CD8-Depleted Allogeneic Lymphocyte Infusion for Tumor Regression
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Solution Overview
Problem
Current cancer immunotherapy methods, such as allogeneic stem cell transplantation, face challenges in effectively reviving exhausted CD8+ T cells and inducing tumor regression while minimizing toxicity, particularly graft-versus-host disease and limited efficacy against solid tumors.
Innovation Solution
Development of allogeneic lymphocyte compositions depleted of CD8+ T cells and enriched with modified CD4+ T cells that promote Th1 differentiation, reducing the risk of sustained engraftment and graft-versus-host disease by enhancing anti-tumor activity and reversing T cell exhaustion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If allogeneic stem cell transplantation is used to revive exhausted T cells, then anti-tumor activity is improved, but graft-versus-host disease and toxicity increase
Solution Approach 1:
The patent extracts and removes CD8+ T cells from the allogeneic lymphocyte infusion, retaining only CD4+ T cells. This extraction prevents the harmful graft-versus-host disease caused by CD8+ T cell engraftment while preserving the beneficial anti-tumor activity through CD4+ T cell-mediated help to recipient CD8+ T cells.
Solution Approach 2:
The patent segments the T cell population into functional subsets (CD4+ and CD8+) and selectively uses only CD4+ T cells for the infusion. This segmentation allows the therapeutic effect (CD4+ help to CD8+) to be separated from the harmful effect (CD8+ graft-versus-host disease).
2Object-affected harmful factors
If CD8-depleted allogeneic donor lymphocyte infusion is used, then graft-versus-host disease is reduced, but efficacy against solid tumors is limited
Solution Approach 1:
The patent changes the functional parameters of CD4+ T cells by modifying them to enhance Th1 differentiation and resistance to exhaustion. This parameter modification increases the anti-tumor efficacy of the CD4+ T cells while maintaining the safety profile of CD8 depletion.
Solution Approach 2:
The patent creates a composite therapeutic composition combining modified CD4+ T cells with specific cytokine profiles (Th1-skewed) that work synergistically to revive exhausted CD8+ T cells and induce tumor regression without causing GVHD.
3Reliability
If donor CD8+ T cells are included in the infusion, then anti-tumor activity is enhanced, but sustained engraftment and toxicity increase
Solution Approach 1:
The patent extracts CD8+ T cells from the donor lymphocyte population, removing the source of sustained engraftment and toxicity while preserving anti-tumor activity through CD4+ T cell-mediated mechanisms.
Solution Approach 2:
The patent introduces CD4+ T cells as intermediary cells that mediate anti-tumor activity indirectly by providing help to recipient CD8+ T cells, rather than using CD8+ T cells as direct effectors. This intermediary approach avoids sustained engraftment while maintaining therapeutic efficacy.
Data Source
AI summary
Provided herein are methods and compositions to augment the efficacy and reduce toxicity of non-engrafting, CD8-depeleted allogeneic donor lymphocyte infusions. The compositions comprise isolated leukocytes obtained from a donor subject that (i) are mismatched to a recipient subject for at least one human leukocyte antigen (HLA) Class II allele mismatch in the donor versus recipient (graft-versus-host) direction relative to the recipient subject or (ii) is mismatched to a recipient subject for at least one human leukocyte antigen (HLA) Class II allele mismatch in the donor versus recipient (graft-versus-host) direction relative to the recipient subject, is matched to the recipient for at least one human leukocyte antigen (HLA) Class II allele, and has CD4+ T cell immunity against an antigen present in a recipient subject.