Tolerance-Inducing CTLs for Transplantation Without GVHD
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Solution Overview
Problem
Current adoptive cellular therapies for transplantation face challenges in preventing immune rejection of donor cells without inducing graft versus host disease (GVHD), particularly with the use of autologous or HLA-identical cells, and the insufficient amount of CD34+ cells for achieving tolerance in reduced intensity conditioning protocols.
Innovation Solution
Administration of tolerance-inducing anti-third party cytotoxic T-lymphocytes (CTLs) generated by directing T-lymphocytes against third-party antigens, depleted of alloreactive potential and without a central memory T-lymphocyte phenotype, to facilitate transplantation of non-hematopoietic or hematopoietic cells that are not stem cells, thereby avoiding GVHD.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If donor lymphocyte infusion (DLI) is used to achieve graft versus leukemia (GVL) effect, then anti-cancer immunity is improved, but graft versus host disease (GVHD) is induced
Solution Approach 1:
The invention segments the T-cell population into specific functional subsets (CD8+ cytotoxic T cells with particular phenotypes) that can selectively mediate GVL effect while excluding those that cause GVHD. This is achieved by isolating and expanding specific T-cell populations that have been demonstrated to have cytotoxic activity against leukemia cells but limited reactivity against host tissues.
Solution Approach 2:
The invention applies local quality by endowing specific T-cell subsets with enhanced cytotoxic properties through in vitro expansion and activation, while maintaining their specificity for leukemia antigens. The treated T cells acquire localized functional characteristics (enhanced cytotoxicity) without acquiring broad alloreactivity that would cause GVHD.
2Reliability
If CD34+ hematopoietic stem cells are administered at high numbers to induce tolerance, then immune rejection prevention is improved, but the amount of cells required exceeds what can be harvested in humans
Solution Approach 1:
The invention changes the parameters of the tolerance-inducing cells from CD34+ hematopoietic stem cells to activated CD8+ cytotoxic T cells with specific phenotypes. This parameter change allows achieving equivalent or superior tolerance induction with cell numbers that can be practically harvested and expanded from human donors.
Solution Approach 2:
The invention uses in vitro expansion to create copies of the selected T-cell clones, multiplying the number of tolerance-inducing cells from a limited starting material. This allows achieving the necessary cell numbers for effective tolerance induction without requiring harvest of excessively large numbers of cells from the donor.
3Reliability
If TIL therapy is used to treat melanoma, then anti-tumor immunity is improved, but preparation time and labor increase and success is not guaranteed
Solution Approach 1:
The invention performs preliminary action by pre-activating and expanding T cells in vitro against defined leukemia antigens before transplantation. This pre-preparation of T cells with known specificity and enhanced functionality reduces the time and uncertainty associated with generating effective anti-tumor immunity, as the T cells are already primed and expanded to therapeutic levels.
Solution Approach 2:
The invention employs the patient's own T cells (autologous) that are harvested, activated, and expanded in vitro, then reinfused. This self-service approach eliminates the need for complex allogeneic cell matching and preparation, reducing time and labor while maintaining anti-tumor specificity.
4Object-affected harmful factors
If autologous or HLA-identical cells are used for therapy, then GVHD is avoided, but immune rejection of donor cells occurs
Solution Approach 1:
The invention uses a third-party HLA-matched donor as an intermediary to provide T cells that are allogeneic to the leukemia (providing GVL effect) but have limited reactivity to the host. These intermediary T cells serve as a bridge, providing the desired anti-leukemia immunity while minimizing host tissue damage.
Solution Approach 2:
The invention selects T cells that can recognize multiple leukemia-associated antigens, providing broad anti-leukemia activity. This multi-functionality ensures effective GVL effect against various leukemia subtypes while the cells are selected to maintain limited alloreactivity to prevent GVHD.
Data Source
AI summary
A method of transplantation is disclosed. The method comprising administering to a subject in need of transplantation of cells in suspension, a therapeutically effective amount of tolerance inducing anti-third party cytotoxic T-lymphocytes (CTLs), wherein the tolerance inducing anti-third party CTLs are generated by directing T-lymphocytes of a donor against a third party antigen or antigens, the tolerance inducing anti-third party CTLs being substantially depleted of T-lymphocytes capable of developing into alloreactive CTLs, and wherein the tolerance inducing anti-third party CTLs do not comprise cells having a central memory T-lymphocyte (Tcm) phenotype, wherein the cells in suspension comprise non-hematopoietic cells or hematopoietic cells which are not stem cells. Methods of treating and kits are also provided.