International Journal of Molecular Sciences

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4 pages, 166 KiB

Open AccessEditorial

State-of-the-Art Cancer Immunotherapies

by Hisashi Nagase, Takuma Kato and Takayuki Yoshimoto

Int. J. Mol. Sci. 2024, 25(5), 2532; https://doi.org/10.3390/ijms25052532 - 22 Feb 2024

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Abstract

Cancer immunotherapy is a type of cancer therapy utilizing the immune system to fight against tumors [...] Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Immunotherapies)

Research

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16 pages, 1866 KiB

Open AccessArticle

GT-00AxIL15, a Novel Tumor-Targeted IL-15-Based Immunocytokine for the Treatment of TA-MUC1-Positive Solid Tumors: Preclinical In Vitro and In Vivo Pharmacodynamics and Biodistribution Studies

by Johanna Gellert, Anika Jäkel, Antje Danielczyk, Christoph Goletz, Timo Lischke, Anke Flechner, Laura Dix, Alexandra Günzl and Patrik Kehler

Int. J. Mol. Sci. 2024, 25(3), 1406; https://doi.org/10.3390/ijms25031406 - 24 Jan 2024

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Abstract

GT-00AxIL15 is a novel interleukin-15-based immunocytokine targeting a tumor-specific, glycosylated epitope of MUC1 (TA-MUC1). We characterized mode of action, pharmacokinetic (PK) and pharmacodynamic (PD) properties and investigated the relevance of TA-MUC1 binding for the concept of delivering IL-15 to solid tumors. In vitro [...] Read more.

GT-00AxIL15 is a novel interleukin-15-based immunocytokine targeting a tumor-specific, glycosylated epitope of MUC1 (TA-MUC1). We characterized mode of action, pharmacokinetic (PK) and pharmacodynamic (PD) properties and investigated the relevance of TA-MUC1 binding for the concept of delivering IL-15 to solid tumors. In vitro pharmacology was analyzed in binding and cell-based assays. The in vivo PK profile and IL-15-mediated PD effects of GT-00AxIL15 were investigated in tumor-free mice. Tumor accumulation, immune infiltration and anti-tumor activity were assessed in TA-MUC1+ syngeneic and xenogeneic murine tumor models. GT-00AxIL15 was shown to specifically bind TA-MUC1 on tumor cells via its mAb moiety, to IL-15 receptors on immune cells via its IL-15 fusion modules and to FcγRs via its functional Fc-part. In vitro, NK, NKT and CD8+ T cells were activated and proliferated, leading to anti-tumor cytotoxicity and synergism with antibody-dependent cellular cytotoxicity (ADCC)-mediating mAbs. In vivo, GT-00AxIL15 exhibited favorable PK characteristics with a serum half-life of 13 days and specifically accumulated in TA-MUC1+ tumors. In the tumor microenvironment, GT-00AxIL15 induced robust immune activation and expansion and mediated anti-metastatic and anti-tumor effects in syngeneic and xenograft tumor models. These results support the rationale to improve PK and anti-tumor efficacy of IL-15 by increasing local concentrations at the tumor site via conjugation to a TA-MUC1 binding mAb. The tumor-selective expression pattern of TA-MUC1, powerful immune activation and anti-tumor cytotoxicity, long serum half-life and tumor targeting properties, render GT-00AxIL15 a promising candidate for treatment of solid tumors with high medical need, e.g., ovarian, lung and breast cancer. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Immunotherapies)

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22 pages, 5762 KiB

Open AccessArticle

Comparative Study of Metastasis Suppression Effects of Extracellular Vesicles Derived from Anaplastic Cell Lines, Nanog-Overexpressing Melanoma, and Induced Pluripotent Stem Cells

by Celine Swee May Khoo, Takuya Henmi and Mikako Saito

Int. J. Mol. Sci. 2023, 24(24), 17206; https://doi.org/10.3390/ijms242417206 - 06 Dec 2023

Cited by 1 | Viewed by 1108

Abstract

Previous studies have demonstrated that extracellular vesicles (EVs) derived from an anaplastic mouse melanoma cell line made using Nanog overexpression of F10 (Nanog⁺F10) suppressed the metastasis of Nanog⁺F10. Here, an induced pluripotent stem (iPS) cell line was focused [...] Read more.

