Selective Allogeneic Lymphocyte Infusion for Transient CD4+ T Cell Help
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Solution Overview
Problem
Cancer treatment methods face challenges due to unresponsiveness of lymphocytes to cancer-specific antigens, with CD4+ T cells being functionally defective, leading to ineffective CD8+ T cell responses, and current allogeneic stem cell transplantation risks graft-versus-host disease and sustained donor cell engraftment.
Innovation Solution
Infusion of allogeneic lymphocytes containing CD4+ T cells, depleted of CD8+ T cells and regulatory T cells, with prior chemotherapy to promote homeostatic expansion and deplete suppressor cells, minimizing sustained engraftment and graft-versus-host disease, and utilizing HLA Class II allele mismatches to enhance anti-tumor immunity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If allogeneic stem cell transplantation is performed to treat cancer, then anti-tumor immune responses are enhanced, but graft-versus-host disease and sustained donor cell engraftment occur
Solution Approach 1:
The patent extracts and removes CD8+ T cells from the donor lymphocyte composition, retaining primarily CD4+ T cells. This selective removal eliminates the harmful graft-versus-host effectors while preserving the beneficial antigen-presenting and helper functions needed for anti-tumor immunity.
Solution Approach 2:
The patent segments the T cell population into functional subsets (CD4+ helper T cells and CD8+ cytotoxic T cells) and selectively administers only the CD4+ subset. This segmentation allows separation of beneficial immune helper functions from harmful cytotoxic graft-versus-host functions.
2Reliability
If allogeneic lymphocytes are infused to provide CD4+ T cell help, then endogenous CD8+ T cell responses are enhanced, but sustained donor cell engraftment occurs
Solution Approach 1:
The patent removes CD8+ T cells from the donor lymphocyte product, eliminating the cells capable of sustained engraftment and graft-versus-host disease while preserving CD4+ T cells that provide transient helper functions to activate recipient CD8+ T cells against tumor antigens.
Solution Approach 2:
The patent creates a dynamic, transient interaction where donor CD4+ T cells temporarily assist recipient immune cells and then naturally die off. This transient engraftment provides sufficient immune activation without leading to persistent donor cell populations or chronic graft-versus-host disease.
3Productivity
If chemotherapy is administered prior to allogeneic cell infusion to promote homeostatic expansion, then anti-tumor effect is augmented, but host immune suppression increases
Solution Approach 1:
The patent applies chemotherapy before allogeneic cell infusion to temporarily suppress the host immune system and create space for donor cell homeostatic expansion. This preliminary immune suppression allows the infused CD4+ T cells to proliferate and effectively activate recipient CD8+ T cells against tumor antigens.
Data Source
AI summary
The invention provides methods and compositions for administration of allogeneic lymphocytes as an exogenous source of CD4+ T cell help for endogenous, tumor-reactive CD8+ T cells. Depletion of CD8+ T cells from the donor lymphocyte infusion reduces the risk of sustained engraftment and graft-versus-host disease. Removal of regulatory T cells from the infused population may augment the ability of non-regulatory T cells to provide help for endogenous effectors of anti-tumor immunity. Allogeneic T cell therapy is typically given in the context of allogeneic stem cell transplantation, in which the patient receives highly immunosuppressive conditioning followed by an infusion of a stem cell graft containing unselected populations of mature T cells. In the treatment described here, the graft is engineered to minimize the possibility of sustained donor cell engraftment, and the anti-tumor effector T cells derive from the host.