ABSTRACT
Despite the curative potential of hematopoietic stem cell transplantation (HSCT), transplant conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADC) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely involved syngeneic HSCT; however, for treatment of acute leukemias or tolerance induction for solid organ transplantation, strategies for allogeneic HSCT (allo-HSCT) are needed. Using murine allo-HSCT models, we show that combining CD45-targeted ADCs with the Janus kinase inhibitor baricitinib enables multilineage alloengraftment with >80-90% donor chimerism. Mechanistically, baricitinib impaired T and NK cell survival, proliferation and effector function, with NK cells being particularly susceptible due to inhibited IL-15 signaling. Unlike irradiated mice, CD45-ADC-conditioned mice did not manifest graft-versus-host alloreactivity when challenged with mismatched T cells. Our studies demonstrate novel allo-HSCT conditioning strategies that exemplify the promise of immunotherapy to improve the safe application of HSCT for treating hematologic diseases.
Competing Interest Statement
S.P.P.: None to declare J.K.R: None to declare J.C.: Consultancy: Daewoong Pharmaceutical; Research support: Mallinckrodt Pharmaceuticals, Incyte Corporation. P.G.R.: None to declare M.L.C.: None to declare M.P.R.: None to declare J.F.D.: Consulting/Advisory Committees: Rivervest; Research support: Macrogenics, BioLine, NeoImmuneTech, Incyte Corporation; Ownership Investment: Magenta Therapeutics, Wugen.
ABBREVIATIONS
- 7-AAD
- 7-aminoactinomycin D
- Allo-HSCT
- allogeneic hematopoietic stem cell transplantation
- ACK
- Ammonium chloride-potassium bicarbonate
- ADC
- antibody-drug conjugate
- AML
- acute myeloid leukemia
- APC
- antigen presenting cell
- BSA
- bovine serum albumin
- CBC
- Complete blood count
- CD
- Cluster of differentiation
- CFU
- colony forming unit
- FBS
- fetal bovine serum
- EDTA
- ethylenediaminetetraacetic acid
- FACS
- fluorescence-activated cell sorting
- GFP
- green fluorescent protein
- vGHD
- graft-versus-host disease
- GvL
- graft-versus-leukemia
- Hct
- hematocrit
- HEPES
- A-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
- HSC/HSCT
- hematopoietic stem cell/hematopoietic stem cell transplantation
- IFN
- Interferon
- Ig
- immunoglobulin
- IL
- Interleukin
- IMDM
- Iscove’s Modified Dulbecco’s Media
- JAK
- Janus kinase
- LK
- Lineage-Sca1-cKit+
- LSK
- Lineage-Sca1+cKit+
- miHA
- minor histocompatibility antigen
- MHC
- major histocompatibility complex
- MLR
- mixed leukocyte reaction
- PLTS
- platelets
- PBS
- phosphate buffered saline
- Running buffer
- PBS + 0.5% BSA + 2 mM EDTA
- NK
- natural killer cell
- RAG
- recombinase activating gene
- RPMI-1640
- Roswell Park Memorial Institute-1640 media
- sAV
- streptavidin
- SAP
- saporin-conjugated
- Stat
- signal transducer and transactivator
- TBI
- Total body irradiation
- TCD
- T cell depletion/depleted
- TNF
- Tumor necrosis factor
- WBC
- white blood cells