Interferon-γ–Dependent Infiltration of Human T Cells into Neuroblastoma Tumors<i>In vivo</i>

Reid, Gavin D.; Shan, Xiaochuan; Coughlin, Christina M.; Lassoued, Wiem; Pawel, Bruce; Wexler, Leonard H.; Thiele, Carol J.; Tsokos, Maria; Pinkus, Jack L.; Pinkus, Geraldine S.; Grupp, Stephan A.; Vonderheide, Robert H.

doi:10.1158/1078-0432.ccr-09-0829

Cited by 32 publications

(28 citation statements)

References 24 publications

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“…Recombinant human interferon-g has been demonstrated to enhance expression of MHC class I molecules and antigen processing components on human neuroblastoma cells, to increase trafficking of human T cells into neuroblastoma tumors in vivo, and to augment the killing of neuroblastoma cells by tumor-specific T cells. 42,43 However, immunotherapeutic use of interferon-g in the treatment of human solid tumors is limited by negative feedback loops preventing long-lasting biological effects. 44,45 Adoptive T-cell therapy using autologous ex vivo-expanded tumor-infiltrating T cells transferred back into patients, represents a fascinating option for adjuvant treatment of patients with aggressive neuroblastoma.…”

Section: Discussionmentioning

confidence: 99%

Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma

et al. 2015

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Neuroblastoma grows within an intricate network of different cell types including epithelial, stromal and immune cells. The presence of tumor-infiltrating T cells is considered an important prognostic indicator in many cancers, but the role of these cells in neuroblastoma remains to be elucidated. Herein, we examined the relationship between the type, density and organization of infiltrating T cells and clinical outcome within a large collection of neuroblastoma samples by quantitative analysis of immunohistochemical staining. We found that infiltrating T cells have a prognostic value greater than, and independent of, the criteria currently used to stage neuroblastoma. A variable structural organization and different concurrent infiltration of T-cell subsets were detected in tumors with various outcomes. Low-risk neuroblastomas were characterized by a higher number of proliferating T cells and a more structured T-cell organization, which was gradually lost in tumors with poor prognosis. We defined an immunoscore based on the presence of CD3, CD4 and CD8 infiltrating T cells that associates with favorable clinical outcome in MYCN-amplified tumors, improving patient survival when combined with the v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) status. These findings support the hypothesis that infiltrating T cells influence the behavior of neuroblastoma and might be of clinical importance for the treatment of patients.

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Section: Discussionmentioning

confidence: 99%

Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma

et al. 2015

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“…These include decreased expression of peptide presenting HLA class I molecules by tumor cells, which can impair target peptide recognition by CTLs (25, 39–41). Also, neuroblastoma cells express low levels of antigen processing genes, including LMP-2, LMP-7, and TAP-1, which are necessary for preparation of peptides from proteins for presentation by HLA class I molecules to CTLs (42, 43).…”

