Recombinant Alpha-A-Crystallin Combinations for Immunogenic Cell Death
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Solution Overview
Problem
Current cancer treatments, such as chemotherapy and radiotherapy, induce immunogenic cell death with limited efficiency by not expressing all three pre-apoptotic DAMP signals, are immunosuppressive, and fail to effectively activate and expand dendritic cells, leading to poor anti-tumor immune responses and adverse effects.
Innovation Solution
A recombinant polypeptide with at least 95% sequence identity to SEQ ID NO: 9, combined with immune cell growth factors, IL-10 inhibitory agents, and TNFa inhibitory agents, is administered in specific sequences and durations to induce robust immunogenic cell death and activate dendritic cells, enhancing anti-tumor immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemotherapy and radiotherapy are used to induce immunogenic cell death, then some pre-apoptotic DAMP signals are expressed, but not all three pre-apoptotic DAMP signals are expressed and immune suppression occurs
Solution Approach 1:
The invention divides the immunogenic cell death induction process into three distinct functional components corresponding to the three pre-apoptotic DAMP signals (CRT, HSP70, HSP90). Each component is targeted by specific therapeutic agents that can be administered individually or in combination, allowing selective enhancement of each DAMP signal pathway independently rather than relying on a single chemotherapy or radiotherapy approach.
Solution Approach 2:
The invention employs composite therapeutic regimens that combine multiple agents with different mechanisms of action to simultaneously induce all three pre-apoptotic DAMP signals. This composite approach integrates chemotherapy agents, radiotherapy, and immunomodulatory compounds into a unified treatment strategy that achieves complete DAMP signal expression while mitigating individual agent toxicities.
2Productivity
If conventional therapies are used to treat cancer, then tumor cells are killed, but dendritic cells are not effectively activated and expanded
Solution Approach 1:
The invention introduces dendritic cells as intermediary elements between tumor cell death and T-cell activation. By enhancing DAMP signal expression on dying tumor cells, the invention improves dendritic cell recognition, uptake, and processing of tumor antigens, thereby effectively activating and expanding dendritic cell populations as functional intermediaries in the anti-tumor immune response.
Solution Approach 2:
The invention establishes a feedback mechanism where activated dendritic cells present tumor antigens to T-cells, generating anti-tumor immune responses that subsequently kill more tumor cells, which in turn release more DAMP signals to further activate dendritic cells. This positive feedback loop amplifies the immune response over time, creating a self-sustaining anti-tumor immunity.
3Quantity of substance
If T-cell priming is performed to expand antigen-specific T-cells, then T-cell numbers increase, but a 90-day interval is required to optimally boost memory T cells
Solution Approach 1:
The invention performs preliminary action by pre-activating and expanding dendritic cell populations before T-cell priming occurs. By ensuring a robust dendritic cell pool is available in advance, the invention accelerates the T-cell activation and memory formation process, reducing the waiting time from 90 days to a shorter interval while maintaining or enhancing memory T-cell generation efficiency.
Solution Approach 2:
The invention changes key parameters of the immune response process by modulating DAMP signal expression levels and dendritic cell activation states. These parameter changes create more favorable conditions for rapid T-cell proliferation and differentiation into memory cells, compressing the time required for effective memory T-cell boosting without sacrificing quality or quantity.
Data Source
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AI summary
The present disclosure provides methods of preventing, delaying the progression of, treating or alleviating a symptom of, or otherwise ameliorating cancer in a subject by administering a recombinant polypeptide, an immune cell growth factor (e.g. FLT3L), a TNFa inhibitory agent (e.g. TNF alpha receptor), an IL-10 inhibitory agent (e.g. Interferon gamma) and/or an immunotherapy agent (e.g. anti-PD-1 antibody) to a subject in need thereof.