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US-12618046-B2 - Generation of tumor immunity using astrocytes and astrocyte-dendritic cell combinations

US12618046B2US 12618046 B2US12618046 B2US 12618046B2US-12618046-B2

Abstract

Disclosed are means, methods, and compositions of matter useful for treatment of oncological indications through stimulation of protective anti-cancer immunity. In one embodiment the invention discloses the unexpected effect of astrocytes to augment immune stimulating activities of dendritic cells. In one embodiment dendritic cells are pulsed with tumor lysates and subsequently co-cultured with astrocytes in the presence of toll-like receptor agonists.

Inventors

  • James Veltmeyer

Assignees

  • James Veltmeyer

Dates

Publication Date
20260505
Application Date
20230328

Claims (13)

  1. 1 . A method of treatment cancer comprising the steps of: a) obtaining a population of astrocyte cells; b) contacting said population of astrocyte cells with a population of dendritic cells; c) introducing one or more tumor antigens into said culture of astrocyte cells with dendritic cells; d) inducing maturation of said dendritic cells and e) administering said activated dendritic cells into a mammal in need of treatment.
  2. 2 . The method of claim 1 , wherein said astrocyte cells are derived from mammalian astrocyte progenitor cells being CD44 immunoreactive.
  3. 3 . The method of claim 2 , wherein said astrocyte progenitor cells express CD105.
  4. 4 . The method of claim 2 , wherein said astrocyte progenitor cells express CD123.
  5. 5 . The method of claim 2 , wherein said astrocyte progenitor cells express IL-3 receptor.
  6. 6 . The method of claim 2 , wherein said astrocyte progenitor cells express c-met.
  7. 7 . The method of claim 2 , wherein said astrocyte progenitor cells express Nanog.
  8. 8 . The method of claim 2 , wherein said astrocyte progenitor cells express Sox-2.
  9. 9 . The method of claim 2 , wherein said astrocyte progenitor cells express aldehyde dehydrogenase family 1 member L1 (Aldh1L1).
  10. 10 . The method of claim 2 , wherein said astrocyte progenitor cells express aldolase C (AldoC).
  11. 11 . The method of claim 2 , wherein said astrocyte progenitor cells glutamate transporter-1 (Glt1).
  12. 12 . The method of claim 2 , wherein said astrocyte progenitor cells express S100 calcium-binding protein B (S100b).
  13. 13 . The method of claim 2 , wherein said astrocyte progenitor cells express Aquaporin 4.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63/324,593, titled “Generation of Tumor Immunity Using Astrocytes and Astrocyte-Dendritic Cell Combinations” filed Mar. 28, 2022, which is hereby incorporated by reference herein in its entirety. FIELD OF THE INVENTION The invention relates to cancer treatments using astrocytes and astrocyte-like cells for immune modulation. BACKGROUND OF THE INVENTION There is currently a great desire to induce immunologically mediated treatments of chronic diseases. Immunotherapy, such as immune checkpoint inhibitors, include antibodies that block negative regulators of T-cell activation. These approaches have radically transformed cancer treatment (Eggermont et al., 2018; Gandhi et al., 2018; Schachter et al., 2017). However, even in metastatic melanoma and non-small cell lung cancer (NSCLC), malignancies that are highly responsive to immune checkpoint inhibitor therapy, response rates rarely exceed 40%. Furthermore, many common malignances, including prostate cancer (PCa) and pancreatic ductal adenocarcinoma (PDAC), are refractory to immune checkpoint inhibitors but causes of treatment failure are largely unknown. Early work correlated responsiveness with mutational burden, which presumably drives production of neoantigens that are recognized by CTL. Although this correlation may hold for a single tumor type, several malignances initially predicted to be nonresponsive based on low mutational burdens, e.g., renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), were found to be nearly as responsive to PD-1 inhibitors as highly mutated NSCLC. There is a need to induce immunotherapeutic responses in patients who are refractory to current immune stimulatory approaches due to limited ability to induce sufficient dendritic cell activation to overcome tolerogenic processes. The current invention provides means of augmenting DC activation and lymphoid in terms of proliferation, cytotoxic activity and immune stimulatory activity. SUMMARY OF THE INVENTION Preferred embodiments are directed to methods of treating cancer comprising the steps of: a) obtaining a population of astrocyte or astrocyte-like cells; b) contacting said population of astrocyte or astrocyte-like cells with a population of dendritic cells; c) introducing one or more tumor antigens into said culture of astrocyte and/or astrocyte-like cells with dendritic cells; d) inducing maturation of said dendritic cells and e) administering said activated dendritic cells into a mammal in need of treatment. Preferred methods include embodiments wherein said astrocyte-like cells are derived from mammalian astrocyte restricted precursor cells being CD44 immunoreactive and generating astrocytes but not oligodendrocytes. Preferred methods include embodiments wherein said astrocyte progenitors express CD105. Preferred methods include embodiments wherein said astrocyte progenitors express CD123. Preferred methods include embodiments wherein said astrocyte progenitors express IL-3 receptor. Preferred methods include embodiments wherein said astrocyte progenitors express c-met. Preferred methods include embodiments wherein said astrocyte progenitors express Nanog. Preferred methods include embodiments wherein said astrocyte progenitors express Sox-2. Preferred methods include embodiments wherein said astrocyte progenitors express aldehyde dehydrogenase family 1 member L1 (Aldh1L1). Preferred methods include embodiments wherein said astrocyte progenitors express aldolase C (AldoC). Preferred methods include embodiments wherein said astrocyte progenitors glutamate transporter-1 (Glt1). Preferred methods include embodiments wherein said astrocyte progenitors express S100 calcium-binding protein B (S100b). Preferred methods include embodiments wherein said astrocyte progenitors express Aquaporin 4. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a bar graph showing the proliferation of HEL alone, HEL DC, and HEL DC and Astrocytes FIG. 2 is a bar graph showing the Interferon Gamma levels of HEL alone, HEL DC, and HEL DC and Astrocytes FIG. 3 is a bar graph showing the tumor size of mice based on Lysate alone, Lysate DC, and Lysate DC and Astrocytes FIG. 4 is a bar graph showing the tumor size of mice based on DCs, Astrocytes, and DCs and Astrocytes FIG. 5 is a bar graph showing the tumor size of mice based on DCs, Astrocytes, and DCs and Astrocytes FIG. 6 is a bar graph showing the tumor size of mice based on DCs, Astrocytes, and DCs and Astrocytes FIG. 7 is a bar graph showing the tumor size of mice based on DCs, Astrocytes, and DCs and Astrocytes FIG. 8 is a bar graph showing the tumor size of mice based on Anti CTLA4, Astrocytes, and CTLA4 plus Astrocytes DETAILED DESCRIPTION OF THE INVENTION The invention provides means of enhancing the immune activation ability of dendritic cells using coculture techniques with astrocytes and/or astrocyte progenitors. Through enhancing ab