scholarly journals Alpha-Fetoprotein and Hepatocellular Carcinoma Immunity

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Xiaoping Wang ◽  
Qiaoxia Wang
Keyword(s):  
Liver Cancer ◽  
Cancer Immunotherapy ◽  
Antitumor Immunity ◽  
Immune Cell ◽  
Diagnostic Marker ◽  
Peptide Vaccine ◽  
Alpha Fetoprotein ◽  
Cell Vaccine ◽  
Biological Functions

Hepatocarcinoma is one of the most prevalent gastroenterological cancers in the world with less effective therapy. As an oncofetal antigen and diagnostic marker for liver cancer, alpha-fetoprotein (AFP) possesses a variety of biological functions. Except for its diagnosis in liver cancer, AFP has become a target for liver cancer immunotherapy. Although the immunogenicity of AFP is weak and it could induce the immune escapes through inhibiting the function of dendritic cells, natural killer cells, and T lymphocytes, AFP has attracted more attention in liver cancer immunotherapy. By in vitro modification, the immunogenicity and immune response of AFP could be enhanced. AFP-modified immune cell vaccine or peptide vaccine has displayed the specific antitumor immunity against AFP-positive tumor cells and laid a better foundation for the immunotherapy of liver cancer.

scholarly journals 114 Preclinical development of a novel iPSC-derived CAR-MICA/B NK cell immunotherapy to overcome solid tumor escape from NKG2D-mediated mechanisms of recognition and killing

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A126-A126
Author(s):  
John Goulding ◽  
Mochtar Pribadi ◽  
Robert Blum ◽  
Wen-I Yeh ◽  
Yijia Pan ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Immune Cell ◽  
Nk Cell ◽  
Tumor Escape ◽  
Car T Cells ◽  
Car T

BackgroundMHC class I related proteins A (MICA) and B (MICB) are induced by cellular stress and transformation, and their expression has been reported for many cancer types. NKG2D, an activating receptor expressed on natural killer (NK) and T cells, targets the membrane-distal domains of MICA/B, activating a potent cytotoxic response. However, advanced cancer cells frequently evade immune cell recognition by proteolytic shedding of the α1 and α2 domains of MICA/B, which can significantly reduce NKG2D function and the cytolytic activity.MethodsRecent publications have shown that therapeutic antibodies targeting the membrane-proximal α3 domain inhibited MICA/B shedding, resulting in a substantial increase in the cell surface density of MICA/B and restoration of immune cell-mediated tumor immunity.1 We have developed a novel chimeric antigen receptor (CAR) targeting the conserved α3 domain of MICA/B (CAR-MICA/B). Additionally, utilizing our proprietary induced pluripotent stem cell (iPSC) product platform, we have developed multiplexed engineered, iPSC-derived CAR-MICA/B NK (iNK) cells for off-the-shelf cancer immunotherapy.ResultsA screen of CAR spacer and ScFv orientations in primary T cells delineated MICA-specific in vitro activation and cytotoxicity as well as in vivo tumor control against MICA+ cancer cells. The novel CAR-MICA/B design was used to compare efficacy against NKG2D CAR T cells, an alternative MICA/B targeting strategy. CAR-MICA/B T cells showed superior cytotoxicity against melanoma, breast cancer, renal cell carcinoma, and lung cancer lines in vitro compared to primary NKG2D CAR T cells (p<0.01). Additionally, using an in vivo xenograft metastasis model, CAR-MICA/B T cells eliminated A2058 human melanoma metastases in the majority of the mice treated. In contrast, NKG2D CAR T cells were unable to control tumor growth or metastases. To translate CAR-MICA/B functionality into an off-the-shelf cancer immunotherapy, CAR-MICA/B was introduced into a clonal master engineered iPSC line to derive a multiplexed engineered, CAR-MICA/B iNK cell product candidate. Using a panel of tumor cell lines expressing MICA/B, CAR-MICA/B iNK cells displayed MICA specificity, resulting in enhanced cytokine production, degranulation, and cytotoxicity. Furthermore, in vivo NK cell cytotoxicity was evaluated using the B16-F10 melanoma cell line, engineered to express MICA. In this model, CAR-MICA/B iNK cells significantly reduced liver and lung metastases, compared to untreated controls, by 93% and 87% respectively.ConclusionsOngoing work is focused on extending these preclinical studies to further support the clinical translation of an off-the-shelf, CAR-MICA/B iNK cell cancer immunotherapy with the potential to overcome solid tumor escape from NKG2D-mediated mechanisms of recognition and killing.ReferenceFerrari de Andrade L, Tay RE, Pan D, Luoma AM, Ito Y, Badrinath S, Tsoucas D, Franz B, May KF Jr, Harvey CJ, Kobold S, Pyrdol JW, Yoon C, Yuan GC, Hodi FS, Dranoff G, Wucherpfennig KW. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 2018 Mar 30;359(6383):1537–1542.

