Allogeneic T Cell Therapy for CMV Retinitis
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Solution Overview
Problem
Current treatments for CMV retinitis in solid organ transplant recipients are inadequate, particularly for patients who have failed previous therapies or have ongoing immune suppression, as they often face resistance to antiviral agents and challenges in achieving adequate drug concentrations within the eye due to the immune-privileged status of the retina and species-specific limitations of murine CMV models.
Innovation Solution
Administering a population of allogeneic T cells specific to CMV, derived from a donor other than the transplant donor, which are sensitized to CMV antigens and administered in a manner that matches HLA alleles shared with the patient's CMV-infected cells, either alone or in combination with anti-viral agents, to enhance T-cell immunity and target CMV-infected cells within the retina.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antiviral agents are administered for prolonged periods to treat CMV retinitis in patients with ongoing immune suppression, then the disease can be controlled, but significant toxicities occur
Solution Approach 1:
The patent extracts the therapeutic function from systemic antiviral drugs and relocates it to locally-produced CMV-specific T cells. By harvesting and expanding patient-specific or donor-derived CMV-specific T cells, the therapy eliminates the need for prolonged systemic antiviral administration, thereby removing the source of significant toxicities while maintaining disease control through localized immune action in the retina
Solution Approach 2:
The therapy employs self-service by utilizing the patient's own immune system (autologous T cells) or donor-derived immune cells that are specifically activated against CMV. These T cells are expanded in vitro and then re-infused to provide sustained, specific immunity without requiring continuous external drug intervention, thus eliminating long-term toxicity while maintaining reliable disease control
2Reliability
If donor-derived CMV-specific T cells are used to treat CMV retinitis, then CMV infection can be controlled, but the risk of organ allograft rejection increases
Solution Approach 1:
The patent segments the immune response by using HLA-matched or HLA-identical donor-derived T cells that are specifically activated against CMV epitopes. This segmentation allows the T cells to recognize and attack CMV-infected cells through shared HLA molecules without triggering broad allograft rejection, as the specificity is restricted to CMV antigens presented on common HLA molecules
Solution Approach 2:
The therapy applies local quality by ensuring that the T cells are specifically activated against CMV epitopes presented on HLA molecules that are shared between donor and recipient. This creates a localized immune response targeted at CMV infection sites rather than causing system-wide rejection of the allograft, as the T cell specificity is restricted to CMV antigens rather than being broadly alloreactive
3Loss of information
If murine CMV models are used to study CMV retinitis, then mechanistic insights can be gained, but species-specific limitations prevent direct translation to human disease
Solution Approach 1:
The patent creates a functional copy of the human immune response system by using human T cells that are specifically activated against human CMV epitopes. These human T cells are expanded in vitro and then used to treat human patients, creating a direct functional copy of the therapeutic mechanism that can be directly translated from preclinical studies to clinical practice without species-specific limitations
Solution Approach 2:
The therapy applies parameter changes by transitioning from murine CMV models to human CMV-specific T cell therapy. This involves changing the biological parameters from mouse to human systems, using human T cells with specific HLA restrictions and CMV epitope specificities that are directly relevant to human disease, thereby eliminating the translational barriers present in murine models
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach effectively reduces CMV viral load and retinal inflammation, stabilizes or improves vision, and is associated with minimal toxicity, even in cases resistant to conventional antiviral therapies, without inducing organ allograft rejection or uveitis, demonstrating a viable alternative for treating CMV retinitis in immunocompromised patients.
Implementation Method 1
administering a population of allogeneic T cells comprising CMV-specific T cells... wherein the human patient has been the recipient of a solid organ transplant
Implementation Method 2
This approach effectively reduces CMV viral load and retinal inflammation, stabilizes or improves vision
Data Source
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AI summary
Disclosed herein is a population of allogeneic T cells comprising cytomegalovirus (CMV)-specific T cells for use in a method of treating CMV retinitis in a human patient, wherein the human patient has been the recipient of a solid organ transplant from a transplant donor.