Tumor-Targeting Immunostimulatory Bacteria With Reduced Immune Cell Toxicity
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Solution Overview
Problem
Current cancer immunotherapies face challenges in overcoming immune tolerance and evading tumor evasion mechanisms while minimizing autoimmune-related toxicities, necessitating innovative approaches to enhance anti-tumor immune responses.
Innovation Solution
Engineered immunostimulatory bacteria, such as Salmonella strains, are modified to preferentially accumulate in tumors and tumor-resident immune cells, encoding therapeutic products like cytokines and immune checkpoint inhibitors to stimulate anti-tumor responses, while reducing toxicity and immune cell death.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer immunotherapies are used to stimulate anti-tumor immune responses, then immune activation is improved, but autoimmune-related toxicities increase
Solution Approach 1:
The bacteria are engineered to preferentially accumulate in tumors and tumor-resident immune cells through modifications to surface proteins and metabolic pathways. This localized accumulation enables immune stimulation specifically at the tumor site while minimizing systemic autoimmune effects. The patent describes modifications to bacterial surface proteins that enhance tumor targeting and intracellular delivery to tumor-resident immune cells, achieving local quality improvement.
Solution Approach 2:
The engineered bacteria serve as intermediary carriers that deliver immunostimulatory products (such as cytokines and immune checkpoint inhibitors) directly to tumor-resident immune cells. This intermediary approach allows the immune stimulation to be mediated through the bacterial vector in a controlled manner, improving anti-tumor response while limiting harmful systemic effects through the bacteria's targeted delivery mechanism.
2Productivity
If bacteria are engineered to accumulate in tumors, then therapeutic efficacy is improved, but bacterial toxicity and immune cell death increase
Solution Approach 1:
The patent converts potentially harmful bacterial virulence factors into beneficial traits for tumor targeting. Modifications to bacterial surface proteins and metabolic pathways that could originally cause pathology are instead engineered to enhance tumor accumulation and intracellular delivery to tumor-resident immune cells. The bacteria's ability to invade and survive in the tumor microenvironment is harnessed as a therapeutic advantage rather than a harmful effect.
Solution Approach 2:
The bacterial strains undergo specific genetic modifications that change their physiological parameters to favor tumor accumulation. These include alterations in surface protein composition, metabolic pathway modifications, and changes in bacterial growth characteristics that enable preferential accumulation in tumors. The patent describes specific gene modifications that alter bacterial parameters to achieve enhanced therapeutic efficacy while controlling toxicity.
3Ease of operation
If systemic administration of immunostimulatory bacteria is performed, then treatment accessibility is improved, but control over bacterial distribution worsens
Solution Approach 1:
The engineered bacteria are designed to autonomously navigate the circulatory system and self-target to tumor sites through intrinsic modifications to their surface proteins and metabolic pathways. This self-service capability allows systemic administration while maintaining precise distribution control, as the bacteria automatically respond to tumor microenvironment cues and accumulate preferentially in tumors without requiring external guidance systems.
Data Source
AI summary
Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella, or by modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin and/or pagP−. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine or purine auxotrophs. The bacteria optionally are one or more of asd−, purI−, and msbB−. The immunostimulatory bacteria, such as Salmonella species, are modified to encode immunostimulatory proteins that confer anti-tumor activity in the tumor microenvironment, and/or are modified so that the bacteria preferentially infect immune cells in the tumor microenvironment, or tumor-resident immune cells, and/or are modified to induce less cell death in immune cells than in other cells. Also provided are methods of inhibiting the growth or reducing the volume of a solid tumor by administering the immunostimulatory bacteria.