Induction of tumor-specific protective immunity by in situ Langerhans cell vaccine

Kumamoto, Tadashi; Huang, Eric; Paek, Hyun Joon; Morita, Akimichi; Matsue, Hiroyuki; Valentini, Robert F.; Takashima, Akira

doi:10.1038/nbt0102-64

Cited by 77 publications

(65 citation statements)

References 47 publications

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“…The extent of DTH induced by chemoimmunotherapy is also consistent with an increase in the proportion of CD8 + -IFN-γ + cells (39,40). In the present study, increased proportions of IFN-γ-producing CD8 + and CD4 + T cells were observed over time with each treatment; however, the proportions were significantly greater in the patients receiving combination therapy.…”

Section: Discussionsupporting

confidence: 36%

“…Therefore, additional studies with larger numbers of patients and studies taking place at different institutions are necessary to confirm the results of the present study. In addition, the patients in the present study were sensitized to DNP via its topical application; therefore, further studies assessing the possible additive effects of using laser therapy with a previously described DNP-modified melanoma cell vaccine are necessary (33,40). Finally, the mechanism by which combination therapy enhances OS and DFS was not examined.…”

Section: Discussionmentioning

confidence: 99%

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Dinitrophenyl hapten with laser immunotherapy for advanced malignant melanoma: A clinical study

Chen

Zhao

et al. 2016

Oncology Letters

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Abstract. The present study aimed to evaluate the efficacy and safety of in situ immunotherapy with dinitrophenyl (DNP) hapten in combination with laser therapy for patients with malignant melanoma (MM). Between February 2008 and March 2012, 72 patients with stage III or IV MM were enrolled. Patients received in situ DNP alone (n=32) or in combination with laser therapy (n=32), and each group received dacarbazine chemotherapy. The levels of peripheral cluster of differentiation (CD)4 + CD25 + regulatory T cells (Tregs), interleukin (IL)-10 and tumor growth factor (TGF)-β were detected by ELISA. The association between delayed-type hypersensitivity (DTH) and survival time was evaluated. Although peripheral Treg levels significantly decreased over time in the two groups (P<0.001), there was no significant difference between the treatment groups (P= 0.098). Patients receiving the combination treatment exhibited significantly higher interferon-γ production by CD8 + and CD4 + T cells (both P<0.001), as well as significantly reduced levels of IL-10, TGF-β1 and TGF-β2. In addition, patients in the combination treatment group experienced significantly longer overall survival (OS; P=0.024) and disease-free survival (DFS; P=0.007) times; a DTH response of ≥15 mm was also associated with increased OS time and DFS time (P≤0.001). Finally, no severe adverse events were observed in either treatment group. Overall, in situ immunization with DNP in combination with laser immunotherapy may activate focal T cells, producing a regional antitumor immune response that increases cell-mediated immunity and improves survival in MM patients. Thus, this may represent a novel therapeutic strategy for patients with unresectable, advanced MM. IntroductionDerived from neural crest cells, malignant melanoma (MM) accounts for ~1.5% of all tumors and is the cutaneous malignancy with the highest mortality rate (1). There are >10 million new cases of MM diagnosed every year (1). In total, ~21% of MM patients present with focal skin metastasis and 50% with regional lymph node metastasis (1). MM patients with distant metastasis (stage IV) usually have poor prognoses, with a median survival time of 5-8 months, and the ≥5-year survival rate is <2% (2). With social and economic development, the incidence of MM is increasing each year (3).The poor prognosis of MM patients is reflective of the lack of an effective therapy. Systemic chemotherapy, including mono-and poly-chemotherapies, immunomodulatory therapies and vaccination therapy with dendritic cells (DCs) or genetically modified tumor cells, remains controversial (2). Although there is evidence showing that the combined use of interleukin (IL)-2, interferon (IFN) and chemotherapeutics may achieve a response rate as high as 64% (4,5), the efficacy of systemic therapy remains disappointing; systemic monotherapy usually achieves a clinical response rate of <15% (6-10). However, prospective, randomized clinical trials have shown no evidence that other drugs are superior to dacarbazine (DTIC) for MM pa...

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Section: Discussionsupporting

confidence: 36%

Section: Discussionmentioning

confidence: 99%

Dinitrophenyl hapten with laser immunotherapy for advanced malignant melanoma: A clinical study

Chen

Zhao

et al. 2016

Oncology Letters

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“…Recent studies have shown that ELC/ CCL19 released from polymer rods entrapped migratory Langerhans cells. The Langerhans cells, when loaded with tumor-associated Ags in situ, led to potent CTL activities and protective antitumor immunity (27). Nomura et al (28) showed an enhancement of anti-tumor immunity by tumor cells transfected with ELC/ CCL19 and stromal cell-derived factor-1␣ chemokine genes.…”

