Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation
Stephen P. Persaud, Julie K. Ritchey, Sena Kim, Sora Lim, Peter G. Ruminski, Matthew L. Cooper, Michael P. Rettig, Jaebok Choi, John F. DiPersio
Stephen P. Persaud, Julie K. Ritchey, Sena Kim, Sora Lim, Peter G. Ruminski, Matthew L. Cooper, Michael P. Rettig, Jaebok Choi, John F. DiPersio
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Research Article Immunology

Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation

Abstract

Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADCs) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT using this approach. Mechanistic studies using the JAK1/2 inhibitor baricitinib revealed marked impairment of T and NK cell survival, proliferation, and effector function. NK cells were exquisitely sensitive to JAK1/2 inhibition due to interference with IL-15 signaling. Unlike irradiated mice, ADC-conditioned mice did not develop pathogenic graft-versus-host alloreactivity when challenged with mismatched T cells. Finally, the combination of ADCs and baricitinib balanced graft-versus-host disease and graft-versus-leukemia responses in delayed donor lymphocyte infusion models. Our allo-HSCT conditioning strategy exemplifies the promise of immunotherapy to improve the safety of HSCT for treating hematologic diseases.

Authors

Stephen P. Persaud, Julie K. Ritchey, Sena Kim, Sora Lim, Peter G. Ruminski, Matthew L. Cooper, Michael P. Rettig, Jaebok Choi, John F. DiPersio

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Figure 7

CD45-SAP and cKit-SAP conditioning do not promote graft-versus-host alloreactivity.

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CD45-SAP and cKit-SAP conditioning do not promote graft-versus-host allo...
(A) Schematic and legend for parent-to-F1 adoptive transfer model, with sublethal TBI or ADC conditioning. (B) Clinical outcomes for mice treated per A, pooled from 2 (cKit-SAP and no-conditioning groups) or 3 (all other groups) experiments; X indicates death or euthanasia. (C) CBCs at 3 weeks after splenocyte infusion. (D) Plasma inflammatory cytokine concentrations 7 days after splenocyte infusion. (E–G) Absolute donor CD4+ and CD8+ T cell counts in spleen and bone marrow pooled from 3 experiments (E), donor CD8+ T cell cytolytic enzyme expression (F), and host APC phenotyping (G) 7 days after splenocyte infusion. In F, inset numbers show cell frequencies within each quadrant; in G, inset numbers show MFIs. For F and G, plots are from 1 representative mouse from 3 experiments. Data points and error bars represent mean ± SEM. Mantel-Cox test (B, survival), mixed effects model (B, weights and clinical scores), 1-way ANOVA (C and E), and Kruskal-Wallis test (D) were used for statistical comparisons. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.