Humanized Mice as a Valuable Pre-Clinical Model for Cancer Immunotherapy Research

Immunotherapy with checkpoint inhibitors opened new horizons in cancer treatment. Clinical trials for novel immunotherapies or unexplored combination regimens either need years of development or are simply impossible to perform like is the case in cancer patients with limited life expectancy. Thus, the need for preclinical models that rapidly and safely allow for a better understanding of underlying mechanisms, drug kinetics and toxicity leading to the selection of the best regimen to be translated into the clinic, is of high importance. Humanized mice that can bear both human immune system and human tumors, are increasingly used in recent preclinical immunotherapy studies and represent a remarkably unprecedented tool in this field. In this review, we describe, summarize, and discuss the recent advances of humanized mouse models used for cancer immunotherapy research and the challenges faced during their establishment. We also highlight the lack of preclinical studies using this model for radiotherapy-based research and argue that it can be a great asset to understand and answer many open questions around radiation therapy such as its presumed associated “abscopal effect”.

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Gut microbiota and cancer immunotherapy: prognostic and therapeutic implications

Future Oncology ◽

10.2217/fon-2019-0783 ◽

2020 ◽

Author(s):

Deniz Can Guven ◽

Burak Yasin Aktas ◽

Cem Simsek ◽

Sercan Aksoy

Keyword(s):

Cancer Immunotherapy ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Clinical Implications ◽

Gastrointestinal Microbiota ◽

Therapeutic Implications ◽

New Horizons ◽

Novel Strategy ◽

The Relationship

The immune checkpoint inhibitors have opened new horizons in oncology. Although the indications for the use of Immune checkpoint inhibitors in cancer patients are expanding, there is still a need for markers that can aid in patient selection. Gastrointestinal microbiota can be among these markers. Recently, gastrointestinal microbiota stated to have a bidirectional relation with cancer immunotherapy with roles in both prognostic and therapeutic sides. Preclinical data suggest that modulation of the microbiota could become a novel strategy for improving the efficacy of immunotherapy. However, its labile structure prone to be affected by many factors. Further research can delineate the mechanisms of the relationship between microbiota and immunotherapy can have clinical implications.

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Recent Progress in Dendritic Cell-Based Cancer Immunotherapy

Cancers ◽

10.3390/cancers13102495 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2495

Author(s):

Kazuhiko Matsuo ◽

Osamu Yoshie ◽

Kosuke Kitahata ◽

Momo Kamei ◽

Yuta Hara ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Immune Checkpoint ◽

Targeted Delivery ◽

Cancer Vaccines ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Host Immune Responses ◽

Near Future ◽

Identification And Characterization

Cancer immunotherapy aims to treat cancer by enhancing cancer-specific host immune responses. Recently, cancer immunotherapy has been attracting much attention because of the successful clinical application of immune checkpoint inhibitors targeting the CTLA-4 and PD-1/PD-L1 pathways. However, although highly effective in some patients, immune checkpoint inhibitors are beneficial only in a limited fraction of patients, possibly because of the lack of enough cancer-specific immune cells, especially CD8+ cytotoxic T-lymphocytes (CTLs), in the host. On the other hand, studies on cancer vaccines, especially DC-based ones, have made significant progress in recent years. In particular, the identification and characterization of cross-presenting DCs have greatly advanced the strategy for the development of effective DC-based vaccines. In this review, we first summarize the surface markers and functional properties of the five major DC subsets. We then describe new approaches to induce antigen-specific CTLs by targeted delivery of antigens to cross-presenting DCs. In this context, the chemokine receptor XCR1 and its ligand XCL1, being selectively expressed by cross-presenting DCs and mainly produced by activated CD8+ T cells, respectively, provide highly promising molecular tools for this purpose. In the near future, CTL-inducing DC-based cancer vaccines may provide a new breakthrough in cancer immunotherapy alone or in combination with immune checkpoint inhibitors.

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Cancer immunotherapy in special challenging populations: recommendations of the Advisory Committee of Spanish Melanoma Group (GEM)

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001664 ◽

2021 ◽

Vol 9 (3) ◽

pp. e001664

Author(s):

Maria Gonzalez-Cao ◽

Teresa Puertolas ◽

Mar Riveiro ◽

Eva Muñoz-Couselo ◽

Carolina Ortiz ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Multidisciplinary Approach ◽

