Antibody Conditioning Enables MHC-Mismatched Hematopoietic Stem Cell Transplants and Organ Graft Tolerance

George, Benson M.; Kao, Kevin S.; Kwon, Hye-Sook; Velasco, Brenda J.; Poyser, Jessica; Chen, Angela; Le, Alan; Chhabra, Akanksha; Burnett, Cassandra E.; Cajuste, Devon; Hoover, Malachia; Loh, Kyle M.; Shizuru, Judith A.; Weissman, Irving L.

doi:10.1016/j.stem.2019.05.018

Cited by 56 publications

(45 citation statements)

References 76 publications

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“…25 Currently, ex vivo HSC gene therapy requires myeloablative chemotherapy to ensure engraftment of gene-modified cells, but alternative nonchemotherapy and nonirradiation approaches aimed at reducing short-and long-term toxicities associated with conditioning warrant further investigation. Early protocols and clinical studies that explored naked antibody-based conditioning for HSCT still required the use of chemotherapy and/or radiation, 26 or application to particular disease states. 27 More recently, preclinical models were used to investigate approaches coupling cytotoxic conjugates, such as saporin, to antibodies targeting either CD45, expressed exclusively on most hematopoietic cells including HSCs, or CD117 (c-Kit), a marker of HSCs and hematopoietic progenitors.…”

Section: Resultsmentioning

confidence: 99%

Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease

et al. 2020

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Section: Resultsmentioning

confidence: 99%

Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease

et al. 2020

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“…By simultaneously targeting the stem cell compartment and malignant cells, the therapeutic goals of HSCT can hypothetically be achieved with toxicities largely confined to the hematopoietic system. Indeed, recent work in murine 17,18,22,23,25,50 , non-human primates 51,52,53 , and early human trials 54 have demonstrated feasibility and limited toxicities of antibody and ADC-based therapies alongside high efficacy in depleting recipient HSCs and/or malignant cells.…”

Section: Discussionmentioning

confidence: 99%

Antibody-drug conjugates targeting CD45 plus Janus kinase inhibitors effectively condition for allogeneic hematopoietic stem cell transplantation

Persaud¹,

Ritchey²,

Choi³

et al. 2020

Preprint

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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.

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“…Another novel strategy, developed with CIRM support, represents an evolution of the antibody‐based approaches to clearing niche space that were described above. In this case, a pretreatment comprising six monoclonal antibodies that target and suppress HSCs, CD47, T cells, and NK cells was administered prior to allogenic HSCT in mice . Remarkably, this procedure enabled murine recipients to engraft donor cells with mismatches at half (haploid identical) or all major histocompatibility complex (MHC) genes without conditioning or radiation.…”

Section: Medical and Procedural Risks Of Hsctmentioning

confidence: 99%

Unleashing the cure: Overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies

Talib

Shepard

2020

Stem Cells Translational Medicine

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Hematopoietic stem cell transplantation (HSCT) is broadly used for treating and curing hematological cancers and various disorders of the blood and immune system. However, its true therapeutic potential remains vastly constrained by significant scientific and technical hurdles that preclude expansion to new indications and limit the number of patients who could benefit from, gain access to, or financially afford the procedure. To define and overcome these challenges, the California Institute for Regenerative Medicine (CIRM) held multiple workshops related to HSCT and has subsequently invested in a new generation of approaches to address the most compelling needs of the field, including new sources of healthy and immunologically compatible hematopoietic stem cells for transplant; safe and efficient genome modification technologies for correction of inherited genetic defects and other forms of gene therapy; safer and more tractable transplantation procedures such as nongenotoxic conditioning regimens, methods to accelerate immune reconstitution and recovery of immune function, and innovations to minimize the risk of immune rejection; and other life‐threatening complications from transplant. This Perspective serves to highlight these needs through examples from the recent CIRM‐funded and other notable investigations, presents rationale for comprehensive, systematic, and focused strategies to unleash the full potential of HSCT, thereby enabling cures for a greatly expanded number of disorders and making HSCT feasible, accessible, and affordable to all who could benefit.

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Antibody Conditioning Enables MHC-Mismatched Hematopoietic Stem Cell Transplants and Organ Graft Tolerance

Cited by 56 publications

References 76 publications

Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease

Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease

Antibody-drug conjugates targeting CD45 plus Janus kinase inhibitors effectively condition for allogeneic hematopoietic stem cell transplantation

Unleashing the cure: Overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies

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