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. 2017 Sep 22;8:1178. doi: 10.3389/fimmu.2017.01178

Table 1.

Preclinical studies on natural killer T (NKT) cell-targeted immunotherapeutics.

Therapy regimen Murine model/cancer type Outcome Immunological response Reference
Injection of α-GalCer/IL-12
IL-12 injection FBL-3 erythroleukemia, B16 melanoma Inhibition of tumor growth and metastasis

  1. NKT cell produced IL-12-mediated tumor rejection

  2. NKT cell-mediated direct cytotoxicity

 (168)
α-GalCer (i.v.) Colon 26 hepatic metastasis adenocarcinoma model

  1. Regression of Colon 26 nodules

  2. Inhibition of tumor growth in liver

 Activation of natural killer (NK) cells, T cells, and NK1+ T cells (169)
α-GalCer (i.p.) B16 melanoma cells Prevented liver metastasis NK cell-mediated killing (170)
α-GalCer (i.v.) Spontaneous liver metastasis of reticulum cell sarcoma (M5076) Suppressed growth of established liver metastases, prolonged survival time Increased IFN-γ and IL-12 production by liver NKT cells (171)
α-GalCer + OVA (i.v.) or OCH + OVA (i.v.) C57BL/6 mice s.c. injected with murine thymoma that express OVA Slower growth of tumor up until 10 days followed by rapid regression Induction of cytotoxic effector cells with potent antitumor activity (172)
α-GalCer (i.v.) + IL-12 i.p. BL6-B16 melanoma Effective against metastatic tumor NKT activation with induction of Th1 immunity and CD4+, CD8+ T cells, and B cells activation (173)
α-GalCer (i.v.) + IL-12 i.p. BL6-B16-HM melanoma Prevention of tumor at early stages NKT and NK activation (174)
α-GalCer (i.p.) 2 μg single dose B16-BL6 melanoma cells Subcutaneous tumor growth and tumor-induced angiogenesis at early time points

  1. IFN-γ-dependent inhibition of tumor angiogenesis by α-GalCer

  2. α-GalCer-activated NKT cells and secondarily activated NK cells contributed to the inhibition of endothelial cell proliferation via their IFN-γ production

 (175)
α-GalCer (i.p.) MCA induced sarcoma, mammary carcinomas in Her-2/neu transgenic mice, spontaneous sarcomas in p53−/−mice Inhibition of primary tumor formation

  1. NK cell and T cell activation

  2. Higher serum levels of IFN-γ and IL-4

  3. TRAIL-dependent antimetastatic activity

 (176)
α-GalCer (i.p.) + IL-12 i.p. TRAMP prostate tumor Reversion of prostrate tumor-mediated IFN-γ secretion by type I NKT cells α-GalCer and IL-12 bypasses tumor cell-induced block of IFN-γ production (91)
α-GalCer (i.v.) single dose Mantle cell lymphoma

  1. Inhibition of disease development

  2. Delayed disease progression

 NKT activation (177)
α-GalCer (i.p.) 2 μg 5T33 multiple myeloma Significant reduction in micro vessel density Possible role of IFN-γ from stimulated type I NKT cells in the antiangiogenic process (178)

  • Priming with DNA vaccine expressing human papillomavirus type 16 E7+

  • α-GalCer and boosting with E7-pulsed DC-1

 E7-expressing tumor model TC-1 Prolonged survival of vaccinated animals E7-specific CD8+ T-cell responses (179)
Ex vivo-generated dendritic cell (DC) loaded with α-GalCer/dying tumor cells
α-GalCer-loaded DC B16 melanoma cells, LLC (lung metastatic model)

  1. Inhibition of tumor metastasis in liver and lung

  2. Eradication of established tumor metastasis

 Activation of NKT cells (180)
α-GalCer-loaded ES DC genetically engineered to express a model antigen OVA + SLC/CCL21 MO4 (ova expressing melanoma)

  1. Protection against tumor

  2. Enhanced antitumor activity, rejection of tumor cell

 Synergic activation of antigen reactive CTL and α-GalCer-activated NKT cells (181)
α-GalCer + CD4-hepatic NKT MCA-induced sarcoma Tumor regression NA (115)
α-GalCer-loaded irradiated tumor cells A20 lymphoma, Meth A sarcoma, J558 Long-lived tumor immunity Type I NKT, CD8+ T cells, CD4+ T cells contribute to tumor resistance

  1. Activation and proliferation of antigenic specific T cells

  2. Secretion of IFN-γ and IL-2

 (182)
α-GalCer-loaded DC Ductal pancreatic adenocarcinoma Decrease in tumor growth and prolonged survival Expansion of IFN-γ-producing NKT (183)
α-GalCer-loaded tumor cell A20 lymphoma Tumor regression, resistance to tumor challenge CD4+ T cells mediate antitumor activity (184)
α-GalCer-loaded tumor cell B16 melanoma cells, WEHI-3B myelomonocytic leukemia, EL4 thymoma tumor cells transfected with CD1d Better survival with metastatic development thwarted NKT and NK cell activation with induction of IFN-γ and IL-12p70 secretion (185)
BM DC loaded with combination of tumor Ag and α-GalCer and anti-CD25 Ab B16 melanoma cells Delayed onset of tumor growth Prolonged proliferative burst of responding CD8+ T cells (186)
α-GalCer-loaded irradiated tumor cells VK*Myc mice, AML-ET09G, Eu-myc lymphoma Reduction in tumor load, resistance to rechallenge

