD4+ versus CD8+ T cell plots are pregated on viable CD3+ events. (F and G) Means and standard deviations for Igk+ (F) or CD8+ T cells (G) on week 6. (H) Separate experiment wherein serum human IgG+ NSG+hIL6 mice were given 4 doses (black arrowheads) of saline (black, n = 3, 10 μL/g) or bortezomib (red, n = 3, 1 mg/kg i.v.) over 4 weeks. Statistics were calculated with 2-tailed Mann-Whitney t tests.