Implantable and Injectable Biomaterial Scaffolds for Cancer Immunotherapy

Cancer immunotherapy has become an emerging strategy recently producing durable immune responses in patients with varieties of malignant tumors. However, the main limitation for the broad application of immunotherapies still to reduce side effects by controlling and regulating the immune system. In order to improve both efficacy and safety, biomaterials have been applied to immunotherapies for the specific modulation of immune cells and the immunosuppressive tumor microenvironment. Recently, researchers have constantly developed biomaterials with new structures, properties and functions. This review provides the most recent advances in the delivery strategies of immunotherapies based on localized biomaterials, focusing on the implantable and injectable biomaterial scaffolds. Finally, the challenges and prospects of applying implantable and injectable biomaterial scaffolds in the development of future cancer immunotherapies are discussed.

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Oncolytic Virotherapy in Solid Tumors: The Challenges and Achievements

Cancers ◽

10.3390/cancers13040588 ◽

2021 ◽

Vol 13 (4) ◽

pp. 588

Author(s):

Ke-Tao Jin ◽

Wen-Lin Du ◽

Yu-Yao Liu ◽

Huan-Rong Lan ◽

Jing-Xing Si ◽

...

Keyword(s):

Immune Responses ◽

Cancer Immunotherapy ◽

Tumor Antigens ◽

Adoptive Cell Therapy ◽

Oncolytic Viruses ◽

Oncolytic Virotherapy ◽

Immunosuppressive Tumor Microenvironment ◽

Delivery Strategies ◽

Therapeutic Tools ◽

Immune Checkpoint Blockers

Oncolytic virotherapy (OVT) is a promising approach in cancer immunotherapy. Oncolytic viruses (OVs) could be applied in cancer immunotherapy without in-depth knowledge of tumor antigens. The capability of genetic modification makes OVs exciting therapeutic tools with a high potential for manipulation. Improving efficacy, employing immunostimulatory elements, changing the immunosuppressive tumor microenvironment (TME) to inflammatory TME, optimizing their delivery system, and increasing the safety are the main areas of OVs manipulations. Recently, the reciprocal interaction of OVs and TME has become a hot topic for investigators to enhance the efficacy of OVT with less off-target adverse events. Current investigations suggest that the main application of OVT is to provoke the antitumor immune response in the TME, which synergize the effects of other immunotherapies such as immune-checkpoint blockers and adoptive cell therapy. In this review, we focused on the effects of OVs on the TME and antitumor immune responses. Furthermore, OVT challenges, including its moderate efficiency, safety concerns, and delivery strategies, along with recent achievements to overcome challenges, are thoroughly discussed.

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Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy

Cancers ◽

10.3390/cancers13235912 ◽

2021 ◽

Vol 13 (23) ◽

pp. 5912

Author(s):

Angèle Luby ◽

Marie-Clotilde Alves-Guerra

Keyword(s):

Cancer Immunotherapy ◽

Immune Cells ◽

Immune Checkpoint ◽

Metabolic Pathways ◽

Cancer Metabolism ◽

Metabolic Stress ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

New Therapeutic Approaches ◽

Immunosuppressive Tumor Microenvironment

Over the past decade, advances in cancer immunotherapy through PD1–PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.

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Nanoparticles as Smart Carriers for Enhanced Cancer Immunotherapy

Frontiers in Chemistry ◽

10.3389/fchem.2020.597806 ◽

2020 ◽

Vol 8 ◽

Author(s):

Neelam Thakur ◽

Saloni Thakur ◽

Sharmistha Chatterjee ◽

Joydeep Das ◽

Parames C. Sil

Keyword(s):