Section: Discussionmentioning

confidence: 99%

EBV-Induced Molecule 1 Ligand Chemokine (ELC/CCL19) Promotes IFN-γ-Dependent Antitumor Responses in a Lung Cancer Model

Hillinger

Yang

Zhu

et al. 2003

The Journal of Immunology

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The antitumor efficacy of EBV-induced molecule 1 ligand CC chemokine (ELC/CCL19) was evaluated in a murine lung cancer model. The ability of ELC/CCL19 to chemoattract both dendritic cells and T lymphocytes formed the rationale for this study. Compared with diluent-treated tumor-bearing mice, intratumoral injection of recombinant ELC/CCL19 led to significant systemic reduction in tumor volumes (p < 0.01). ELC/CCL19-treated mice exhibited an increased influx of CD4 and CD8 T cell subsets as well as dendritic cells at the tumor sites. These cell infiltrates were accompanied by increases in IFN-γ, MIG/CXCL9, IP-10/CXCL10, GM-CSF, and IL-12 but a concomitant decrease in the immunosuppressive molecules PGE2 and TGFβ. Transfer of T lymphocytes from ELC/CCL19 treated tumor-bearing mice conferred the antitumor therapeutic efficacy of ELC/CCL19 to naive mice. ELC/CCL19 treated tumor-bearing mice showed enhanced frequency of tumor specific T lymphocytes secreting IFN-γ. In vivo depletion of IFN-γ, MIG/CXCL9, or IP-10/CXCL10 significantly reduced the antitumor efficacy of ELC/CCL19. These findings provide a strong rationale for further evaluation of ELC/CCL19 in tumor immunity and its use in cancer immunotherapy.

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“…Short term (7-day) Th1 or Th2 cultures were generated from DO11.10 CD4 ϩ T cells in the presence of IL-12 plus anti-IL-4 mAb or IL-4 plus anti-IL-12 mAb, respectively (33). Bone marrowderived DC were generated from BALB/c mice in complete RPMI 1640 medium (34) in the presence of 10 ng/ml GM-CSF as described previously (35,36). The resulting DC preparations harvested on days 5-7 contained 72-92% CD11c ϩ cells and expressed a characteristic phenotype of immature DC.…”

Section: Cd4mentioning

confidence: 99%

Contrasting Impacts of Immunosuppressive Agents (Rapamycin, FK506, Cyclosporin A, and Dexamethasone) on Bidirectional Dendritic Cell-T Cell Interaction During Antigen Presentation

Matsue

Yang

Matsue

et al. 2002

The Journal of Immunology

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127

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Rapamycin (RAP), tacrolimus (FK506), cyclosporin A, and glucocorticoids represent modern and classic immunosuppressive agents being used clinically. Although these agents have distinct molecular mechanisms of action and exhibit different immunoregulatory profiles, their direct influences on Ag presentation processes remain relatively unknown. Here we report quantitative and qualitative differences among the above four immunosuppressants in their impact on Ag-specific, bidirectional interaction between dendritic cells (DC) and CD4+ T cells. In the presence of relevant Ag, bone marrow-derived DC delivered activation signals to CD4+ T cells isolated from the DO11.10 TCR transgenic mice, leading to clonal expansion; secretion of IFN-γ, IL-2, and IL-4; and surface expression of CD69. Conversely, DO11.10 T cells delivered maturation signals to DC, leading to IL-6 and IL-12 production and CD40 up-regulation. FK506 (10−10–10−8 M) and cyclosporin A (10−9–10−7 M) each blocked efficiently and uniformly all the changes resulting from intercellular signaling in both DC→T cell and T cell→DC directions. Dexamethasone (10−9–10−6 M) suppressed all changes, except for CD69 up-regulation, rather incompletely. Remarkably, RAP (10−10–10−8 M) efficiently inhibited DC-induced T cell proliferation and T cell-mediated CD40 up-regulation by DC without abrogating other changes. Interestingly, T cell-independent DC maturation triggered by LPS stimulation was inhibited by dexamethasone, but not by other agents. Our results demonstrate contrasting pharmacological effects of RAP vs calcineurin inhibitors on Ag presentation, thus forming a conceptual framework for rationale-based selection (and combination) of immunosuppressive agents for clinical application.

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Induction of tumor-specific protective immunity by in situ Langerhans cell vaccine

Cited by 77 publications

References 47 publications

Dinitrophenyl hapten with laser immunotherapy for advanced malignant melanoma: A clinical study

Dinitrophenyl hapten with laser immunotherapy for advanced malignant melanoma: A clinical study

EBV-Induced Molecule 1 Ligand Chemokine (ELC/CCL19) Promotes IFN-γ-Dependent Antitumor Responses in a Lung Cancer Model

Contrasting Impacts of Immunosuppressive Agents (Rapamycin, FK506, Cyclosporin A, and Dexamethasone) on Bidirectional Dendritic Cell-T Cell Interaction During Antigen Presentation

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