CD4 T cell depletion increases memory differentiation of endogenous and CAR T cells and enhances the efficacy of Super2 and IL-33-armored CAR T cells against solid tumors
Background Responsiveness to chimeric antigen receptor (CAR) T cell therapy correlates with CAR T cell expansion and persistence in vivo. Multiple strategies improve persistence by increasing stem-like properties or sustaining CAR T cell activity with combination therapies. Here, we describe the int...
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BMJ Publishing Group
2025-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/2/e009994.full |
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| author | Chrystal Paulos Mary Jo Turk Megen C Wittling Yina H Huang Asmaa O Mohamed David Tyler Boone Shannon L Ferry Melanie C Peck Alicia M Santos Haille E Soderholm |
| author_facet | Chrystal Paulos Mary Jo Turk Megen C Wittling Yina H Huang Asmaa O Mohamed David Tyler Boone Shannon L Ferry Melanie C Peck Alicia M Santos Haille E Soderholm |
| author_sort | Chrystal Paulos |
| collection | DOAJ |
| description | Background Responsiveness to chimeric antigen receptor (CAR) T cell therapy correlates with CAR T cell expansion and persistence in vivo. Multiple strategies improve persistence by increasing stem-like properties or sustaining CAR T cell activity with combination therapies. Here, we describe the intrinsic ability of CAR T cells to differentiate into memory T cells, the effect of cytokine armoring, and neoadjuvant CD4 depletion therapy on CAR and tumor-specific endogenous memory T cells.Methods TRP1-specific or NKG2D CAR T cells alone or with Super2+IL-33 (S233) armoring and/or CD4 depletion were evaluated in immunocompetent B16F10 melanoma or MC38 colon cell carcinoma models without preconditioning. We characterized CAR and endogenous tumor-specific memory T cell precursors, establishment of circulating (TCIRC) and resident (TRM) memory T cell subsets, and ability to protect against secondary tumors.Results TRP1-specific or NKG2D CAR T cells had no effect on primary tumor growth in immunocompetent mice unless they were combined with S233 armoring or CD4 depletion. Unarmored CAR T cells expressed a stem-like phenotype in the tumor-draining lymph node and differentiated into CAR TCIRC memory cells in lymphoid organs and CAR TRM cells in the skin. In contrast, S233-armored CAR T cells exhibited an activated effector phenotype and differentiated inefficiently into CAR effector and central memory T cells. Combining CD4 therapy with unarmored CAR T cells increased CAR TCIRC and TRM memory T cells. Either CD4 depletion therapy or S233-armored CAR T cells induced activation of tumor-specific endogenous T cells that differentiated into both TCIRC and TRM memory T cells. CD4 depletion and S233-armored CAR T cell combination therapy synergized to increase endogenous memory T cells.Conclusions Unarmored TRP-1-specific or NKG2D CAR T cells have intrinsic stem-like properties and differentiate into memory T cell subsets but are non-protective against primary or secondary tumors. S233 cytokine armoring alone or with CD4 depletion improved effector responses but limited CAR memory T cell generation. S233-armored CAR T cells or CD4 depletion therapy induced endogenous tumor-specific TCIRC and TRM T cells, but the combination potentiated endogenous memory T cell generation and resulted in improved protection against B16F10 rechallenge. |
| format | Article |
| id | doaj-art-fc466aadf47b4130b7db5f8accca6f55 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-fc466aadf47b4130b7db5f8accca6f552025-02-11T19:50:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-02-0113210.1136/jitc-2024-009994CD4 T cell depletion increases memory differentiation of endogenous and CAR T cells and enhances the efficacy of Super2 and IL-33-armored CAR T cells against solid tumorsChrystal Paulos0Mary Jo Turk1Megen C Wittling2Yina H Huang3Asmaa O Mohamed4David Tyler Boone5Shannon L Ferry6Melanie C Peck7Alicia M Santos8Haille E Soderholm9Departments of Surgery and Microbiology/Immunology, Emory University School of Medicine, Atlanta, Georgia, USADartmouth Cancer Center and the Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, UK3Winship Cancer Institute of Emory University, Atlanta, GA, USADepartment of Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USADepartment