Cancer Immunotherapy ◽

Immune Cells ◽

Targeted Delivery ◽

Cancer Antigens ◽

Immune Mediated ◽

Effective Delivery ◽

Immunosuppressive Tumor Microenvironment ◽

Theranostic Applications ◽

Antigen Presenting

Cancer immunotherapy has emerged as a promising strategy for the treatment of many forms of cancer by stimulating body's own immune system. This therapy not only eradicates tumor cells by inducing strong anti-tumor immune response but also prevent their recurrence. The clinical cancer immunotherapy faces some insurmountable challenges including high immune-mediated toxicity, lack of effective and targeted delivery of cancer antigens to immune cells and off-target side effects. However, nanotechnology offers some solutions to overcome those limitations, and thus can potentiate the efficacy of immunotherapy. This review focuses on the advancement of nanoparticle-mediated delivery of immunostimulating agents for efficient cancer immunotherapy. Here we have outlined the use of the immunostimulatory nanoparticles as a smart carrier for effective delivery of cancer antigens and adjuvants, type of interactions between nanoparticles and the antigen/adjuvant as well as the factors controlling the interaction between nanoparticles and the receptors on antigen presenting cells. Besides, the role of nanoparticles in targeting/activating immune cells and modulating the immunosuppressive tumor microenvironment has also been discussed extensively. Finally, we have summarized some theranostic applications of the immunomodulatory nanomaterials in treating cancers based on the earlier published reports.

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Delivery strategies of cancer immunotherapy: recent advances and future perspectives

Journal of Hematology & Oncology ◽

10.1186/s13045-019-0817-3 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 7

Author(s):

Zhongwei Zhao ◽

Liyun Zheng ◽

Weiqian Chen ◽

Wei Weng ◽

Jingjing Song ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Clinical Status ◽

Efficacy And Safety ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Future Perspectives ◽

Vascular Leak Syndrome ◽

Delivery Strategies ◽

Cancer Immunotherapeutic ◽

Target Effects

AbstractImmunotherapy has become an emerging strategy for the treatment of cancer. Immunotherapeutic drugs have been increasing for clinical treatment. Despite significant advances in immunotherapy, the clinical application of immunotherapy for cancer patients has some challenges associated with safety and efficacy, including autoimmune reactions, cytokine release syndrome, and vascular leak syndrome. Novel strategies, particularly improved delivery strategies, including nanoparticles, scaffolds, and hydrogels, are able to effectively target tumors and/or immune cells of interest, increase the accumulation of immunotherapies within the lesion, and reduce off-target effects. Here, we briefly describe five major types of cancer immunotherapy, including their clinical status, strengths, and weaknesses. Then, we introduce novel delivery strategies, such as nanoparticle-based delivery of immunotherapy, implantable scaffolds, injectable biomaterials for immunotherapy, and matrix-binding molecular conjugates, which can improve the efficacy and safety of immunotherapies. Also, the limitations of novel delivery strategies and challenges of clinical translation are discussed.

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Antibody:CD47 ratio regulates macrophage phagocytosis through competitive receptor phosphorylation

10.1101/2020.07.31.231779 ◽

2020 ◽

Cited By ~ 1

Author(s):

Emily C. Suter ◽

Eva M. Schmid ◽

Erik Voets ◽

Brian Francica ◽

Daniel A. Fletcher

Keyword(s):

Immune Responses ◽

Cancer Immunotherapy ◽

Tumor Cells ◽

Effector Function ◽

Fc Gamma Receptors ◽

Chimeric Receptors ◽

Macrophage Phagocytosis ◽

Cancer Immunotherapies ◽

Blocking Antibodies

ABSTRACTCancer immunotherapies often modulate macrophage effector function by introducing either targeting antibodies that activate Fc gamma receptors or blocking antibodies that disrupt inhibitory SIRPα-CD47 engagement. Yet how these competing signals are integrated is poorly understood mechanistically, raising questions about how to effectively titrate immune responses. Here we find that macrophage phagocytic decisions are regulated by the ratio of activating ligand to inhibitory ligand on targets over a broad range of absolute molecular densities. Using endogenous as well as chimeric receptors, we show that activating:inhibitory ligand ratios of at least 10:1 are required to promote phagocytosis of model antibody-opsonized CD47-inhibited targets and that lowering this ratio reduces FcγR phosphorylation due to inhibitory phosphatases recruited to CD47-bound SIRPα. We demonstrate that ratiometric signaling is critical for phagocytosis of tumor cells and can be modified by blocking SIRPα in vitro, indicating that balancing targeting and blocking antibodies may be important for controlling macrophage phagocytosis in cancer immunotherapy.