Checkpoint Inhibitors ◽

Solid Organ Transplantation ◽

Latent Tuberculosis ◽

Solid Organ ◽

Chronic Infections ◽

Immunosuppressed Patients ◽

History Of ◽

Evidence Based Guidelines

Cancer immunotherapy based on the use of antibodies targeting the so-called checkpoint inhibitors, such as programmed cell death-1 receptor, its ligand, or CTLA-4, has shown durable clinical benefit and survival improvement in melanoma and other tumors. However, there are some special situations that could be a challenge for clinical management. Persons with chronic infections, such as HIV-1 or viral hepatitis, latent tuberculosis, or a history of solid organ transplantation, could be candidates for cancer immunotherapy, but their management requires a multidisciplinary approach. The Spanish Melanoma Group (GEM) panel in collaboration with experts in virology and immunology from different centers in Spain reviewed the literature and developed evidence-based guidelines for cancer immunotherapy management in patients with chronic infections and immunosuppression. These are the first clinical guidelines for cancer immunotherapy treatment in special challenging populations. Cancer immunotherapy in chronically infected or immunosuppressed patients is feasible but needs a multidisciplinary approach in order to decrease the risk of complications related to the coexistent comorbidities.

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PD-L1 Targeting Immune-Microbubble Complex Enhances Therapeutic Index in Murine Colon Cancer Models

Pharmaceuticals ◽

10.3390/ph14010006 ◽

2020 ◽

Vol 14 (1) ◽

pp. 6

Author(s):

Daehyun Kim ◽

Seung Soo Lee ◽

Hyungwon Moon ◽

So Yeon Park ◽

Hak Jong Lee

Keyword(s):

Cancer Immunotherapy ◽

Focused Ultrasound ◽

Therapeutic Potential ◽

Checkpoint Inhibitors ◽

Therapeutic Index ◽

Treatment Regimens ◽

Cancer Models ◽

Programmed Death ◽

Murine Colon ◽

Cell Death Protein

Cancer immunotherapy has revolutionized the way different neoplasms are treated. Among the different variations of cancer immunotherapy, the checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis have been validated and are currently used in the clinics. Nevertheless, these therapeutic antibodies are associated with significant side effects and are known to induce immune-related toxicities. To address these issues, we have developed an immune-microbubble complex (IMC) which not only reduces the toxicities associated with the antibodies but also enhances the therapeutic efficacy when combined with focused ultrasound. The concept of IMCs could be applied to any type of antibody-based treatment regimens to maximize their therapeutic potential.

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Peptide Blocking CTLA-4 and B7-1 Interaction

Molecules ◽

10.3390/molecules26020253 ◽

2021 ◽

Vol 26 (2) ◽

pp. 253

Author(s):

Stepan V. Podlesnykh ◽

Kristina E. Abramova ◽

Anastasia Gordeeva ◽

Andrei I. Khlebnikov ◽

Andrei I. Chapoval

Keyword(s):

Cancer Immunotherapy ◽

Functional Activity ◽

Synthetic Peptide ◽

Checkpoint Inhibitors ◽

Specific Interaction ◽

Protein A ◽

Tumor Rejection ◽

Immune Checkpoints ◽

3D Computer Model ◽

Molecular Compounds

Discovery of the B7 family immune checkpoints such as CTLA-4 (CD152), PD-1 (CD279), as well as their ligands B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), and B7-DC (PD-L2, CD273), has opened new possibilities for cancer immunotherapy using monoclonal antibodies (mAb). The blockade of inhibitory receptors (CTLA-4 and PD-1) with specific mAb results in the activation of cancer patients’ T lymphocytes and tumor rejection. However, the use of mAb in clinics has several limitations including side effects and cost of treatment. The development of new low-molecular compounds that block immune checkpoints’ functional activity can help to overcome some of these limitations. In this paper, we describe a synthetic peptide (p344) containing 14 amino acids that specifically interact with CTLA-4 protein. A 3D computer model suggests that this peptide binds to the 99MYPPPY104 loop of CTLA-4 protein and potentially blocks the contact of CTLA-4 receptor with B7-1 ligand. Experimental data confirm the peptide-specific interaction with CTLA-4 and its ability to partially block CTLA-4/B7-1 binding. The identified synthetic peptide can be used for the development of novel immune checkpoint inhibitors that can block CTLA-4 functional activity for cancer immunotherapy.

