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Natural Killer T Cell ^ Based Cancer Immunotherapy 55 Commentaryonmotohashietal.,P.6079 Hansj.J

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Natural Killer T Cell ^ Based Cancer Immunotherapy 55 Commentaryonmotohashietal.,P.6079 Hansj.J The Biology Behind Natural Killer T Cell ^ Based Cancer Immunotherapy 55 CommentaryonMotohashietal.,p.6079 HansJ.J. van der Vliet,1, 2 Steven P. Balk,1and Mark A. Exley1 In this issue of Clinical Cancer Research, Motohashi et al. (1) lymphoma, sarcoma, melanoma, and lung carcinoma, suggest- present data on the first clinical trial using adoptive transfer ing broad clinical applicability(reviewed in ref. 6). On pre- of invariant natural killer T (iNKT) cells in patients with sentation of a-GalCer byCD1d-expressing antigen-presenting advanced or recurrent non–small cell lung cancer. This study cells, iNKT are activated and rapidlyproduce large amounts of follows up on several other recentlydone clinical trials targeting predominantlyIFN- g but also IL-4 that cumulativelyresult in iNKT that all aim to induce the same robust antitumor effects the activation of NK cells, B cells, CD4+ and CD8+ T cells, in humans as previouslyobserved in murine tumor models. and the antigen-presenting cells with which theyinteract. iNKT constitute an evolutionary conserved T lymphocyte Through the production of IFN-g, as well as through direct lineage that displays an extremely restricted T-cell antigen CD1d signaling (7), iNKT enhance dendritic cell maturation receptor repertoire with limited junctional diversity(V a24-Ja18 and IL-12 production. It is this cascade of events that is even- in human and Va14-Ja18 in mouse). iNKT can recognize tuallybelieved to result in the development of a Th1-biased certain glycolipid antigens, which may include the endogenous proinflammatoryantitumor immune response that is pivotal isoglobotrihexosylceramide and the synthetic a-galactosylcer- for the antimetastatic activityof a-GalCer bypromoting the amide (a-GalCer), in the context of the monomorphic generation of a long-lasting antitumor effector cell population nonclassic MHC class I–like antigen-presenting molecule and byinhibiting tumor angiogenesis (8, 9). CD1d. One of the features that distinguish iNKT from CD1d is constitutivelyexpressed bydendritic cells and other conventional T cells is their capacityto rapidlyand in some antigen-presenting cells at low levels bycertain other tissues cases simultaneouslyproduce large amounts of both T helper and can be up-regulated in response to stress (2, 8). The (Th) 1 proinflammatory(promoting cellular immune possible contribution of tumor cell CD1d expression remains responses) and Th2-type anti-inflammatory (promoting certain unclear. iNKT can mediate antitumor immunitythrough the antibodyresponses) cytokinesupon triggering, therebymedi- activation of other immune cells, in which case tumor ating the regulation of a varietyof immune responses, regression would be independent of tumor cell CD1d including antitumor immune responses (2). expression. Direct lysis of CD1d-expressing tumor cells has iNKT playa physiologicrole in tumor immunosurveillance been reported (10), however, although some tumors might against carcinogen-induced tumors (3) and are required for escape direct lysis by iNKT through shedding of neutral the antitumor effects of low-dose interleukin (IL)-12 treat- glycolipids (11) and/or their absence of costimulatory signals ment (4) through their capacityfor Th1 cytokineproduction that could lead to altered iNKT activation and consequent (Fig. 1). Manystudies designed to evaluate the antitumor suppression of antitumor responses (2, 8). activities of iNKT have used the model and highlyspecific Clinical evaluation of the antitumor activityof iNKT began glycolipid antigen a-GalCer (KRN7000) that was originally when i.v. administration of a-GalCer was evaluated in a phase isolated from the marine sponge Agelas mauritianus in a screen 1 clinical trial in patients with solid tumors. Although no for novel antitumor agents bythe KIRIN pharmaceutical clinical responses were observed, this studyshowed that a- company(Gunma, Japan; ref. 5). Antitumor effects of a-GalCer GalCer was well tolerated and indicated the importance of a were observed in a varietyof tumor metastasis models of liver, sizeable pool of iNKT in patients treated with a-GalCer, as signs lung, and lymph nodes, including colon carcinoma, T-cell of immune activation onlyoccurred in the smaller subset of patients with relativelynormal iNKT numbers (12). Simultaneously, studies showed quantitative and qualitative defects in the iNKT pool in various types of cancer, including colon cancer, lung cancer, breast cancer, melanoma, head and 1 Authors’ Affiliations: Cancer Biology Program, Division of Hematology and neck squamous cell carcinoma, prostate cancer, myelodys- Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts