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Therapeutic immunity by adoptive tumor-primed CD4(+) T-cell transfer in combination with in vivo GITR ligation.

ABSTRACT: Tumor-primed CD4(+) T cells from splenocytes of tumor-rejection mice in combination with in vivo glucocorticoid-induced tumor necrosis factor receptor (GITR) ligation (the combination therapy) elicited effective host CD8(+) T cell-dependent therapeutic immunity against a murine breast tumor. GITR ligation in vitro enhanced tumor-primed CD4(+) T-cell activity and partially abrogated regulatory T cells (Treg) suppressor function. Dendritic cells (DCs) from tumor-draining lymph nodes (TDLNs) of tumor-bearing mice treated by the combination therapy stimulated Ag-specific T cells and produced interleukin (IL)-12 ex vivo. Whereas tumor-primed CD4(+) T cells or in vivo GITR ligation alone induced a tumor-specific interferon (IFN)-gamma-producing cellular response, the combination therapy enhanced and sustained it. Furthermore, the combination therapy in vivo attenuated Treg's ability to suppress IL-12 production by DCs and IFN-gamma production by effectors ex vivo. Importantly, tumor-primed CD4(+) CD25(-) T cells from splenocytes of untreated tumor-bearing mice in combination with in vivo GITR ligation also elicited an effective therapeutic effect in this model. These data suggest that the combination therapy may improve DC function, accentuate tumor-specific T-cell responses, and attenuate Treg suppressor function, thereby eliciting effective therapeutic immunity.

SUBMITTER: Liu Z

PROVIDER: S-EPMC2731416 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Therapeutic immunity by adoptive tumor-primed CD4(+) T-cell transfer in combination with in vivo GITR ligation.

Liu Zuqiang Z Tian Shenghe S Falo Louis D LD Sakaguchi Shimon S You Zhaoyang Z

Molecular therapy : the journal of the American Society of Gene Therapy 20090505 7

Tumor-primed CD4(+) T cells from splenocytes of tumor-rejection mice in combination with in vivo glucocorticoid-induced tumor necrosis factor receptor (GITR) ligation (the combination therapy) elicited effective host CD8(+) T cell-dependent therapeutic immunity against a murine breast tumor. GITR ligation in vitro enhanced tumor-primed CD4(+) T-cell activity and partially abrogated regulatory T cells (Treg) suppressor function. Dendritic cells (DCs) from tumor-draining lymph nodes (TDLNs) of tum ...[more]

PMID: 19417739

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Project description:Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells.In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28-costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8(+) T cells, and ELISA performed serially after transplant.T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in >90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3-specific CD8 T cells in 7 of 8 evaluable HLA-A2(+) patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%-100%] and 2-year event-free survival was 56% (95% CI, 37%-85%).A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF-primed MAGE-A3 vaccine.

Dataset Information

Therapeutic immunity by adoptive tumor-primed CD4(+) T-cell transfer in combination with in vivo GITR ligation.

Publications

Therapeutic immunity by adoptive tumor-primed CD4(+) T-cell transfer in combination with in vivo GITR ligation.

Similar Datasets

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