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Design and Encapsulation of Immunomodulators onto Gold Nanoparticles in Cancer Immunotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms22158037 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8037

Author(s):

Akshita Chauhan ◽

Tabassum Khan ◽

Abdelwahab Omri

Keyword(s):

Immune System ◽

Immune Responses ◽

Cancer Immunotherapy ◽

Cytotoxic T Lymphocytes ◽

Recent Progress ◽

Checkpoint Inhibitors ◽

Drug Clearance ◽

Cell Permeability ◽

Plasmonic Effect ◽

Cancer Immunotherapeutic

The aim of cancer immunotherapy is to reactivate autoimmune responses to combat cancer cells. To stimulate the immune system, immunomodulators, such as adjuvants, cytokines, vaccines, and checkpoint inhibitors, are extensively designed and studied. Immunomodulators have several drawbacks, such as drug instability, limited half-life, rapid drug clearance, and uncontrolled immune responses when used directly in cancer immunotherapy. Several strategies have been used to overcome these limitations. A simple and effective approach is the loading of immunomodulators onto gold-based nanoparticles (GNPs). As gold is highly biocompatible, GNPs can be administered intravenously, which aids in increasing cancer cell permeability and retention time. Various gold nanoplatforms, including nanospheres, nanoshells, nanorods, nanocages, and nanostars have been effectively used in cancer immunotherapy. Gold nanostars (GNS) are one of the most promising GNP platforms because of their unusual star-shaped geometry, which significantly increases light absorption and provides high photon-to-heat conversion efficiency due to the plasmonic effect. As a result, GNPs are a useful vehicle for delivering antigens and adjuvants that support the immune system in killing tumor cells by facilitating or activating cytotoxic T lymphocytes. This review represents recent progress in encapsulating immunomodulators into GNPs for utility in a cancer immunotherapeutic regimen.

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Treatment of rheumatic immune-related adverse events due to cancer immunotherapy with immune checkpoint inhibitors—is it time for a paradigm shift?

Clinical Rheumatology ◽

10.1007/s10067-020-05420-w ◽

2020 ◽

Author(s):

Katerina Chatzidionysiou ◽

Matina Liapi ◽

Georgios Tsakonas ◽

Iva Gunnarsson ◽

Anca Catrina

Keyword(s):

Adverse Events ◽

Cancer Immunotherapy ◽

Potential Risk ◽

Immune Checkpoint ◽

Paradigm Shift ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Current Evidence ◽

Inadequate Response ◽

High Efficacy

Abstract Immunotherapy has revolutionized cancer treatment during the last years. Several monoclonal antibodies that are specific for regulatory checkpoint molecules, that is, immune checkpoint inhibitors (ICIs), have been approved and are currently in use for various types of cancer in different lines of treatment. Cancer immunotherapy aims for enhancing the immune response against cancer cells. Despite their high efficacy, ICIs are associated to a new spectrum of adverse events of autoimmune origin, often referred to as immune-related adverse events (irAEs), which limit the utility of these drugs. These irAEs are quite common and can affect almost every organ. The grade of toxicity varies from very mild to life-threatening. The pathophysiological mechanisms behind these events are not fully understood. In this review, we will summarize current evidence specifically regarding the rheumatic irAEs and we will focus on current and future treatment strategies. Treatment guidelines largely support the use of glucocorticoids as first-line therapy, when symptomatic therapy is not efficient, and for more persistent and/or moderate/severe degree of inflammation. Targeted therapies are higher up in the treatment pyramid, after inadequate response to glucocorticoids and conventional, broad immunosuppressive agents, and for severe forms of irAEs. However, preclinical data provide evidence that raise concerns regarding the potential risk of impaired antitumoral effect. This potential risk of glucocorticoids, together with the high efficacy and potential synergistic effect of newer, targeted immunomodulation, such as tumor necrosis factor and interleukin-6 blockade, could support a paradigm shift, where more targeted treatments are considered earlier in the treatment sequence.

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P06.07 In vivo studies of immunomodulatory a-CTLA-4 antibody in a humanized mouse model

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-itoc8.41 ◽

2021 ◽

Vol 9 (Suppl 1) ◽

pp. A22.1-A22

Author(s):

C Reitinger ◽

F Nimmerjahn

Keyword(s):

