Levels of peripheral CD4+FoxP3+ regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer

Yao, Xin; Ahmadzadeh, Mojgan; Lu, Yong; Liewehr, David J.; Dudley, Mark E.; Liu, Fang; Schrump, David S.; Steinberg, Seth M.; Rosenberg, Steven A.; Robbins, Paul F.

doi:10.1182/blood-2011-10-386482

Cited by 168 publications

(137 citation statements)

References 36 publications

(60 reference statements)

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“…In contrast, miR-155 levels increased in miR-155 cells in the setting of lymphodepletion, a finding consistent with the notion that lymphocyte activation augments transgene expression (26). A major mechanism behind the increased efficacy of tumorspecific T cells in the lymphopenic environment is the removal of CD4 + T reg cells (3,4). We therefore hypothesized that miR-155 might enable CD8 + T cells to overcome T reg cell suppression.…”

Section: Mir-155 Enhances T-cell Function Under Conditions Of Limitedsupporting

confidence: 47%

“…Lymphodepleting preconditioning regimens and high-dose interleukin 2 (IL-2) are routinely used to enhance the engraftment and antitumor function of transferred T cells (2). Lymphodepletion enhances T-cell-based immunotherapies by eliminating immunosuppressive CD25 + FOXP3 + regulatory T (T reg ) cells (3,4) and activating antigen-presenting cells through Toll-like receptor signaling (5). Perhaps most important, lymphodepletion removes endogenous cellular cytokine sinks, thus increasing the availability of homeostatic cytokines that support the proliferation and function of transferred cells (6).…”

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confidence: 99%

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miR-155 augments CD8 ⁺ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ _c cytokines

Ji¹,

Wrzesinski

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

103

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Lymphodepleting regimens are used before adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic "cytokine sinks." These conditioning modalities, however, are often associated with severe toxicities. We found that microRNA-155 (miR-155) enabled tumorspecific CD8 + T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T-cell responsiveness to limited amounts of homeostatic γc cytokines, resulting in delayed cellular contraction and sustained cytokine production. miR-155 restrained the expression of the inositol 5-phosphatase Ship1, an inhibitor of the serinethreonine protein kinase Akt, and multiple negative regulators of signal transducer and activator of transcription 5 (Stat5), including suppressor of cytokine signaling 1 (Socs1) and the protein tyrosine phosphatase Ptpn2. Expression of constitutively active Stat5a recapitulated the survival advantages conferred by miR-155, whereas constitutive Akt activation promoted sustained effector functions. Our results indicate that overexpression of miR-155 in tumorspecific T cells can be used to increase the effectiveness of adoptive immunotherapies in a cell-intrinsic manner without the need for life-threatening, lymphodepleting maneuvers.

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Section: Mir-155 Enhances T-cell Function Under Conditions Of Limitedsupporting

confidence: 47%

mentioning

confidence: 99%

miR-155 augments CD8 ⁺ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ _c cytokines

Ji¹,

Wrzesinski

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

103

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“…þ regulatory T cells after lymphodepletion, and the latter was inversely associated with clinical responses (37). In addition, patients with objective clinical response after ACT received fewer doses of IL2 compared with nonresponders (1).…”

