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

Persaud, Stephen P.; Ritchey, Julie; Kim, Se-Na; Lim, Sora; Ruminski, Peter; Cooper, Matthew; Rettig, Michael P.; Choi, Jaebok; DiPersio, John F.

doi:10.1172/jci145501

Cited by 18 publications

(28 citation statements)

References 63 publications

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“…Further studies are needed to determine whether this represents a slowly rejecting alloimmune effector response versus a tolerogenic response; however, importantly, it is clear that the skin was grossly and histologically intact more than one year after allotransplantation following CD117-SAP conditioning and without chronic immunosuppression. Subsequent efforts by Persaud et al have shown a similar ability to achieve allotransplantation in mismatched settings with both CD117-SAP and CD45-SAP in combination with JAK1/2 inhibitors [178].…”

Section: Anti-cd117mentioning

confidence: 93%

“…Further, correction of sickle cell disease using this approach has been demonstrated in a surrogate mouse model [167]. Given these studies, clinical development has begun to generate CD45-ADCs able to deplete human HSCs and additional work in mice has shown potential utility in immunodeficiency models [168,169], autoimmune models [170,171] and allogeneic settings [172][173][174]178].…”

Section: Anti-cd45mentioning

confidence: 99%

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Antibody-Based Preparative Regimens for Cell, Tissue and Organ Transplantation

Hentenryck,

Li,

Murphy

et al. 2021

OBM Transplant

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The ability to successfully transplant cells and organs from a donor into an immunologically disparate recipient is one of the greatest treatment advances in the history of medicine. Nevertheless, acute and chronic rejection, graft versus host disease, and the inability to identify suitable donors continue to be challenges and limit broader application of cell and organ transplantation to the many patients that could benefit. Immunosuppression before and after allogeneic transplant has been found to dramatically improve allograft survival and, despite side effects, has been a mainstay of patient management. Inducing donor-specific tolerance is the holy grail in allotransplantation and is readily established in experimental animals but has been difficult to achieve in patients in settings apart from hematopoietic cell transplantation. Antibody-based conditioning to prepare the recipient is a promising approach towards achieving transplant tolerance in both hematopoietic and solid organ transplant settings, and multiple targets are currently under consideration including those on circulating lymphocytes and hematopoietic stem cells. Here we review progress in the use of antibodies to support cell and tissue transplantation with a particular focus on induction of donor-specific tolerance for solid organ transplantation.

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Section: Anti-cd117mentioning

confidence: 93%

Section: Anti-cd45mentioning

confidence: 99%

Antibody-Based Preparative Regimens for Cell, Tissue and Organ Transplantation

Hentenryck,

Li,

Murphy

et al. 2021

OBM Transplant

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“…This combination has been taken into a Phase Ib clinical trial by Forty Seven, Inc. (Menlo Park, CA, USA). A recent follow-up to this strategy combined pharmacologic Janus kinase 1/2 inhibition with anti-CD45 or anti-c-Kit antibodies to enable robust multilineage alloengraftment in mice, balancing graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) responses [14]. These kinds of approaches promise a future of stem cell transplants without chemotherapy or irradiation, and come along with other new cell therapy strategies that are pursued to reduce relapse and unrelated mortality due to transplant toxicity for patients, as follows.…”

Section: Hematopoietic Stem Cellsmentioning

confidence: 99%

The Hematology of Tomorrow Is Here—Preclinical Models Are Not: Cell Therapy for Hematological Malignancies

Arranz

2022

Cancers

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The purpose of this review is to present the current knowledge on the clinical use of several forms of cell therapy in hematological malignancies and the preclinical models available for their study. In the context of allogeneic hematopoietic stem cell transplants, mesenchymal stromal cells are pursued to help stem cell engraftment and expansion, and control graft versus host disease. We further summarize the status of promising forms of cellular immunotherapy including CAR T cell and CAR NK cell therapy aimed at eradicating the cells of origin of leukemia, i.e., leukemia stem cells. Updates on other forms of cellular immunotherapy, such as NK cells, CIK cells and CAR CIK cells, show encouraging results in AML. The considerations in available in vivo models for disease modelling and treatment efficacy prediction are discussed, with a particular focus on their strengths and weaknesses for the study of healthy and diseased hematopoietic stem cell reconstitution, graft versus host disease and immunotherapy. Despite current limitations, cell therapy is a rapidly evolving field that holds the promise of improved cure rates, soon. As a result, we may be witnessing the birth of the hematology of tomorrow. To further support its development, improved preclinical models including humanized microenvironments in mice are urgently needed.

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“…Granulocyte stimulants like gCSF are also being em in the post-HCT to enhance neutrophil recovery [95]. Finally, new condition that avoid genotoxicity altogether represent the next wave of HCT develo CD117 and anti-CD45 antibodies have been conjugated with immunotoxins in experimental models to effectively condition mice without concomita [96,97]. Similarly, chimeric antigen receptor t-cells targeted against CD117 h…”

Section: Toward the Futurementioning

confidence: 99%

“…Finally, new conditioning strategies that avoid genotoxicity altogether represent the next wave of HCT development. Anti-CD117 and anti-CD45 antibodies have been conjugated with immunotoxins and deployed in experimental models to effectively condition mice without concomitant cytopenias [96,97]. Similarly, chimeric antigen receptor t-cells targeted against CD117 have also been employed in murine models to condition effectively without chemotherapy or radiation [98].…”

Section: Toward the Futurementioning

confidence: 99%

Across the Myeloablative Spectrum: Hematopoietic Cell Transplant Conditioning Regimens for Pediatric Patients with Sickle Cell Disease

Limerick

Abraham

2022

JCM

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One out of every five hundred African American children in the United States has sickle cell disease (SCD). While multiple disease-modifying therapies are available, hematopoietic cell transplantation (HCT) remains the only curative option for children with SCD. HLA-matched sibling HCT has demonstrated excellent efficacy, but its availability remains limited; alternative donor strategies are increasingly explored. While Busulfan-Cyclophosphamide has become the most widespread conditioning regimen employed in HCT for pediatric SCD, many other regimens have been examined. This review explores different conditioning regimens across the intensity spectrum: from myeloablative to non-myeloablative. We describe survival and organ function outcomes in pediatric SCD patients who have received HCT and discuss the strengths and weaknesses of the various conditioning intensities. Finally, we posit novel directions in allogeneic HCT for SCD.

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

Cited by 18 publications

References 63 publications

Antibody-Based Preparative Regimens for Cell, Tissue and Organ Transplantation

Antibody-Based Preparative Regimens for Cell, Tissue and Organ Transplantation

The Hematology of Tomorrow Is Here—Preclinical Models Are Not: Cell Therapy for Hematological Malignancies

Across the Myeloablative Spectrum: Hematopoietic Cell Transplant Conditioning Regimens for Pediatric Patients with Sickle Cell Disease

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