Immune System ◽

Mouse Model ◽

Cancer Immunotherapy ◽

Model Systems ◽

Checkpoint Control ◽

Human Immune System ◽

Humanized Mouse ◽

Humanized Mouse Model ◽

Human Immune

BackgroundRecent findings in cancer immunotherapy have reinforced the hypothesis that the immune system is able to control most cancers. Immunomodulatory antibodies can enhance immune responses, having the potential to generate anti-cancer immunity.1–4Materials and MethodsMost current studies addressing this question are performed in murine mouse model systems or use in vitro culture systems, which do not reflect the human in vivo situation, potentially leading to results that cannot be fully translated into human cancer therapy. Therefore, it is necessary to establish a new mouse model, which allows the study of cancer immunotherapy in the context of a human immune system. We focused on the establishment of a humanized mouse model, in which different immunomodulatory antibodies can be tested in the presence of a human immune system.ResultsFirst experiments concerning the suitability to test immunomodulatory antibodies in the humanized mouse model, revealed that effects of checkpoint-control antibody a-CTLA-4 were similar to the effects seen in patients of clinical studies. To analyse the anti-tumor activities of immunomodulatory antibodies in vivo we are establishing a human melanoma-like tumor model in humanized mice.ConclusionsThis enables us to test the efficacy of immunomodulatory agonistic antibodies (such as CP-870,893) and checkpoint control antibodies (such as anti-CTLA-4) in eliminating a melanoma-like tumor. Furthermore, parameters like tumor infiltrating human cells und cytokine/chemokine production can be analysed.ReferencesSchuster M, Nechansky A, Loibner H. Cancer immunotherapy. Biotechnol J 2006;1:138–147.Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature rev 2011;480:480–489.Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Annals of Oncology 2012;23:vii6–vii9.Langer LF, Clay TM, Morse MA. Update on anti-CTLA-4 in clinical trials. Expert Opin Biol Ther 2007;8:1245–1256.Disclosure InformationC. Reitinger: None. F. Nimmerjahn: None.

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The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity

Frontiers in Immunology ◽

10.3389/fimmu.2021.682435 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhengguo Wu ◽

Shang Li ◽

Xiao Zhu

Keyword(s):

Immune Response ◽

Immune System ◽

Tumor Microenvironment ◽

Cancer Immunotherapy ◽

Tumor Immunity ◽

Checkpoint Inhibitors ◽

The Body ◽

Research Progress ◽

Effective Population ◽

Cell Components

Cancer immunotherapy is a kind of therapy that can control and eliminate tumors by restarting and maintaining the tumor-immune cycle and restoring the body’s normal anti-tumor immune response. Although immunotherapy has great potential, it is currently only applicable to patients with certain types of tumors, such as melanoma, lung cancer, and cancer with high mutation load and microsatellite instability, and even in these types of tumors, immunotherapy is not effective for all patients. In order to enhance the effectiveness of tumor immunotherapy, this article reviews the research progress of tumor microenvironment immunotherapy, and studies the mechanism of stimulating and mobilizing immune system to enhance anti-tumor immunity. In this review, we focused on immunotherapy against tumor microenvironment (TME) and discussed the important research progress. TME is the environment for the survival and development of tumor cells, which is composed of cell components and non-cell components; immunotherapy for TME by stimulating or mobilizing the immune system of the body, enhancing the anti-tumor immunity. The checkpoint inhibitors can effectively block the inhibitory immunoregulation, indirectly strengthen the anti-tumor immune response and improve the effect of immunotherapy. We also found the checkpoint inhibitors have brought great changes to the treatment model of advanced tumors, but the clinical treatment results show great individual differences. Based on the close attention to the future development trend of immunotherapy, this study summarized the latest progress of immunotherapy and pointed out a new direction. To study the mechanism of stimulating and mobilizing the immune system to enhance anti-tumor immunity can provide new opportunities for cancer treatment, expand the clinical application scope and effective population of cancer immunotherapy, and improve the survival rate of cancer patients.

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Repurposing Infectious Pathogen Vaccines in Cancer Immunotherapy

Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications ◽

10.5772/intechopen.92780 ◽

2020 ◽

Author(s):

Matteo Conti

Keyword(s):

Cancer Immunotherapy ◽

Checkpoint Inhibitors ◽

Mouse Tumor ◽

Combined Approach ◽

Anticancer Immunotherapy ◽

Intratumoral Delivery ◽

Infectious Pathogen ◽

Novel Strategy ◽

Mouse Tumor Models

Reports in the literature show that certain vaccines against infectious pathogens, can be effective in eliciting antitumor immune response when injected intratumorally. In mouse tumor models, intratumoral delivery of rotavirus, yellow fever, and influenza vaccines have been shown to also synergize with checkpoint inhibitors, in the leading immunotherapy in the clinical practice today. The combined approach can thus become a very promising novel strategy for anticancer immunotherapy. In humans, an attenuated poliomyelitis virus vaccine, a peptide-based vaccines against papilloma and one based on detoxified diphtheria protein have already been tested as intratumoral treatments readily. In those studies, the role of available anti-pathogen immunity appears an important element in mediating the activity of the repurposed vaccines against cancer. We therefore suggest how evaluating or eventually developing anti-pathogen immunity before intratumoral delivery could be helpful in repurposing infectious pathogen vaccines in cancer immunotherapy.

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