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
View: Text | PDF
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

×

Figure 5

Baricitinib overcomes NK cell–mediated rejection by impairing NK cell survival and effector function.

Options: View larger image (or click on image) Download as PowerPoint
Baricitinib overcomes NK cell–mediated rejection by impairing NK cell su...
(A) Schematic and results for parent-to-F1 HSCT model to study baricitinib effects on NK cell–mediated rejection, pooled from 2 experiments. (B) Peripheral blood NK cell frequencies (insets) of recipients in A immediately before HSCT. (C–E) Functional assays of IL-15–stimulated B6 splenic NK cells incubated with baricitinib (3 technical replicates per condition): IFN-γ production and survival after 15 hours (C), expansion and cell death after 72 hours (D), and cytolytic enzyme expression after 24 hours (E). (F) YAC-1 killing by splenic NK cells primed with IL-15 for 48 hours without baricitinib, then washed and plated with target cells for 4 hours with baricitinib. (G) NK cell phospho-Stat5 after IL-15 stimulation with or without baricitinib present. Inset numbers in E are cell frequencies within each quadrant. C–G show 1 representative of 3 experiments. Data points and error bars represent mean ± SEM. Repeated measures ANOVA (A, overall donor chimerism) and 1-way ANOVA (B–D) were used for statistical comparisons. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.