Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation
Stephen P. Persaud, … , Jaebok Choi, John F. DiPersio
Stephen P. Persaud, … , Jaebok Choi, John F. DiPersio
Published November 2, 2021
Citation Information: J Clin Invest. 2021;131(24):e145501. https://doi.org/10.1172/JCI145501.
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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 8

Baricitinib and PTCy curtail pathogenic graft-versus host alloreactivity.

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Baricitinib and PTCy curtail pathogenic graft-versus host alloreactivity...
(A) Clinical outcomes of irradiated CB6F1 mice infused with B6 splenocytes as per Figure 7 receiving baricitinib or PTCy (red) or their respective vehicle controls (blue). Mice were pooled from 3 experiments; X indicates death or euthanasia. (B) CBCs at 3 weeks after splenocyte infusion; dotted lines represent the lower reference limit. (C) Plasma inflammatory cytokine concentrations 7 days after splenocyte infusion. (D) Absolute donor splenic and bone marrow CD4+ and CD8+ T cell counts and splenic host and donor Treg counts, 7 days after splenocyte infusion. (E and F) Splenic donor CD8+ T cell cytolytic enzyme expression (E) and recipient splenic APC phenotyping (F) from mice in D. For E, inset numbers indicate cell frequencies within each quadrant; for F, inset numbers shows MFIs. FACS plots in E and F are from 1 representative mouse from 3 experiments. Data points and error bars represent mean ± SEM. Mantel-Cox test (A, survival), mixed effects model (A, weights and clinical scores), Student’s t test (B and D, spleen counts), and Mann-Whitney U test (C and D, bone marrow counts) were used for statistical comparisons. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.