Innate targeting of adoptive cellular therapies
Inventors
Gunn, Harold David • Mullins, David W. • Bazett, Mark • Kalyan, Shirin
Assignees
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Publication Number
US-12491153-B2
Publication Date
2025-12-09
Expiration Date
Abstract
Therapeutic modalities are provided for targeting adoptive cellular therapies to specific sites of disease, involving the use of specific repertoirs of PRR ligands. In effect, innate immune system signaling is provoked so as to facilitate the homing of adoptive immune cells to sites of disease, for example to the site of a solid tumor.
Core Innovation
The invention relates to enhancing an anti-tumor efficacy of an adoptive immune cell against a cancer in a mammalian subject with a solid tumor in a target tissue by co-administering an immunogenic composition and the adoptive immune cell. The adoptive immune cell is activated and has a receptor for a cancer antigen expressed by the cancer cells of the tumor. The immunogenic composition upregulates expression of a chemotactic cytokine by the tumor or target tissue so the adoptive immune cell localizes to the tumor.
A central aspect is that the adoptive immune cell comprises a cytokine receptor for the chemotactic cytokine, and comprises a CXCR3 receptor while the chemotactic cytokine is CXCL9 or CXCL10. The immunogenic composition and the adoptive immune cell are administered so that the immunogenic composition produces an innate immune response in the target tissue and causes the adoptive immune cell to localize to the tumor in the target tissue, thereby enhancing anti-tumor efficacy.
The immunogenic composition comprises a whole killed bacterial cell or recombinant bacterial cell of a bacterial mammalian pathogen pathogenic in the target tissue, including Escherichia coli (E. coli) or Klebsiella pneumoniae (K. pneumoniae). The approach is further specified for particular pathogen-cancer-target tissue combinations, including E. coli with ovarian cancer in ovary or colon cancer in colon, and K. pneumoniae with melanoma with metastases to lung and target tissue lung.
Claims Coverage
The provided material includes one independent claim (clm-00001). It contains multiple inventive features centering on chemotactic cytokine upregulation (CXCL9/CXCL10), matching CXCR3 on activated adoptive immune cells, and use of a whole killed or recombinant bacterial mammalian pathogen immunogenic composition that induces innate immune response in the target tissue.
Chemotactic-cytokine upregulation with CXCR3-matched adoptive immune localization
Administering to the subject an effective amount of an immunogenic composition in combination with an effective amount of the adoptive immune cell, where the immunogenic composition upregulates expression of a chemotactic cytokine by the tumor or target tissue, the adoptive immune cell comprises a cytokine receptor for the chemotactic cytokine and comprises a CXCR3 receptor, and the chemotactic cytokine is CXCL9 or CXCL10 such that the immunogenic composition produces an innate immune response in the target tissue and causes the adoptive immune cell to localize to the tumor in the target tissue, thereby enhancing anti-tumor efficacy.
Innate immune response produced in the target tissue by pathogen-derived immunogenic composition
Employing an immunogenic composition comprising a whole killed bacterial cell or recombinant bacterial cell of a bacterial mammalian pathogen that is pathogenic in the target tissue, and administering the immunogenic composition and the adoptive immune cell so the immunogenic composition produces an innate immune response in the target tissue and causes the adoptive immune cell to localize to the tumor in the target tissue to enhance anti-tumor efficacy.
Pathogen–cancer–target tissue combination specificity
Limiting the bacterial mammalian pathogen and cancer/target tissue relationship where the bacterial mammalian pathogen is E. coli and the cancer is ovarian cancer with target tissue ovary or colon cancer with target tissue colon, or where the bacterial mammalian pathogen is K. pneumoniae and the cancer is a melanoma with metastases to lung and target tissue is lung.
CXCL9/CXCL10-driven recruitment via CXCR3 on the adoptive immune cell
Activating the adoptive immune cell and selecting it such that it comprises a CXCR3 receptor and a cytokine receptor for the chemotactic cytokine, with the chemotactic cytokine being CXCL9 or CXCL10, so that co-administration with the immunogenic composition results in localization to the tumor in the target tissue and enhanced anti-tumor efficacy.
Across the independent claim, the main inventive thrust is coordinated co-administration where a pathogen-derived immunogenic composition induces innate immune response in the target tissue and upregulates CXCL9 or CXCL10 so that CXCR3-expressing activated adoptive immune cells localize to the tumor, enhancing anti-tumor efficacy, with specified pathogen-cancer-target tissue combinations including E. coli with ovarian or colon cancer and K. pneumoniae with lung-metastatic melanoma.
Stated Advantages
Enhancing the anti-tumor efficacy of an adoptive immune cell against a cancer in a mammalian subject.
Causing the adoptive immune cell to localize to the tumor in the target tissue.
Documented Applications
Use of E. coli as the bacterial mammalian pathogen for ovarian cancer with target tissue ovary.
Use of E. coli as the bacterial mammalian pathogen for colon cancer with target tissue colon.
Use of K. pneumoniae as the bacterial mammalian pathogen for melanoma with metastases to lung with target tissue lung.
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