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Superkine IL-2 and IL-33 Armored CAR T Cells Reshape the Tumor Microenvironment and Reduce Growth of Multiple Solid Tumors.

ABSTRACT: Chimeric-antigen receptor (CAR) T-cell therapy has shown remarkable efficacy against hematologic tumors. Yet, CAR T-cell therapy has had little success against solid tumors due to obstacles presented by the tumor microenvironment (TME) of these cancers. Here, we show that CAR T cells armored with the engineered IL-2 superkine Super2 and IL-33 were able to promote tumor control as a single-agent therapy. IFNγ and perforin were dispensable for the effects of Super2- and IL-33-armored CAR T cells. Super2 and IL-33 synergized to shift leukocyte proportions in the TME and to recruit and activate a broad repertoire of endogenous innate and adaptive immune cells including tumor-specific T cells. However, depletion of CD8+ T cells or NK cells did not disrupt tumor control, suggesting that broad immune activation compensated for loss of individual cell subsets. Thus, we have shown that Super2 and IL-33 CAR T cells can promote antitumor immunity in multiple solid tumor models and can potentially overcome antigen loss, highlighting the potential of this universal CAR T-cell platform for the treatment of solid tumors.

SUBMITTER: Brog RA

PROVIDER: S-EPMC9357153 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Superkine IL-2 and IL-33 Armored CAR T Cells Reshape the Tumor Microenvironment and Reduce Growth of Multiple Solid Tumors.

Brog Rachel A RA Ferry Shannon L SL Schiebout Courtney T CT Messier Cameron M CM Cook W James WJ Abdullah Leena L Zou Jia J Kumar Prathna P Sentman Charles L CL Frost H Robert HR Huang Yina H YH

Cancer immunology research 20220801 8

Chimeric-antigen receptor (CAR) T-cell therapy has shown remarkable efficacy against hematologic tumors. Yet, CAR T-cell therapy has had little success against solid tumors due to obstacles presented by the tumor microenvironment (TME) of these cancers. Here, we show that CAR T cells armored with the engineered IL-2 superkine Super2 and IL-33 were able to promote tumor control as a single-agent therapy. IFNγ and perforin were dispensable for the effects of Super2- and IL-33-armored CAR T cells. ...[more]

PMID: 35696724

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Project description:BackgroundResponsiveness 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.MethodsTRP1-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.ResultsTRP1-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.ConclusionsUnarmored 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.

Dataset Information

Superkine IL-2 and IL-33 Armored CAR T Cells Reshape the Tumor Microenvironment and Reduce Growth of Multiple Solid Tumors.

Publications

Superkine IL-2 and IL-33 Armored CAR T Cells Reshape the Tumor Microenvironment and Reduce Growth of Multiple Solid Tumors.

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