Previous studies have demonstrated that extracellular vesicles (EVs) derived from an anaplastic mouse melanoma cell line made using Nanog overexpression of F10 (Nanog⁺F10) suppressed the metastasis of Nanog⁺F10. Here, an induced pluripotent stem (iPS) cell line was focused as a more anaplastic cell line, potentially producing EVs with higher metastasis-suppressive effects. The EVs were introduced into the tail vein nine times before introducing Nanog⁺F10 cells. Two weeks later, the liver and lung were resected and metastatic colonies were quantified. The involvement of macrophages (invasion inhibiting ability, phagocytic activity) and cytotoxic T cells (cytotoxicity) was evaluated using J774.1 and CTLL-2 cell lines. iPS EVs showed similar level effects to Nanog⁺F10 EVs in every item relevant to metastasis suppression. Differential expression analysis of miRNAs in EVs and functional network database analysis revealed that dominant regulatory miRNAs were predicted. The candidate hub genes most highly associated with the metastasis suppression mechanism were predicted as six genes, including Trp53 and Hif1a, for Nanog⁺F10 EVs and ten genes, including Ins1 and Kitl, for iPS EVs. Regarding the mechanism, Nanog⁺F10 EVs and iPS EVs were very different. This suggests synergistic effect when used together as metastasis preventive vaccine. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Immunotherapies)

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17 pages, 3591 KiB

Open AccessArticle

Alterations in Intratumoral Immune Response before and during Early-On Nivolumab Treatment for Unresectable Advanced or Recurrent Gastric Cancer

by Yasuyoshi Sato, Hiroharu Yamashita, Yukari Kobayashi, Koji Nagaoka, Tetsuro Hisayoshi, Takuya Kawahara, Akihiro Kuroda, Noriyuki Saito, Ryohei Iwata, Yasuhiro Okumura, Koichi Yagi, Susumu Aiko, Sachiyo Nomura, Kazuhiro Kakimi and Yasuyuki Seto

Int. J. Mol. Sci. 2023, 24(23), 16602; https://doi.org/10.3390/ijms242316602 - 22 Nov 2023

Cited by 1 | Viewed by 1188

Abstract

We investigated the tumor immune response in gastric cancer patients receiving third-line nivolumab monotherapy to identify immune-related biomarkers for better patient selection. Nineteen patients (10 males, median age 67 years) who received nivolumab as a third- or later-line therapy were enrolled. We analyzed [...] Read more.

We investigated the tumor immune response in gastric cancer patients receiving third-line nivolumab monotherapy to identify immune-related biomarkers for better patient selection. Nineteen patients (10 males, median age 67 years) who received nivolumab as a third- or later-line therapy were enrolled. We analyzed the tumor immune response in durable clinical benefit (DCB) and non-DCB patients. Pre-treatment and early-on-treatment tumor transcriptomes were examined, and gene expression profiles, immunograms, and T cell receptor (TCR) repertoire were analyzed. DCB was observed in 15.8% of patients, with comparable secondary endpoints (ORR; objective response rate, OS; overall survival, PFS; progression-free survival) to previous trials. The immunograms of individual subjects displayed no significant changes before or early in the treatment, except for the regulatory T cell (Treg) score. Moreover, there were no consistent alterations observed among cases experiencing DCB. The intratumoral immune response was suppressed by previous treatments in most third- or later-line nivolumab recipients. TCR repertoire analysis revealed newly emerged clonotypes in early-on-treatment tumors, but clonal replacement did not impact efficacy. High T cell/Treg ratios and a low UV-radiation-response gene signature were linked to DCB and treatment response. This study emphasizes the tumor immune response’s importance in nivolumab efficacy for gastric cancer. High T cell/Treg ratios and specific gene expression signatures show promise as potential biomarkers for treatment response. The tumor-infiltrating immune response was compromised by prior treatments in third-line therapy, implying that, to enhance immunotherapeutic outcomes, commencing treatment at an earlier stage might be preferable. Larger cohort validation is crucial to optimize immune-checkpoint inhibitors in gastric cancer treatment. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Immunotherapies)

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13 pages, 2260 KiB

Open AccessArticle

CAR-NK Cells Generated with mRNA-LNPs Kill Tumor Target Cells In Vitro and In Vivo

by Vita Golubovskaya, John Sienkiewicz, Jinying Sun, Shiming Zhang, Yanwei Huang, Hua Zhou, Hizkia Harto, Shirley Xu, Robert Berahovich and Lijun Wu

Int. J. Mol. Sci. 2023, 24(17), 13364; https://doi.org/10.3390/ijms241713364 - 29 Aug 2023

Cited by 3 | Viewed by 5295

Abstract

Natural killer (NK) cells are cytotoxic lymphocytes that are critical for the innate immune system. Engineering NK cells with chimeric antigen receptors (CARs) allows CAR-NK cells to target tumor antigens more effectively. In this report, we present novel CAR mRNA-LNP (lipid nanoparticle) technology [...] Read more.