Section: Discussionmentioning

confidence: 99%

Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen

Andersen

Donia

Ellebæk

et al. 2016

Clinical Cancer Research

244

206

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Purpose: Adoptive cell transfer therapy (ACT) based on autologous tumor-infiltrating lymphocytes (TIL) has achieved impressive clinical results in several phase I and II trials performed outside of Europe. Although transient, the toxicities associated with high-dose (HD) bolus IL2 classically administered together with TILs are severe. To further scrutinize whether similar results can be achieved with lower doses of IL2, we have carried out a phase I/II trial of TIL transfer after classical lymphodepleting chemotherapy followed by an attenuated IL2 regimen.Experimental Design: Twenty-five patients with progressive treatment-refractory metastatic melanoma, good clinical performance, age < 70 years, and at least one resectable metastasis were eligible. TIL infusion was preceded by standard lymphodepleting chemotherapy and followed by attenuated doses of IL2 administered in an intravenous, continuous decrescendo regimen (ClinicalTrials.gov Identifier: NCT00937625).Results: Classical IL2-related toxicities were observed but patients were manageable in a general oncology ward without the need for intervention from the intensive care unit. RECIST 1.0 evaluation displayed three complete responses and seven partial responses (ORR 42%). Median overall survival was 21.8 months. Tumor regression was associated with a higher absolute number of infused tumor-reactive T cells. Moreover, induction and persistence of antimelanoma T-cell responses in the peripheral blood was strongly correlated to clinical response to treatment.Conclusions: TIL-ACT with a reduced IL2 decrescendo regimen results in long-lasting complete responses in patients with treatment-refractory melanoma. Larger randomized trials are needed to elucidate whether clinical efficacy is comparable with TIL-ACT followed by HD bolus IL2.

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“…Therefore, depletion of Treg cells in the vicinity of tumors is a potentially promising strategy for boosting tumor-associated Agspecific immunity (35)(36)(37)(38). We have shown that a therapeutic anti-CCR4 mAb does deplete Treg cells in vitro (39,40) and in vivo in humanized mice (27).…”

Section: Discussionmentioning

confidence: 99%

Autologous Tax-Specific CTL Therapy in a Primary Adult T Cell Leukemia/Lymphoma Cell–Bearing NOD/Shi-scid, IL-2Rγnull Mouse Model

Awata

Ishida

Suzuki

et al. 2013

The Journal of Immunology

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We expanded human T-lymphotropic virus type 1 Tax-specific CTL in vitro from PBMC of three individual adult T cell leukemia/lymphoma (ATL) patients and assessed their therapeutic potential in an in vivo model using NOG mice bearing primary ATL cells from the respective three patients (ATL/NOG). In these mice established with cells from a chronic-type patient, treatment by i.p. injection of autologous Tax-CTL resulted in greater infiltration of CD8-positive T cells into each ATL lesion. This was associated with a significant decrease of ATL cell infiltration into blood, spleen, and liver. Tax-CTL treatment also significantly decreased human soluble IL-2R concentrations in the sera. In another group of ATL/NOG mice, Tax-CTL treatment led to a significant prolongation of survival time. These findings show that Tax-CTL can infiltrate the tumor site, recognize, and kill autologous ATL cells in mice in vivo. In ATL/NOG mice with cells from an acute-type patient, whose postchemotherapeutic remission continued for >18 mo, antitumor efficacy of adoptive Tax-CTL therapy was also observed. However, in ATL/NOG mice from a different acute-type patient, whose ATL relapsed after 6 mo of remission, no efficacy was observed. Thus, although the therapeutic effects were different for different ATL patients, to the best of our knowledge, this is the first report that adoptive therapy with Ag-specific CTL expanded from a cancer patient confers antitumor effects, leading to significant survival benefit for autologous primary cancer cell–bearing mice in vivo. The present study contributes to research on adoptive CTL therapy, which should be applicable to several types of cancer.

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Levels of peripheral CD4+FoxP3+ regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer

Cited by 168 publications

References 36 publications

miR-155 augments CD8 ⁺ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ _c cytokines

miR-155 augments CD8 ⁺ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ _c cytokines

Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen

Autologous Tax-Specific CTL Therapy in a Primary Adult T Cell Leukemia/Lymphoma Cell–Bearing NOD/Shi-scid, IL-2Rγnull Mouse Model

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Levels of peripheral CD4+FoxP3+ regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer

Cited by 168 publications

References 36 publications

miR-155 augments CD8 + T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ c cytokines

miR-155 augments CD8 + T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ c cytokines

Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen

Autologous Tax-Specific CTL Therapy in a Primary Adult T Cell Leukemia/Lymphoma Cell–Bearing NOD/Shi-scid, IL-2Rγnull Mouse Model

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miR-155 augments CD8 ⁺ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ _c cytokines

miR-155 augments CD8 ⁺ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ _c cytokines