GABARAP Modulation for Immunogenic Cell Death in Cancer Therapy
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Solution Overview
Problem
Current immunotherapy strategies for cancer face challenges due to intrinsic resistance in patients, where tumors lack lymphocyte infiltration and exhibit reduced immune response, and the mechanisms behind immunogenic cell death (ICD) induction are not fully understood, limiting the effectiveness of chemotherapy and immunotherapy combinations.
Innovation Solution
Increasing the copy number, expression level, and/or activity of GABARAP, calreticulin (CRT), and STING, or decreasing the copy number, expression level, and/or activity of stanniocalcin 1 (STC1), in combination with ICD inducers like proteasome inhibitors, to enhance immunogenic cell death and immune response in cancer treatment, while using STING agonists to potentiate anti-tumor immunity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If chemotherapy is used to kill proliferating cells, then cell proliferation is controlled, but immune response is not activated and tumors remain non-inflammatory
Solution Approach 1:
The patent converts the harmful effect of chemotherapy (non-specific cell death) into a beneficial effect by selecting agents that specifically induce immunogenic cell death. This transforms chemotherapy from a purely cytotoxic treatment into an immunotherapeutic approach that activates antitumor immunity while maintaining cell proliferation control.
Solution Approach 2:
The patent changes the parameter of cell death mode from conventional necrosis/apoptosis to immunogenic cell death. By modifying the death process to include specific molecular markers (calreticulin exposure, ATP release, HMGB1 secretion), the treatment transforms inert tumor cells into immunogenic targets that actively engage the immune system.
2Reliability
If immunotherapy is used to improve adaptive immune response, then antitumor immunity is enhanced, but intrinsic resistance develops due to lack of lymphocyte infiltration
Solution Approach 1:
The patent applies preliminary action by first inducing immunogenic cell death to create an inflammatory tumor microenvironment and recruit lymphocytes before administering checkpoint inhibitors. This preparatory step transforms cold tumors into hot tumors, making them responsive to subsequent immunotherapy that would otherwise fail due to lack of immune cell infiltration.
Solution Approach 2:
The patent introduces immunogenic cell death as an intermediary process between chemotherapy and immunotherapy. This intermediate step generates danger signals and immune attractants that bridge the gap between cytotoxic treatment and adaptive immunity activation, enabling checkpoint inhibitors to function effectively in previously resistant tumors.
3Reliability
If combination of immunotherapy and chemotherapy is used, then survival benefit is achieved, but mechanisms of ICD induction are not understood limiting effectiveness
Solution Approach 1:
The patent implements feedback by establishing measurable markers of immunogenic cell death (calreticulin exposure, ATP levels, HMGB1 secretion) that provide real-time information about treatment efficacy. This feedback mechanism allows clinicians to assess whether ICD is being successfully induced and adjust therapy accordingly, transforming the black box combination therapy into a controllable, mechanism-driven treatment.
Data Source
AI summary
The present invention relates, in part, to methods of inducing immunogenic cell death to treat a cancer in a subject comprising administering to the subject a therapeutically effective amount of an agent that increases one or more biomarkers listed in Table 1 in combination with an inducer of immunogenic cell death (ICD).