A Phase I Study of<i>In vitro</i>Expanded Natural Killer T Cells in Patients with Advanced and Recurrent Non–Small Cell Lung Cancer

Motohashi, Shinichiro; Ishikawa, Aki; Ishikawa, Eiichi; Otsuji, Mizuto; Iwamoto, Toshihiko; Hanaoka, Hideki; Shimizu, Naomi; Horiguchi, Susumu; Okamoto, Yoshitaka; Fujii, Shin‐ichiro; Taniguchi, Masaru; Fujisawa, Takehiko; Nakayama, Toshinori

doi:10.1158/1078-0432.ccr-06-0114

Cited by 218 publications

(176 citation statements)

References 38 publications

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“…7,15,16,21,30,31 Although clinical trials examining NKT cell activation therapies in patients with advanced/recurrent disease have reported few cases of objective tumor regression, tumors tended to remain stable without the appearance of new metastatic foci. 15,[17][18][19][20]35 This suggests that NKT cell activation therapy might be more effective at targeting metastatic disease than primary tumors. Since primary breast cancer tumors are effectively treated by surgical resection, and disseminated metastasis remains the primary cause of mortality, 50 NKT cell activation therapy presents a promising therapeutic avenue.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 Preclinical and clinical studies have shown that NKT cell activation with exogenous glycolipids provides significant protection from tumor progression. [15][16][17][18][19][20] Although several studies have examined the role of NKT cell activation on primary mammary carcinoma growth, 21,22 the potential therapeutic benefits of NKT cell activation in metastatic breast cancer have not been explored in detail. The aim of this work was to examine the role of NKT cell activation in a postsurgical breast cancer metastasis model.…”

Section: Introductionmentioning

confidence: 99%

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Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

et al. 2015

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Metastatic lesions are responsible for over 90% of breast cancer associated deaths. Therefore, strategies that target metastasis are of particular interest. This study examined the efficacy of natural killer T (NKT) cell activation as a postsurgical immunotherapy in a mouse model of metastatic breast cancer. Following surgical resection of orthotopic 4T1 mammary carcinoma tumors, BALB/c mice were treated with NKT cell activating glycolipid antigens (a-GalCer, a-CGalCer or OCH) or a-GalCer-loaded dendritic cells (DCs). Low doses of glycolipids transiently reduced metastasis but did not increase survival. A high dose of a-GalCer enhanced overall survival, but was associated with increased toxicity and mortality at early time points. Treatment with a-GalCer-loaded DCs limited tumor metastasis, prolonged survival, and provided curative outcomes in »45% of mice. However, survival was not increased further by additional DC treatments or co-transfer of expanded NKT cells. NKT cell activation via glycolipid-loaded DCs decreased the frequency and immunosuppressive activity of myeloid derived suppressor cells (MDSCs) in tumor-resected mice. In vitro, NKT cells were resistant to the immunosuppressive effects of MDSCs and were able to reverse the inhibitory effects of MDSCs on T cell proliferation. NKT cell activation enhanced antitumor immunity in tumor-resected mice, increasing 4T1-specific cytotoxic responses and IFNg production from natural killer (NK) cells and CD8 C T cells. Consistent with increased tumor immunity, mice surviving to day 150 were resistant to a second tumor challenge. This work provides a clear rationale for manipulating NKT cells to target metastatic disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

et al. 2015

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“…Numerical and functional iNKT cell deficiencies have been reported in a number of human diseases [189][190][191][192]. These findings led to clinical trials in humans for cancer involving the adoptive transfer of ex vivo expanded autologous DC, pulsed with a-GC, in the absence or presence of expanded iNKT cells [193][194][195]. Although these treatments were well-tolerated and resulted in the generation of antitumor CD4 + and CD8 + T cell responses, clinical responses have been limited and future refinements are required to optimize the generation of efficient antitumor immunity.…”

Section: Other Unconventional T Cells Bridging Innate and Adaptive Immentioning

confidence: 99%

“…Even more, other unconventional T cell subsets may drive similar reactions, albeit in response to different stimuli and in different anatomical contexts, arguing for a general role of innate T cell subsets as natural adjuvants to promote protective immune responses. In analogy to the exploitation of iNKT cells in the clinic [193][194][195]223,224], approaches specifically targeting Vc9/Vd2 T cells may have a similar potential as vaccine adjuvant, to boost immune responses against pathogens and tumors and to modulate autoimmune responses.…”

Section: Innate Regulation Of Adaptive Immune Responses: Vd2 + Versusmentioning

confidence: 99%

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Tyler

Doherty

Moser

et al. 2015

Cellular Immunology

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a b s t r a c tUnconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vc9/Vd2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vc9/Vd2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines.Ó 2015 Published by Elsevier Inc. Introduction cd T cells represent a third lineage of lymphocytes expressingre-arranged antigen receptors that co-evolved with 'classical' B cells and ab T cells over 400 million years, arguing for a crucial and non-redundant contribution of each lymphocyte to effective immune responses, and hence the evolutionary survival of all jawed vertebrate species [1]. 30 years have passed since the accidental and unexpected cloning of the cd T cell receptor (TCR) and the subsequent realization that ab T cells and cd T cells are fundamentally different with respect to the types of antigens they recognize and the distinct effector functions triggered upon such recognition. However, the manifold contributions of cd T cells to homeostasis, inflammation, infection and tumor surveillance have historically been neglected and are only beginning to be integrated into comprehensive models of the immune system [1][2][3][4][5][6][7].1. Innate-like pattern recognition by human Vc9/Vd2 T cells Like other 'unconventional' T cells carrying an ab TCR such as mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells, cd T cells are characterized by a markedly restrictedTCR usage that allows them to recognize self and non-self molecules in the absence of classical antigen presentation via MHC I or MHC II. Vc9/Vd2 + cd T cells represent the major cd T cell subset in human peripheral blood where they typically comprise 1-5% in healthy adults [8]. In many microbial infections, Vc9/Vd2 T cells increase locally and/or systemically [9,10] and can reach in excess of 50% of all peripheral T cells within a matter of days [11], revealing a fundamental role of this unconventional T cell population in acute disease and suggesting their exploitation for diagnostic and therapeutic purposes [12][13][14]. Vc9/Vd2 T cells uniformly respond to a class of low molecular weight molecules often referred to as 'phosphoantigens' that represent metabolites of the isoprenoid biosynthesis...

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“…The expanded NKT cells were able to lyse glioma cells, which retained expression of CD1d. Adoptive transfer of autologous NKT cells activated in vitro with ␣GalCer and IL-2 was also tested in a phase I clinical trial in cancer patients (73). However, none of these clinical trials to date has succeeded in achieving significant efficacy against human tumors in vivo, in contrast to the studies in mice.…”

Section: Type I Nkt Cells In Tumor Immunity and Immune Regulationmentioning

confidence: 99%

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

Berzofsky

Terabe

2008

The Journal of Immunology

109

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A Phase I Study ofIn vitroExpanded Natural Killer T Cells in Patients with Advanced and Recurrent Non–Small Cell Lung Cancer

Cited by 218 publications

References 38 publications

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

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