  1. Expansion NKT and NK cells

  2. IL-12-dependent IFN-γ production by NKT and NK cells

 (187)
α-GalCer-loaded mature DC 5T33 multiple myeloma Increased survival Increased IFN-γ and Th1 response that tapers off at the end of disease (178)
α-GalCer-loaded irradiated tumor cells Multiple myeloma (MOPC315BM)

  1. Retarded tumor growth

  2. Regression of established tumors

  3. Protection of surviving mice from tumor rechallenge

  1. Expansion and activation of NKT cell in vivo

  2. Induction of strong myeloma specific antibodies and CD8+ CTL and memory T cells

  3. Decreased Treg frequency

 (188)
α-GalCer delivery to CD8a+ DCs with anti-DEC205 decorated nanoparticles B16 F10 melanoma cells expressing Ova Potent antitumor responses Type I NKT-mediated transactivation of NK cells, DCs, and gDT cells (189)
α-GalCer-loaded irradiated tumor cells C1498 leukemia model

  1. Prevention of new leukemia development however no protective benefit in established leukemia

 NKT cells are activated by langerin+CD8+ DC leading to generation of CD4+CD8+ T cells (190)
α-GalCer loaded in CXCL16hi BMDCs B16 melanoma model Inhibition of metastasis Increased IFN-γ+ and Tbet+ type I NKT cells, enhanced serum IFN-γ levels (191)
α-GalCer-loaded tumor cell + TLR9 agonist (CpG1826) Colon cancer

  1. Inhibition of established tumor

  2. Prolonged survival of tumor bearing mice

  3. Resistance to tumor rechallenge

  1. Type I NKT activation and DC maturation

  2. IFN-γ secretion by type I NKT and NK cells

  3. Redirection of Th2 response toward Th1 immune response by DC produced IL-12

 (192)
α-GalCer-loaded DCs + tumor cells B-cell lymphoma Potent long-lasting tumor-specific antitumor immune response

  1. Type I NKT cells secreting IFN-γ

  2. T cells and NK cell-mediated antitumor effect

 (193)
Adoptive transfer of ex vivo-expanded NKT cells
IL-12-activated NKT i.v. injection (4 times) B16 melanoma cells Inhibition of tumor metastasis Strong cytotoxic activity by activated NKT on metastasized tumor cells in liver (194)
In vitro-expanded CD8+ NKT cells redirected with humanized bispecific antibody F(ab′)2HER2xCD3 HER2-expressing ovarian carcinoma Rapid tumor regression with prolonged survival High efficacy of target cell killing by CD8+ NKT (195)
α-GalCer + ex vivo-expanded NKT C1R B-cell lymphoblasts Reduced growth of CD1d+ leukemic cells and eradication of neoplastic clone

  1. NKT cell-mediated cytotoxicity on CD1d+ nodules

  2. Presence of NKT cells infiltrating lymphoid nodules

 (196)
Tumor-sensitive T cells + CD25+ NKT cells + epigenetic drug decitabine Carcinoma Prolonged survival of animals bearing metastatic tumor cells

  1. Decitabine functioned to induce the expression of highly immunogenic cancer testis antigens in the tumor, while also reducing the frequency of myeloid-derived suppressor cells (MDSCs)

  2. The presence of CD25+ NKT cells rendered T cells resistant to remaining MDSCs

 (197)
Monoclonal antibodies stimulating NKT and α-GalCer with fusion proteins
Anti-CD1d mAbs 4T1 mammary carcinoma, R331 renal carcinoma and CT26L5 colon adenocarcinoma Suppression of established tumor growth

  1. Activation of CD1d+ antigen-presenting cell to produce tumor inhibiting IFN-γ and IL-12

  2. Blocking of type II NKT cells activity in these models

 (198)
Combination mAbs anti-DR5+ CD137+CD1d (1DMab) 4T1 mammary carcinoma, R331 renal carcinoma, and CT26L5 colon adenocarcinoma Suppression and or eradication of established tumors Tumor rejection was dependent on CD8+ T cells, IFN-γ, and CD1d and partially dependent on NK cells and IL-12 (199)
α-GalCer-loaded recombinant soluble (sCD1d) + HER2-specific scFv antibody fragment HER2-expressing B16 melanoma model Potent inhibition of lung metastasis Specific localization to tumor site and accumulation of type I NKT, NK, and T cells at tumor site (200)
α-GalCer-loaded sCD1d fusion proteins MC38 colon carcinoma transfected with human CEA Inhibition of tumor growth

  1. Strong and prolonged reactivity of type I NKT cells

  2. IFN-γ production by NK and NKT cells

  3. Direct lysis by NKT cells

 (201)
Type I NKT chimeric antigen receptor (CAR)
CAR.GD2 NKT with CD28, 4-1BB Metastatic neuroblastoma Potent antitumor activity and long-term survival

  1. Potent dose dependent cytotoxicity against GD2-positive neuroblasts

  2. Enhanced in vivo persistence of NKT cells with systemic elevation of Th1 cytokines

  3. Effective localization to tumor site without inducing GVHD

 (202)
CD62L+CAR.CD19 NKT B-cell lymphoma Prolonged survival of tumor bearing mice and sustained tumor regression CD62L+ NKTs have prolonged persistence in vivo (203)