of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USADepartment of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USADepartment of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USADepartment of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USADepartment of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USADepartment of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USABackground Responsiveness to chimeric antigen receptor (CAR) T cell therapy correlates with CAR T cell expansion and persistence in vivo. Multiple strategies improve persistence by increasing stem-like properties or sustaining CAR T cell activity with combination therapies. Here, we describe the intrinsic ability of CAR T cells to differentiate into memory T cells, the effect of cytokine armoring, and neoadjuvant CD4 depletion therapy on CAR and tumor-specific endogenous memory T cells.Methods TRP1-specific or NKG2D CAR T cells alone or with Super2+IL-33 (S233) armoring and/or CD4 depletion were evaluated in immunocompetent B16F10 melanoma or MC38 colon cell carcinoma models without preconditioning. We characterized CAR and endogenous tumor-specific memory T cell precursors, establishment of circulating (TCIRC) and resident (TRM) memory T cell subsets, and ability to protect against secondary tumors.Results TRP1-specific or NKG2D CAR T cells had no effect on primary tumor growth in immunocompetent mice unless they were combined with S233 armoring or CD4 depletion. Unarmored CAR T cells expressed a stem-like phenotype in the tumor-draining lymph node and differentiated into CAR TCIRC memory cells in lymphoid organs and CAR TRM cells in the skin. In contrast, S233-armored CAR T cells exhibited an activated effector phenotype and differentiated inefficiently into CAR effector and central memory T cells. Combining CD4 therapy with unarmored CAR T cells increased CAR TCIRC and TRM memory T cells. Either CD4 depletion therapy or S233-armored CAR T cells induced activation of tumor-specific endogenous T cells that differentiated into both TCIRC and TRM memory T cells. CD4 depletion and S233-armored CAR T cell combination therapy synergized to increase endogenous memory T cells.Conclusions Unarmored TRP-1-specific or NKG2D CAR T cells have intrinsic stem-like properties and differentiate into memory T cell subsets but are non-protective against primary or secondary tumors. S233 cytokine armoring alone or with CD4 depletion improved effector responses but limited CAR memory T cell generation. S233-armored CAR T cells or CD4 depletion therapy induced endogenous tumor-specific TCIRC and TRM T cells, but the combination potentiated endogenous memory T cell generation and resulted in improved protection against B16F10 rechallenge.https://jitc.bmj.com/content/13/2/e009994.full |
| spellingShingle | Chrystal Paulos Mary Jo Turk Megen C Wittling Yina H Huang Asmaa O Mohamed David Tyler Boone Shannon L Ferry Melanie C Peck Alicia M Santos Haille E Soderholm CD4 T cell depletion increases memory differentiation of endogenous and CAR T cells and enhances the efficacy of Super2 and IL-33-armored CAR T cells against solid tumors Journal for ImmunoTherapy of Cancer |
| title | CD4 T cell depletion increases memory differentiation of endogenous and CAR T cells and enhances the efficacy of Super2 and IL-33-armored CAR T cells against solid tumors |
| title_full | CD4 T cell depletion increases memory differentiation of endogenous and CAR T cells and enhances the efficacy of Super2 and IL-33-armored CAR T cells against solid tumors |
| title_fullStr | CD4 T cell depletion increases memory differentiation of endogenous and CAR T cells and enhances the efficacy of Super2 and IL-33-armored CAR T cells against solid tumors |
| title_full_unstemmed | CD4 T cell depletion increases memory differentiation of endogenous and CAR T cells and enhances the efficacy of Super2 and IL-33-armored CAR T cells against solid tumors |
| title_short | CD4 T cell depletion increases memory differentiation of endogenous and CAR T cells and enhances the efficacy of Super2 and IL-33-armored CAR T cells against solid tumors |
| title_sort | cd4 t cell depletion increases memory differentiation of endogenous and car t cells and enhances the efficacy of super2 and il 33 armored car t cells against solid tumors |
| url | https://jitc.bmj.com/content/13/2/e009994.full |
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