Combined organ and hematopoietic cells for transplantation tolerance of grafts
Inventors
Strober, Samuel • Lowsky, Robert
Assignees
Leland Stanford Junior University
Publication Number
US-12303532-B2
Publication Date
2025-05-20
Expiration Date
2034-02-07
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Abstract
Methods and compositions are provided for combined transplantation of a solid organ and hematopoietic cells to a recipient, where tolerance to the graft is established through development of a persistent mixed chimerism. An individual with persistent mixed chimerism, usually for a period of at least six months, is able to withdraw from the use of immunosuppressive drugs after a period of time sufficient to establish tolerance.
Core Innovation
The invention provides methods and compositions for the combined transplantation of a solid organ and hematopoietic cells to a recipient. Tolerance to the graft is established through the development of stable or persistent mixed chimerism, typically lasting at least six months. This mixed chimerism permits withdrawal from immunosuppressive drugs after a sufficient period, reducing the need for long-term immunosuppression.
The methods involve harvesting a solid organ and hematopoietic cells, such as CD34+ and CD3+ cells, from the same donor, followed by transplantation of the organ and infusion of an engineered hematopoietic cell product into the recipient. The recipient undergoes non-myeloablative conditioning and is maintained on immunosuppression until mixed chimerism is established. Precise dosing and purity of the cells, as well as monitoring for chimerism, are core aspects of the approach.
The problem addressed is that current organ transplantation between genetically non-identical patients requires lifelong immunosuppression to prevent rejection, which carries risks such as infection, cancer, and drug side effects. The invention aims to establish transplantation tolerance, allowing recipients to withdraw from immunosuppressive drugs without inducing graft-versus-host disease (GVHD).
Claims Coverage
The patent includes one independent claim that sets out several main inventive features for manufacturing a cellular product intended to promote engraftment and tolerance in solid organ transplantation.
Manufacturing a cellular product with effective amounts of CD34+ and CD3+ cells
A method comprising: - Receiving an apheresis product from a donor that contains CD34+ cells and CD3+ cells. - Processing this product to produce a cellular product with an effective amount of CD34+ cells per kilogram recipient weight in a cryopreservation solution, and at least 1×10^7 CD3+ T cells per kilogram recipient weight in the cryopreservation solution. - Including a cell type in the cryopreservation solution that facilitates engraftment of hematopoietic stem cells in the bone marrow of a solid organ transplant recipient.
Analyzing the cellular product for quality criteria
The method includes analyzing the resulting cellular product for one or more quality criteria. - The quality criteria may include parameters such as cell count, viability, sterility, or combinations thereof. - Adjustments to hematopoietic stem cell amounts can be made based on these analyses.
The claims cover methods for producing a cryopreserved cellular product containing defined effective amounts of CD34+ and CD3+ cells (from apheresis), combined with analysis of quality parameters, to facilitate hematopoietic stem cell engraftment for recipients of solid organ transplants.
Stated Advantages
Allows recipients to withdraw from immunosuppressive drugs after establishing tolerance due to persistent mixed chimerism.
Reduces the risk of graft-versus-host disease (GVHD) by using specific conditioning regimens and controlled cell dosing.
Enables long-term solid organ graft survival with minimized side effects associated with prolonged immunosuppression.
Addresses the major barrier of immune rejection in transplantation between genetically non-identical individuals.
Documented Applications
Combined transplantation of solid organs (including kidney, heart, intestine, liver, lung, and pancreas) with donor-derived hematopoietic cell infusion to establish transplant tolerance.
Administration of engineered cellular products for recipients undergoing HLA-matched or HLA-mismatched solid organ transplants.
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