and 2Department of Internal Medicine, Vrije Universiteit plastic syndromes, and progressive malignant melanoma, Medisch Centrum, Amsterdam, the Netherlands although not in glioma (reviewed in ref. 6). Murine experi- Received 6/8/06; accepted 6/13/06. ments indicated that the antitumor activityof a-GalCer could Grant support: Netherlands Organization for Scientific Research TALENT grant be enhanced when a-GalCer was loaded onto dendritic cells and grant 920-03-142, Dutch Cancer Society academic grant, NIH grants R01 (13–15), this has thus far been evaluated in three clinical DK066917 and R01AI42955, Harvard Center for Human Cell Therapy pilot grant, Hershey Family Prostate Cancer Research Fund, and Dana-Farber/Harvard Cancer studies. Indeed, therapywith a-GalCer-pulsed dendritic cells Center Skin Cancer Specialized Program of Research Excellence grant P50 seemed more potent and induced inflammatorytumor CA93683. responses, tumor necrosis, and decreases in tumor markers in Requests for reprints: Mark A. Exley, Beth Israel Deaconess Medical Center, several patients as well as expansion of iNKT over several weeks NRB 1030L, 330 Brookline Avenue, Boston, MA 02115. Phone: 617-667-0982; E-mail: [email protected]. to a few months and an increase in adaptive T-cell immunity F 2006 American Association for Cancer Research. (16–18). Again, immunologic responses were most prominent doi:10.1158/1078-0432.CCR-06-1392 in patients with relativelyhigh numbers of circulating iNKT www.aacrjournals.org 5921 Clin Cancer Res 2006;12(20) October 15, 2006 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2006 American Association for Cancer Research. The Biology Behind Fig.1. Simplified model for recognition modes by iNKT.To the left, normal antigen-presenting DC enhanceTh1 antitumor responses through a MHC class 2-like interaction also involving co-stimulation (red hatched to left) and DC Th1cytokines such as IL-12 (red hatched to right).Tothe right, presentation by tumor cells lacking co-stimulation and secreting suppressive cytokines such asTGF-h (blue hatched to right) results in iNKT activation toward Th2 response (IL-4, IL-13) and consequent suppression of antitumor imunity. An intermediate effect might be expected if immature DC or defective intratumoral DC were the predominant presenting cells. Other variables include potential glycolipid antigens from the tumor presented directly by the tumor and/or indirectly via DC to the iNKT, the predominance of certain iNKTsubsets, and the presence of other immunoregulatory cells. (17) and in vivo iNKT responses were strongest using mature ena, which is a concern when transferring cells that seem to dendritic cells (18). regulate self-tolerance. Motohashi et al. selected patients for The quantitative defects in iNKT numbers that are observed inclusion in their studywith relativelyhigh amounts of in manycancer patients are accompanied byqualitative circulating iNKT. Although this is reasonable for toxicity defects in the residual iNKT population, including defective analysis, one might expect that patients with more deficient IFN-g production (19), which therebyhamper antitumor iNKT populations would benefit most from administration of effects of the iNKT ligand a-GalCer. Using this line of iNKT and that this patient group should not be excluded in thinking, beneficial clinical results maybe expected from future trials, which ideallywould also be of larger scale immunotherapeutic strategies directed at expansion and allowing evaluation of clinical responses. activation of Th1-polarized iNKT in cancer patients. This is Clearly, the article of Motohashi et al. sets the stage for further supported bymodels in which the antitumor activity further studies that will focus on optimization of this of adoptivelytransferred iNKT was shown in murine lung interesting type of immunotherapy. We believe that apart from cancer and melanoma (14, 15) and byaccumulating evidence attempts to use more purified populations of iNKT, future in man indicating that numerical defects in the size of the studies should additionallyfocus on a comparison of the effects iNKT pool are indeed of clinical significance, as theyare of different iNKT subsets, as these have been shown to be associated with poor prognosis in patients with neuroblasto- functionallydistinct. CD4 + iNKT produce both Th1- and À À ma and colon cancer (20, 21). Th2-type cytokines, whereas CD4 CD8 double-negative In this issue of Clinical Cancer Research, Motohashi et al. iNKT, and especiallythe rarest subset, CD8 + iNKT, produce describe the results of a clinical phase 1 studyin which six Th1-type cytokines (22–24). As antitumor immune responses patients with advanced or recurrent non–small cell lung cancer have traditionallybeen reported to benefit most from Th1-type received autologous in vitro –expanded
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