Fusion Hybrid of Dendritic Cells and Engineered Tumor Cells Expressing Interleukin-12 Induces Type 1 Immune Responses against Tumor

2005 ◽  
Vol 91 (6) ◽  
pp. 531-538 ◽  
Author(s):  
Meiqing Shi ◽  
Liping Su ◽  
Sigou Hao ◽  
Xulin Guo ◽  
Jim Xiang
Keyword(s):  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Regression ◽  
Interleukin 12 ◽  
Myeloma Cells ◽  
Th1 Cytokine

Aims and Background Dendritic cell (DC)-tumor fusion hybrid vaccinees that facilitate antigen presentation represent a novel powerful strategy in cancer immunotherapy. Preclinical studies have demonstrated that IL-12 promotes specific antitumor immunity mediated by T cells in several types of tumors. In the present study, we investigated the antitumor immunity derived from vaccination of fusion hybrids between DCs and engineered J558/IL-12 myeloma cells secreting Th1 cytokine IL-12. Methods The expression vector pcDNA-IL-12 was generated and transfected into J558 myeloma cells and then bone marrow-derived DCs were fused with engineered J558/IL-12 cells. The antitumor immunity derived from vaccination of the fusion hybrid DC/J558/IL-12 was evaluated in vitro and in vivo. Results DC/J558/IL-12 cells secreted recombinant IL-12 (1.6 ng/mL), and inoculation of BALB/c mice with DC/J558/IL-12 hybrid induced a Th1 dominant immune response and resulted in tumor regression. Immunization of mice with engineered DC/J558/IL-12 hybrid elicited stronger J558 tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro as well as more potent protective immunity against J558 tumor challenge in vivo than immunization with the mixture of DCs and J558/IL-12, J558/IL-12 and J558, respectively. Furthermore, the antitumor immunity mediated by DC/J558/1L-12 tumor cell vaccination in vivo appeared to be dependent on CD8+ CTL. Conclusions These results demonstrate that the engineered fusion hybrid vaccines that combine Th1 cytokine gene-modified tumor cells with DCs may be an attractive strategy for cancer immunotherapy.

scholarly journals Dickkopf-1: A Promising Target for Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Hang Yin Chu ◽  
Zihao Chen ◽  
Luyao Wang ◽  
Zong-Kang Zhang ◽  
Xinhuan Tan ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Suppressor Cells ◽  
Functional Studies ◽  
Promising Target ◽  
Using Data ◽  
Dickkopf 1

Clinical studies in a range of cancers have detected elevated levels of the Wnt antagonist Dickkopf-1 (DKK1) in the serum or tumors of patients, and this was frequently associated with a poor prognosis. Our analysis of DKK1 gene profile using data from TCGA also proves the high expression of DKK1 in 14 types of cancers. Numerous preclinical studies have demonstrated the cancer-promoting effects of DKK1 in both in vitro cell models and in vivo animal models. Furthermore, DKK1 showed the ability to modulate immune cell activities as well as the immunosuppressive cancer microenvironment. Expression level of DKK1 is positively correlated with infiltrating levels of myeloid-derived suppressor cells (MDSCs) in 20 types of cancers, while negatively associated with CD8+ T cells in 4 of these 20 cancer types. Emerging experimental evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. This review introduces the rapidly growing body of literature revealing the cancer-promoting and immune regulatory activities of DKK1. In addition, this review also predicts that by understanding the interaction between different domains of DKK1 through computational modeling and functional studies, the underlying functional mechanism of DKK1 could be further elucidated, thus facilitating the development of anti-DKK1 drugs with more promising efficacy in cancer immunotherapy.

scholarly journals LncRNA PITPNA-AS1 as a Potential Diagnostic Marker and Therapeutic Target Promotes Hepatocellular Carcinoma Progression via Modulating miR-448/ROCK1 Axis

2021 ◽  
Vol 8 ◽  
Author(s):  
Qing-fang Wang ◽  
Qing-lin Wang ◽  
Ming-bo Cao
Keyword(s):  
Hepatocellular Carcinoma ◽  
Antisense Rna ◽  
Diagnostic Marker ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Biological Functions ◽  
Non Coding Rnas ◽  
Hcc Cells