Natural killer (NK) cells are cytotoxic lymphocytes that are critical for the innate immune system. Engineering NK cells with chimeric antigen receptors (CARs) allows CAR-NK cells to target tumor antigens more effectively. In this report, we present novel CAR mRNA-LNP (lipid nanoparticle) technology to effectively transfect NK cells expanded from primary PBMCs and to generate functional CAR-NK cells. CD19-CAR mRNA and BCMA-CAR mRNA were embedded into LNPs that resulted in 78% and 95% CAR expression in NK cells, respectively. BCMA-CAR-NK cells after transfection with CAR mRNA-LNPs killed multiple myeloma RPMI8226 and MM1S cells and secreted IFN-gamma and Granzyme B in a dose-dependent manner in vitro. In addition, CD19-CAR-NK cells generated with CAR mRNA-LNPs killed Daudi and Nalm-6 cells and secreted IFN-gamma and Granzyme B in a dose-dependent manner. Both BCMA-CAR-NK and CD19-CAR-NK cells showed significantly higher cytotoxicity, IFN-gamma, and Granzyme B secretion compared with normal NK cells. Moreover, CD19-CAR-NK cells significantly blocked Nalm-6 tumor growth in vivo. Thus, non-viral delivery of CAR mRNA-LNPs can be used to generate functional CAR-NK cells with high anti-tumor activity. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Immunotherapies)

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15 pages, 3325 KiB

Open AccessArticle

CAR-Modified Vγ9Vδ2 T Cells Propagated Using a Novel Bisphosphonate Prodrug for Allogeneic Adoptive Immunotherapy

by Yizheng Wang, Linan Wang, Naohiro Seo, Satoshi Okumura, Tae Hayashi, Yasushi Akahori, Hiroshi Fujiwara, Yasunori Amaishi, Sachiko Okamoto, Junichi Mineno, Yoshimasa Tanaka, Takuma Kato and Hiroshi Shiku

Int. J. Mol. Sci. 2023, 24(13), 10873; https://doi.org/10.3390/ijms241310873 - 29 Jun 2023

Cited by 4 | Viewed by 1945

Abstract

The benefits of CAR-T therapy could be expanded to the treatment of solid tumors through the use of derived autologous αβ T cell, but clinical trials of CAR-T therapy for patients with solid tumors have so far been disappointing. CAR-T therapy also faces [...] Read more.

The benefits of CAR-T therapy could be expanded to the treatment of solid tumors through the use of derived autologous αβ T cell, but clinical trials of CAR-T therapy for patients with solid tumors have so far been disappointing. CAR-T therapy also faces hurdles due to the time and cost intensive preparation of CAR-T cell products derived from patients as such CAR-T cells are often poor in quality and low in quantity. These inadequacies may be mitigated through the use of third-party donor derived CAR-T cell products which have a potent anti-tumor function but a constrained GVHD property. Vγ9Vδ2 TCR have been shown to exhibit potent antitumor activity but not alloreactivity. Therefore, in this study, CAR-T cells were prepared from Vγ9Vδ2 T (CAR-γδ T) cells which were expanded by using a novel prodrug PTA. CAR-γδ T cells suppressed tumor growth in an antigen specific manner but only during a limited time window. Provision of GITR co-stimulation enhanced anti-tumor function of CAR-γδ T cells. Our present results indicate that, while further optimization of CAR-γδ T cells is necessary, the present results demonstrate that Vγ9Vδ2 T cells are potential source of ‘off-the-shelf’ CAR-T cell products for successful allogeneic adoptive immunotherapy. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Immunotherapies)

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Review

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14 pages, 288 KiB

Open AccessReview

Immunotherapy and Cancer: The Multi-Omics Perspective

by Clelia Donisi, Andrea Pretta, Valeria Pusceddu, Pina Ziranu, Eleonora Lai, Marco Puzzoni, Stefano Mariani, Elena Massa, Clelia Madeddu and Mario Scartozzi

Int. J. Mol. Sci. 2024, 25(6), 3563; https://doi.org/10.3390/ijms25063563 - 21 Mar 2024

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Abstract

Immunotherapies have revolutionized cancer treatment approaches. Because not all patients respond positively to immune therapeutic agents, it represents a challenge for scientists who strive to understand the mechanisms behind such resistance. In-depth exploration of tumor biology, using novel technologies such as omics science, [...] Read more.