Section: Cytotoxic T Lymphocytesmentioning

confidence: 99%

Immunology and immunotherapy of neuroblastoma

Seeger

2011

Seminars in Cancer Biology

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Purpose This review demonstrates the importance of immunobiology and immunotherapy research for understanding and treating neuroblastoma. Principal results The first suggestions of immune system-neuroblastoma interactions came from in vitro experiments showing that lymphocytes from patients were cytotoxic for their own tumor cells and from evaluations of tumors from patients that showed infiltrations of immune system cells. With the development of monoclonal antibody (mAb) technology, a number of mAbs were generated against neuroblastoma cells lines and were used to define tumor associated antigens. Disialoganglioside (GD2) is one such antigen that is highly expressed by virtually all neuroblastoma cells and so is a useful target for both identification and treatment of tumor cells with mAbs. Preclinical research using in vitro and transplantable tumor models of neuroblastoma has demonstrated that cytotoxic T lymphocytes (CTLs) can specifically recognize and kill tumor cells as a result of vaccination or of genetic engineering that endows them with chimeric antigen receptors. However, CTL based clinical trials have not progressed beyond pilot and phase I studies. In contrast, anti-GD2 mAbs have been extensively studied and modified in pre-clinical experiments and have progressed from phase I through phase III clinical trials. Thus, the one proven beneficial immunotherapy for patients with high-risk neuroblastoma uses a chimeric anti-GD2 mAb combined with IL-2 and GM-CSF to treat patients after they have received intensive cyto-reductive chemotherapy, irradiation, and surgery. Ongoing pre-clinical and clinical research emphasizes vaccine, adoptive cell therapy, and mAb strategies. Recently it was shown that the neuroblastoma microenvironment is immunosuppressive and tumor growth promoting, and strategies to overcome this are being developed to enhance anti-tumor immunotherapy. Conclusions Our understanding of the immunobiology of neuroblastoma has increased immensely over the past 40 years, and clinical translation has shown that mAb based immunotherapy can contribute to improving treatment for high-risk patients. Continued immunobiology and pre-clinical therapeutic research will be translated into even more effective immunotherapeutic strategies that will be integrated with new cytotoxic drug and irradiation therapies to improve survival and quality of life for patients with high-risk neuroblastoma.

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“…Previous work from our group and others has demonstrated that exogenous interferon g (IFNg) results in upregulation of MHC Class I on previously MHC Class I-low/negative tumors, and that this upregulation can result in increased T-cell infiltration and enhanced tumor killing in vivo. 39,40 Combining this observation with the robust antitumor activity of the cells described in this study, one could envision a clinical trial design in which high-risk neuroblastoma patients are treated with IFNg surrounding the time of tTCR T-cell infusion to enhance tumor infiltration and antitumor activity. There is also the possibility that not all tumor cells will have undetectable levels of Class I, and some tTCR T cells will be able to engage and activate.…”

Section: Discussionmentioning

confidence: 99%

“…39 This low level of Class I expression has been correlated with a low degree of T-cell infiltration, and thus it has been proposed that reduced MHC expression levels may confer "protection" from cell-mediated immunity in some tumors. In contradistinction, CAR T cells targeting neuroblastoma via an MHC-independent mechanism demonstrate robust tumor infiltration and antitumor responses.…”

Section: Discussionmentioning

confidence: 99%

T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma

Singh¹,

Kulikovskaya²,

Barrett³

et al. 2015

OncoImmunology

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The cancer-testis antigen NY-ESO-1 is expressed by many solid tumors and has limited expression by mature somatic tissues, making it a highly attractive target for tumor immunotherapy. Targeting NY-ESO-1 using engineered T cells has demonstrated clinical efficacy in the treatment of some adult tumors. Neuroblastoma is a significant cause of cancer mortality in children, and is a tumor type shown to be responsive to immunotherapies. We evaluated a large panel of primarily resected neuroblastoma samples and demonstrated that 23% express NY-ESO-1. After confirming antigen-specific activity of T cells genetically engineered to express an NY-ESO-1 directed high-affinity transgenic T cell receptor in vitro, we performed xenograft mouse studies assessing the efficacy of NY-ESO-1-targeted T cells in both localized and disseminated models of neuroblastoma. Disease responses were monitored by tumor volume measurement and in vivo bioluminescence. After delivery of NY-ESO-1 transgenic TCR T cells, we observed significant delay of tumor progression in mice bearing localized and disseminated neuroblastoma, as well as enhanced animal survival. These data demonstrate that NY-ESO-1 is an antigen target in neuroblastoma and that targeted T cells represent a potential therapeutic option for patients with neuroblastoma.

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Interferon-γ–Dependent Infiltration of Human T Cells into Neuroblastoma TumorsIn vivo

Cited by 32 publications

References 24 publications

Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma

Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma

Immunology and immunotherapy of neuroblastoma

T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma

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