Background: Long non-coding RNAs are critical to hepatocellular carcinoma (HCC) developments. LncRNA PITPNA antisense RNA 1 (PITPNA-AS1) is a new regulator in several tumors. However, the mechanism by which PITPNA-AS1 mediates the tumorigenesis of HCC remains unclear.Methods: RT-qPCR was used to detect the level of PITPNA-AS1 in HCC specimens and cells. The biological functions of PITPNA-AS1 were explored by several functional experiments in vivo and in vitro. The binding relationship among PITPNA-AS1, miR-448 and ROCK1 were studied by Luciferase assay and pull-down assays.Results: We found that PITPNA-AS1 expressions were distinctly upregulated in both HCC specimens and cell lines. High PITPNA-AS1 levels were an unfavorable biomarker for patients with HCC. Functionally, knockdown of PITPNA-AS1 suppressed the proliferation, migration and invasion of HCC cells. Mechanistically, PITPNA-AS1 functioned as competing endogenous RNA to increase ROCK1 expressions via sponging miR-448.Conclusion: The newly identified PITPNA-AS/miR-448/ROCK1 axis promoted the oncogenicity of HCC cells. This novel axis is likely to be a promising HCC therapeutic aim.

Molecular Mechanism of Bushen Jianpi Inhibition of Postoperative Recurrence and Metastasis of Hepatocellular Carcinoma

2021 ◽  
Vol 17 (1) ◽  
pp. 53-63
Author(s):  
Zhangjie Zhou ◽  
Shujuan Fu ◽  
Yun Li ◽  
Zujun Que ◽  
Xinhua Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Bile Acid ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Liver Cancer ◽  
Immune Cell ◽  
Cancer Recurrence ◽  
Bile Acid Metabolism

Compared with western medicine, traditional Chinese medicine can better regulate the internal environment and inhibit liver cancer recurrence and metastasis. Bushen Jianpi Recipe (BSJPR) is a traditional Chinese medicine for tonifying the kidney and invigorating the spleen. It has also been used to treat tumors and other related diseases. Here we explore the efficacy of BSJPR inhibition of hepatocellular carcinoma (HCC) in vivo and in vitro . We hypothesize that BSJPR reduces intrahepatic cholestasis and inflammation and increases expression of the bile acid receptor and downstream targets. This study aims to test this hypothesis and determine whether the inhibitory effect of BSJPR on liver cancer recurrence and metastasis is related to bile acid metabolism. We also observed changes in immune cell expression, suggesting that regulation of the immune microenvironment could inhibit the recurrence and metastasis of HCC. These findings provide a basis for the treatment of HCC and new ideas for follow-up studies of BSJPR.

scholarly journals TAS0314, a novel multi-epitope long peptide vaccine, showed synergistic antitumor immunity with PD-1/PD-L1 blockade in HLA-A*2402 mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuki Tanaka ◽  
Hiroshi Wada ◽  
Risa Goto ◽  
Toshihiro Osada ◽  
Keisuke Yamamura ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Cytotoxic T Lymphocytes ◽  
Cancer Vaccines ◽  
Antitumor Immunity ◽  
Peptide Vaccine ◽  
Treatment Model ◽  
Peptide Vaccines ◽  
Specific Ctls ◽  
The Poor ◽  
Ctl Induction

Abstract Cancer peptide vaccines are a promising cancer immunotherapy that can induce cancer-specific cytotoxic T lymphocytes (CTLs) in tumors. However, recent clinical trials of cancer vaccines have revealed that the efficacy of the vaccines is limited. Targeting single antigens and vaccination with short peptides are partly the cause of the poor clinical outcomes. We synthesized a novel multi-epitope long peptide, TAS0314, which induced multiple epitope-specific CTLs in HLA knock-in mice. It also showed superior epitope-specific CTL induction and antitumor activity. We also established a combination treatment model of vaccination with PD-1/PD-L1 blockade in HLA-A*2402 knock-in mice, and it showed a synergistic antitumor effect with TAS0314. Thus, our data indicated that TAS0314 treatment, especially in combination with PD-1/PD-L1 blockade, is a promising therapeutic candidate for cancer immunotherapy.

scholarly journals HLA-G/ILTs Targeted Solid Cancer Immunotherapy: Opportunities and Challenges

2021 ◽  
Vol 12 ◽  
Author(s):  
Aifen Lin ◽  
Wei-Hua Yan
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Human Leukocyte ◽  
Solid Cancer ◽  
Biological Functions ◽  
Leukocyte Antigen ◽  
Promote Tumor Growth ◽  
Clinical Benefits ◽  
Human Leukocyte Antigen G

