Exhausted T Cell Reprogramming for Checkpoint Blockade Response
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Solution Overview
Problem
Cytotoxic CD8 T lymphocytes progressively lose their killing function and become exhausted during cancer or chronic virus infections, rendering them refractory to immune checkpoint blockade therapy, necessitating new treatments to rejuvenate terminally-exhausted T cells.
Innovation Solution
Administering TGFβR1 inhibitors and BMP4, BMP6, or BMP10 agonists, along with CRISPR/Cas9 endonuclease integration systems targeting TGFβR1, and optionally using AAV vectors and antioxidants like vitamin C, to rescue the functional phenotype of exhausted T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune checkpoint blockade therapy is used to treat cancer, then partially-exhausted T cells can be rejuvenated, but terminally-exhausted T cells remain refractory and do not respond
Solution Approach 1:
The patent changes the molecular parameters of exhausted T cells by inhibiting TGFβR1 signaling and activating BMP4/6/10 pathways, thereby altering the epigenetic and transcriptional state of terminally-exhausted T cells to restore their functional plasticity and responsiveness to checkpoint blockade therapy
Solution Approach 2:
The patent applies TGFβR1 inhibition and BMP pathway activation before administering immune checkpoint blockade therapy, preparing the exhausted T cells in advance by reversing terminal exhaustion markers and epigenetic silencing, thereby enabling them to respond subsequently to checkpoint inhibition
2Reliability
If T cells are administered multiple inhibitors and agonists to reverse terminal exhaustion, then T cell functionality can be restored, but the treatment regimen becomes more complex
Solution Approach 1:
The patent uses TGFβR1 inhibitors that simultaneously block multiple downstream effects of TGFβ signaling (including SMAD2/3 activation and epigenetic modifiers), while BMP agonists activate multiple pro-differentiation pathways, thereby achieving multiple therapeutic effects through single agents and reducing overall regimen complexity
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
Reverses T cell exhaustion, enhancing the efficacy of immune checkpoint blockade therapy and improving cancer treatment outcomes by restoring T cell functionality.
Implementation Method 1
administering a vector (such as, for example, an adeno-associated virus (AAV) vector including, but not limited to AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, or AAV9) encoding clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated 9 (Cas9) endonuclease integration system wherein the Cas9 endonuclease complexed with a guide RNA (gRNA) that targets TGFβR1 gene
Implementation Method 2
administering to the subject a 1) transforming growth factor-β receptor 1 (TGFβR1) inhibitor (such as, for example, RepSox, SB525334, GW788388, Vactosertib, SD-208, Galunisertib, and/or LY3200882
Implementation Method 3
a bone morphogenic protein 4 (BMP4), BMP6, BMP10 protein, or a BMP4, BMP6, or BMP10 agonist (such as, for example, the BMP4 agonists SB4, SJ000063181, SJ000291942, and/or SJ000370178)
Implementation Method 4
administering a vector (such as, for example, an adeno-associated virus (AAV) vector including, but not limited to AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, or AAV9) encoding clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated 9 (Cas9) endonuclease integration system
Implementation Method 5
the method further comprises the administration of an antioxidant, including, but not limited to vitamin C
Data Source
AI summary
Disclosed are methods and compositions related to reviving the functionality for exhausted T cells and methods of improving immunotherapy by inhibiting T cell exhaustion. In one aspect, the methods and compositions described herein comprise inhibitors of TGFβR1 and/or BMP4 proteins or agonists to rescue the functional phenotype of exhausted T cells.