Hematopoietic Stem Cell Graft Composition for Lower GVHD Risk
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Solution Overview
Problem
Myeloablative allogeneic hematopoietic cell transplantation (alloHCT) is curative in only some patients and better strategies for alloHCT are needed to improve patient outcomes.
Innovation Solution
A pharmaceutical composition comprising specific populations of therapeutic cells, including hematopoietic stem/progenitor cells (HSPC), memory T cells (Tmem), regulatory T cells (Treg), and optionally invariant natural killer T cells (iNKT), with controlled ratios and dosages, administered with myeloablative and graft-versus-host disease (GVHD) prophylaxis regimens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If myeloablative allogeneic hematopoietic cell transplantation is performed with standard cell compositions, then the treatment can be administered, but the curative rate remains limited and patient outcomes are suboptimal
Solution Approach 1:
The patent applies parameter changes by modifying the cellular composition parameters of the graft - specifically increasing HSPC dose density (>3×10^5 per kg), memory T cell dose (>3×10^5 per kg), and regulatory T cell dose (>5×10^5 per kg), while controlling naïve T cell levels (<3×10^5 per kg). This optimized parameter combination resolves the contradiction by improving engraftment reliability and reducing GVHD, thereby enhancing both curative rate and patient outcomes
Solution Approach 2:
The patent employs composite materials by creating a composite cellular graft consisting of multiple distinct cell populations (HSPC, memory T cells, regulatory T cells, and controlled naïve T cells) in specific ratios. This composite approach allows the graft to simultaneously provide stem cell reconstitution, immune surveillance, and immunosuppression functions, resolving the contradiction between curative efficacy and patient outcome improvement
2Reliability
If standard cellular graft compositions are used, then transplantation can proceed, but engraftment efficiency is insufficient
Solution Approach 1:
The patent changes the dosage parameters by establishing specific threshold levels for each cell type - HSPC >3×10^5 per kg, memory T cells >3×10^5 per kg, regulatory T cells >5×10^5 per kg. These parameter adjustments ensure sufficient engraftment efficiency while maintaining manageable total cell quantities through optimized composition rather than indiscriminate increases
3Productivity
If conventional transplantation approaches are used, then the procedure can be completed, but graft-versus-host disease occurs at high rates
Solution Approach 1:
The patent converts the harmful effect of T cells (which can cause GVHD) into a beneficial effect by selectively enriching for regulatory T cells (>5×10^5 per kg) and memory T cells while limiting naïve T cells (<3×10^5 per kg). Regulatory T cells suppress immune responses and prevent GVHD, while memory T cells provide anti-leukemic activity. This transformation resolves the contradiction by maintaining transplantation success while converting the harmful GVHD potential into protective immunosuppression and targeted immunity
Solution Approach 2:
The patent applies local quality by assigning different functional roles to different cell populations within the graft - regulatory T cells provide localized immunosuppression to prevent GVHD in host tissues, memory T cells provide localized anti-leukemic surveillance, and HSPC provide localized stem cell reconstitution. This functional differentiation allows transplantation success while minimizing harmful GVHD effects through spatial and functional compartmentalization of immune activities
Data Source
AI summary
The present disclosure provides distinct therapeutic populations of cells that form a pharmaceutical composition useful in hematopoietic stem/progenitor cell transplant. For example, the present disclosure provides a therapeutic population of cells, comprising an enriched population of hematopoietic stem/progenitor cells, memory T cells, regulatory T cells, and wherein the population of cells is depleted of naïve conventional αβ-T cells. The present disclosure further provides methods of treatment using the therapeutic population of cells. In other embodiments, the present disclosure provides methods of producing a therapeutic population of cells.