Immune checkpoint inhibitors (ICIs) have become a promising immunotherapy for cancers. Human leukocyte antigen-G (HLA-G), a neoantigen, its biological functions and clinical relevance have been extensively investigated in malignancies, and early clinical trials with “anti-HLA-G strategy” are being launched for advance solid cancer immunotherapy. The mechanism of HLA-G as a new ICI is that HLA-G can bind immune cell bearing inhibitory receptors, the immunoglobulin-like transcript (ILT)-2 and ILT-4. HLA-G/ILT-2/-4 (HLA-G/ILTs) signaling can drive comprehensive immune suppression, promote tumor growth and disease progression. Though clinical benefits could be expected with application of HLA-G antibodies to blockade the HLA-G/ILTs signaling in solid cancer immunotherapy, major challenges with the diversity of HLA-G isoforms, HLA-G/ILTs binding specificity, intra- and inter-tumor heterogeneity of HLA-G, lack of isoform-specific antibodies and validated assay protocols, which could dramatically affect the clinical efficacy. Clinical benefits of HLA-G-targeted solid cancer immunotherapy may be fluctuated or even premature unless major challenges are addressed.

scholarly journals Administration of fusion cytokines induces tumor regression and systemic antitumor immunity

2020 ◽  
Author(s):  
Jinyu Zhang ◽  
Xuan Zhao
Keyword(s):  
Cancer Immunotherapy ◽  
Antitumor Immunity ◽  
Tumor Regression ◽  
Systemic Administration ◽  
Immune Memory ◽  
Therapeutic Effects ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Antitumor Effects

AbstractThe curative effects of cancer immunotherapy are hard to be improved in solid tumors. Cytokines, as powerful immune regulators, show potential in awaking host antitumor immunity. We have previously found that administration of certain cytokine combinations induced complete tumor clearance. Here we constructed the cognate fusion cytokines and evaluated their antitumor effects in various mouse tumor models. In situ induced expression of the fusion cytokine IL12IL2GMCSF led to tumor eradication, even those in high advanced stage. An immune memory against other irrelated syngeneic tumors was elicited. Flow cytometry analysis revealed that tumor infiltrating CD3+ cells greatly increased, accompanied with an elevation of CD8+/CD4+ ratio. The fusion protein exhibited superior immune activating capability to cytokine mixtures in vitro, and induced tumor regression in various immune competent tumor models by intratumoral injection. To improve translational potential, an immunocytokine IL12IL2DiaNFGMCSF for systemic administration was constructed by inserting tumor targeting diabody. The protein also displayed good activities in vitro. Intravenous infusion of IL12IL2DiaNFGMCSF induced a tumor infiltrating immune cell alteration like IL12IL2GMCSF, with moderate serum IFNγ increment. Therapeutic effects were observed in various tumor models after systemic administration of IL12IL2DiaNFGMCSF, with slight toxicity. These results provide the feasibility of developing a versatile cancer immunotherapy remedy.

scholarly journals Leveraging Patient‐Derived Models for Immunotherapy Research

2020 ◽  
pp. e344-e350
Author(s):  
Katerina Politi
Keyword(s):  
Cancer Immunotherapy ◽  
Cancer Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Experimental Models ◽  
Cancer Types ◽  
Cancer Immunotherapies ◽  
Immune Oncology

As cancer immunotherapies become mainstream for the treatment of many different cancer types and the numbers of new agents continue to increase, the need for experimental models is also rising. An approach to develop and study models for immune-oncology that has garnered intense interest in recent years is that of using patient-derived models. Patient-derived models can recapitulate many of the features and heterogeneity of the corresponding human tumors. Historically these models have been used to study cancer cell–intrinsic properties of tumors and drugs that target tumor cells directly. In recent years, increasing recognition of the role immune cells play in cancer and how these represent good therapeutic targets has led to efforts to optimize and use patient-derived models for cancer immunotherapy studies. Patient-derived models are now being used to study the properties of cancer cells that modulate their ability to respond to immune stimulation. Further efforts are underway to use and develop patient-derived models that incorporate human immune cells in vitro and in vivo (humanized mice) so that cancer cell–immune cell interactions can be studied in the context of cancer immunotherapies. As these models are further refined, leveraging patient-derived models for cancer immunotherapy research can provide insight into mechanisms of sensitivity and resistance to cancer immunotherapies, uncover new targets, reveal how specific agents work, and be used to evaluate the antitumor efficacy of therapeutic regimens.

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