Immunotherapies have revolutionized cancer treatment approaches. Because not all patients respond positively to immune therapeutic agents, it represents a challenge for scientists who strive to understand the mechanisms behind such resistance. In-depth exploration of tumor biology, using novel technologies such as omics science, can help decode the role of the tumor immune microenvironment (TIME) in producing a response to the immune blockade strategies. It can also help to identify biomarkers for patient stratification and personalized treatment. This review aims to explore these new models and highlight their possible pivotal role in changing clinical practice. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Immunotherapies)

25 pages, 1525 KiB

Open AccessReview

Checkpoint Inhibitor-Induced Colitis: From Pathogenesis to Management

by Maria Terrin, Giulia Migliorisi, Arianna Dal Buono, Roberto Gabbiadini, Elisabetta Mastrorocco, Alessandro Quadarella, Alessandro Repici, Armando Santoro and Alessandro Armuzzi

Int. J. Mol. Sci. 2023, 24(14), 11504; https://doi.org/10.3390/ijms241411504 - 15 Jul 2023

Cited by 4 | Viewed by 2459

Abstract

The advent of immunotherapy, specifically of immune checkpoint inhibitors (ICIs), for the treatment of solid tumors has deeply transformed therapeutic algorithms in medical oncology. Approximately one-third of patients treated with ICIs may de velop immune-related adverse events, and the gastrointestinal tract is often [...] Read more.

The advent of immunotherapy, specifically of immune checkpoint inhibitors (ICIs), for the treatment of solid tumors has deeply transformed therapeutic algorithms in medical oncology. Approximately one-third of patients treated with ICIs may de velop immune-related adverse events, and the gastrointestinal tract is often affected by different grades of mucosal inflammation. Checkpoint inhibitors colitis (CIC) presents with watery or bloody diarrhea and, in the case of severe symptoms, requires ICIs discontinuation. The pathogenesis of CIC is multifactorial and still partially unknown: anti-tumor activity that collaterally effects the colonic tissue and the upregulation of specific systemic inflammatory pathways (i.e., CD8+ cytotoxic and CD4+ T lymphocytes) are mainly involved. Many questions remain regarding treatment timing and options, and biological treatment, especially with anti-TNF alpha, can be offered to these patients with the aim of rapidly resuming oncological therapies. CIC shares similar pathogenesis and aspects with inflammatory bowel disease (IBD) and the use of ICI in IBD patients is under evaluation. This review aims to summarize the pathogenetic mechanism underlying CIC and to discuss the current evidenced-based management options, including the role of biological therapy, emphasizing the relevant clinical impact on CIC and the need for prompt recognition and treatment. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Immunotherapies)

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15 pages, 3044 KiB

Open AccessReview

A Promising Needle-Free Pyro-Drive Jet Injector for Augmentation of Immunity by Intradermal Injection as a Physical Adjuvant

by Jukito Sonoda, Izuru Mizoguchi, Shinya Inoue, Aruma Watanabe, Ami Sekine, Miu Yamagishi, Satomi Miyakawa, Natsuki Yamaguchi, Eri Horio, Yasuhiro Katahira, Hideaki Hasegawa, Takashi Hasegawa, Kunihiko Yamashita and Takayuki Yoshimoto

Int. J. Mol. Sci. 2023, 24(10), 9094; https://doi.org/10.3390/ijms24109094 - 22 May 2023

Cited by 2 | Viewed by 2835

Abstract

Current worldwide mRNA vaccination against SARS-CoV-2 by intramuscular injection using a needled syringe has greatly protected numerous people from COVID-19. An intramuscular injection is generally well tolerated, safer and easier to perform on a large scale, whereas the skin has the benefit of [...] Read more.

Current worldwide mRNA vaccination against SARS-CoV-2 by intramuscular injection using a needled syringe has greatly protected numerous people from COVID-19. An intramuscular injection is generally well tolerated, safer and easier to perform on a large scale, whereas the skin has the benefit of the presence of numerous immune cells, such as professional antigen-presenting dendritic cells. Therefore, intradermal injection is considered superior to intramuscular injection for the induction of protective immunity, but more proficiency is required for the injection. To improve these issues, several different types of more versatile jet injectors have been developed to deliver DNAs, proteins or drugs by high jet velocity through the skin without a needle. Among them, a new needle-free pyro-drive jet injector has a unique characteristic that utilizes gunpower as a mechanical driving force, in particular, bi-phasic pyrotechnics to provoke high jet velocity and consequently the wide dispersion of the injected DNA solution in the skin. A significant amount of evidence has revealed that it is highly effective as a vaccinating tool to induce potent protective cellular and humoral immunity against cancers and infectious diseases. This is presumably explained by the fact that shear stress generated by the high jet velocity facilitates the uptake of DNA in the cells and, consequently, its protein expression. The shear stress also possibly elicits danger signals which, together with the plasmid DNA, subsequently induces the activation of innate immunity including dendritic cell maturation, leading to the establishment of adaptive immunity. This review summarizes the recent advances in needle-free jet injectors to augment the cellular and humoral immunity by intradermal injection and the possible mechanism of action. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Immunotherapies)

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