Combination Cancer Therapy Using PD-1 Antagonists and Engineered T Cells
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Solution Overview
Problem
Current cancer therapies face challenges in overcoming immune tolerance and suppression within the tumor microenvironment, leading to resistance to checkpoint inhibitor treatments and limited efficacy of T cell activation and persistence, particularly in cancers such as esophageal, stomach, liver, and lung cancers.
Innovation Solution
A combination treatment using a PD-1 axis binding antagonist, such as anti-PD1 or anti-PD-L1 antibodies, in conjunction with modified immunoresponsive cells expressing heterologous T cell receptors (TCR) or Chimeric Antigen Receptors (CAR), to enhance immune response and overcome immunosuppressive tumor microenvironments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If checkpoint inhibitor therapy (anti-PD1 or anti-PD-L1 antibody) is administered, then immune response is enhanced, but tumor resistance and immunosuppression in the microenvironment limit efficacy
Solution Approach 1:
The treatment is divided into two distinct components: (1) checkpoint inhibitor therapy to block PD-1/PD-L1 interactions and release T cell inhibition, and (2) adoptive transfer of engineered T cells (CAR-T or TCR-T) providing direct antitumor activity. This segmentation allows each component to address specific aspects of tumor immunity independently while working synergistically.
Solution Approach 2:
The patent combines checkpoint inhibitor antibodies with adoptively transferred engineered T cells into a single treatment regimen. This merging creates a dual-mechanism therapy where the antibody blocks immunosuppressive signals while the engineered T cells provide persistent, targeted antitumor immunity, overcoming the limitations of either approach alone.
2Productivity
If T cell activation is enhanced to improve antitumor response, then tumor elimination increases, but T cell exhaustion and functional suppression in the tumor microenvironment persist
Solution Approach 1:
T cells are engineered ex vivo with heterologous CAR or TCR specific for tumor antigens before adoptive transfer. This preliminary engineering equips the T cells with enhanced antigen recognition capability and resistance to tumor-induced suppression, allowing them to persist and function effectively in the challenging tumor microenvironment without requiring continuous high-level activation.
Data Source
AI summary
The present invention provides methods of treating, preventing or delaying the progress of cancer and/or tumour in a subject comprising administering to the subject a treatment regimen comprising an effective amount of a PD-1 axis binding antagonist and a population of modified immunoresponsive cells expressing or presenting a heterologous TCR. The invention also provides methods of enhancing immune function in a subject having cancer and/or tumour comprising administering to the subject a treatment regimen comprising an effective amount of a PD-1 axis binding antagonist and a population of modified immunoresponsive cells expressing or presenting a heterologous TCR.