Efficacy and safety of cord blood-derived dendritic cells plus cytokine-induced killer cells combined with chemotherapy in the treatment of patients with advanced gastric cancer: a randomized Phase II study

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Efficacy and safety of cord blood-derived dendritic cells plus cytokine-induced killer cells combined with chemotherapy in the treatment of patients with advanced gastric cancer: a randomized Phase II study

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Author(s): Ying Mu ¹ , Wei-hua Wang ² , Jia-ping Xie ¹ , Ying-xin Zhang ² , Ya-pei Yang ² , Chang-hui Zhou ²

Publication date (Electronic): 25 July 2016

Journal: OncoTargets and therapy

Publisher: Dove Medical Press

Keywords: cord blood, gastric cancer, dendritic cells, cytokine-induced killer cells, immunotherapy

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Abstract

Background

Cellular immunotherapy has been widely used in the treatment of solid tumors. However, the clinical application of cord blood-derived dendritic cells and cytokine-induced killer cells (CB-DC-CIK) for the treatment of gastric cancer has not been frequently reported. In this study, the efficacy and safety of CB-DC-CIK for the treatment of gastric cancer were evaluated both in vitro and in vivo.

Methods

The phenotypes, cytokines, and cytotoxicity of CB-DC-CIK were detected in vitro. Patients with advanced gastric cancer were divided into the following two groups: the experimental group (CB-DC-CIK combined with chemotherapy) and the control group (chemotherapy alone). The curative effects and immune function were compared between the two groups.

Results

First, the results showed that combination therapy significantly increased the overall disease-free survival rate ( P=0.0448) compared with chemotherapy alone. The overall survival rate ( P=0.0646), overall response rate ( P=0.410), and disease control rate ( P=0.396) were improved in the experimental group, but these changes did not reach statistical significance. Second, the percentage of T-cell subsets (CD4 ⁺, CD3 ⁻CD56 ⁺, and CD3 ⁺CD56 ⁺) and the levels of IFN-γ, TNF-α, and IL-2, which reflect immune function, were significantly increased ( P<0.05) after immunotherapy. Finally, no serious side effects appeared in patients with gastric cancer after the application of cellular immunotherapy based on CB-DC-CIK.

Conclusion

CB-DC-CIK combined with chemotherapy is effective and safe for the treatment of patients with advanced gastric cancer.

Most cited references 41

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PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer.

John Dulos, Gregory Carven, Susan J van Boxtel … (2015)

Negative costimulation on T cells is exploited by both prostate cancer and melanoma to evade antitumor immunity. Blocking such mechanisms restores antitumor immunity as was demonstrated by the improved survival of patients with metastatic melanoma after treatment with an antibody blocking the CTLA-4 inhibitory receptor (ipilimumab). Enhanced expression of another inhibitory immunoreceptor, programmed death-1 (PD-1), and its ligand, PD-L1, was found to correlate with a poor prognosis in prostate cancer and melanoma. PD-1-blocking antibodies are being developed to modulate antitumor immune responses. To support preclinical and clinical development of anti-PD-1 therapy, we sought to develop biomarker assays that can detect the effect of PD-1-blocking agents in whole blood and peripheral blood mononuclear cells. In this study, we assessed the effect of PD-1 blockade in modulating super antigen (staphylococcus enterotoxin B)-induced and recall antigen (tetanus toxoid)-induced T-cell reactivity in vitro using whole blood and peripheral blood mononuclear cells from patients with advanced melanoma, prostate cancer, and healthy controls. PD-1 blockade was found to shift antigen-induced cellular reactivity toward a proinflammatory Th1/Th17 response, as evidenced by enhanced production of interferon γ, interleukin (IL)-2, tumor necrosis factor α, IL-6, and IL-17 and reduced production of the Th2 cytokines IL-5 and IL-13. It is interesting to note that suppression of Th2 responsivity was seen with whole blood cells only from patients with cancer. Taken together, we identified novel biomarker assays that might be used to determine the functional consequences of PD-1 blockade in peripheral blood cells from patients with cancer. How these assays translate to the local antitumor response remains to be established in a clinical setting.

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Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma.

William Hughes, Robert Somerville, Carolyn M Laurencot … (2013)

Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8(+)-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. Thirty-four patients received unselected young TILs with a median of 8.0% CD4(+) lymphocytes, and 35 patients received CD8(+)-enriched TILs with a median of 0.3% CD4(+) lymphocytes. One month after TIL infusion, patients who received CD8(+)-enriched TILs had significantly fewer CD4(+) peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8(+)-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8(+)-enriched TILs responded. A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8(+)-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.

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Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity

Carin Dahlberg, Dhifaf Sarhan, Michael Chrobok … (2015)

Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells may provide new possibilities for developing effective cancer immunotherapies by improving NK cell responses and making them less susceptible to the tumor microenvironment. Within this review, we will discuss clinical trials using NK cells with a specific reflection on novel potential strategies, such as genetic modification of NK cells and complementary therapies aimed at improving the clinical outcome of NK cell-based immune therapies.

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Author and article information

Journal

Journal ID (nlm-ta): Onco Targets Ther

Journal ID (iso-abbrev): Onco Targets Ther

Journal ID (publisher-id): OncoTargets and Therapy

Title: OncoTargets and therapy

Publisher: Dove Medical Press

ISSN (Electronic): 1178-6930

Publication date Collection: 2016

Publication date (Electronic): 25 July 2016

Volume: 9

Pages: 4617-4627

Affiliations

[1 ]Department of Gastroenterology

[2 ]Department of Central Laboratory, Liaocheng People’s Hospital, Liaocheng Clinical School of Taishan Medical University, Liaocheng, Shandong Province, People’s Republic of China

Author notes

Correspondence: Chang-hui Zhou, Department of Central Laboratory, Liaocheng People’s Hospital, Liaocheng Clinical School of Taishan Medical University, 67 Dongchang West Road, Liaocheng 252000, Shandong Province, People’s Republic of China, Tel +86 133 9625 6302, Email zhouch2006@ 123456163.com

[*]

These authors contributed equally to this work

Article

Publisher ID: ott-9-4617

DOI: 10.2147/OTT.S107745

PMC ID: 4966574

PubMed ID: 27524915

SO-VID: e145b84d-6b52-45e0-ae44-e499befc2c4c

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Efficacy and safety of cord blood-derived dendritic cells plus cytokine-induced killer cells combined with chemotherapy in the treatment of patients with advanced gastric cancer: a randomized Phase II study

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Abstract

Background

Methods

Results

Conclusion

Most cited references 41

PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer.

Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma.

Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity

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