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MicroRNAs: immune modulators in cancer immunotherapy

Immunotherapy Advances ◽

10.1093/immadv/ltab006 ◽

2021 ◽

Author(s):

Yun Xing ◽

Zhiqiang Wang ◽

Zhou Lu ◽

Jie Xia ◽

Zhangjuan Xie ◽

...

Keyword(s):

Immune Responses ◽

Cancer Immunotherapy ◽

Tumor Cells ◽

Tumor Immunity ◽

Immune Cells ◽

Tumor Suppressors ◽

Immune Modulators ◽

Non Coding Rna ◽

New Findings

Abstract MicroRNA (miRNA) is a class of endogenous small non-coding RNA of 18–25 nucleotides and plays regulatory roles in both physiological and pathological processes. Emerging evidence support that miRNAs function as immune modulators in tumors. MiRNAs as tumor suppressors or oncogenes are also found to be able to modulate anti-tumor immunity or link the crosstalk between tumor cells and immune cells surrounding. Based on the specific regulating function, miRNAs can be used as predictive, prognostic biomarkers and therapeutic targets in immunotherapy. Here, we review new findings about role of miRNAs in modulating immune responses, as well as discuss mechanisms underlying their dysregulation, and their clinical potentials as indicators of tumor prognosis or to sensitize cancer immunotherapy.

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TIM-3 as a Prognostic Marker and a Potential Immunotherapy Target in Human Malignant Tumors: A Meta-Analysis and Bioinformatics Validation

Frontiers in Oncology ◽

10.3389/fonc.2021.579351 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kui Zang ◽

Liangliang Hui ◽

Min Wang ◽

Ying Huang ◽

Xingxing Zhu ◽

...

Keyword(s):

Functional Analysis ◽

T Cell ◽

Immune Responses ◽

Cancer Immunotherapy ◽

T Cell Activation ◽

Malignant Tumors ◽

Killer Cell ◽

Cell Lung Carcinoma ◽

Cox Regression Analysis

BackgroundAs a novel immune checkpoint molecular, T-cell immunoglobulin mucin 3 (TIM-3) is emerging as a therapeutic target for cancer immunotherapy. However, the predictive role of TIM-3 in cancer remains largely undetermined. This study was designed to investigate the role of TIM-3 in cancer.MethodsPublications were searched using multiple databases. The hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. To further confirm the prognostic effect of TIM-3, The Cancer Genome Atlas (TCGA) data were applied. Functional analysis of TIM-3 was also investigated.Results28 studies with 7284 patients with malignant tumors were identified. Based on multivariate Cox regression analysis, TIM-3 was an independent prognostic indicator for poor overall survival (OS) (HR= 1.54, 95% CI = 1.19-1.98, P = 0.001). However, TIM-3 was not correlated with cancer-specific survival and disease-free survival (DFS). Particularly, TIM-3 showed a worse prognosis in non-small cell lung carcinoma and gastric cancer; but it showed a favorable prognosis in breast cancer. Functional analysis showed that TIM-3 was closely correlated with immune responses such as T-cell activation and natural killer cell-mediated cytotoxicity. Moreover, TIM-3 expression was found to be related to worse OS in 9491 TCGA patients (HR = 1.2, P < 0.001), but was not associated with DFS.ConclusionsTIM-3 was an independent prognostic factor. Meanwhile, TIM-3 played a crucial role in tumor immune responses. This supports TIM-3 as a promising target for cancer immunotherapy.

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The Role of Chemoattractant Receptors in Shaping the Tumor Microenvironment

BioMed Research International ◽

10.1155/2014/751392 ◽

2014 ◽

Vol 2014 ◽

pp. 1-33 ◽

Cited By ~ 19

Author(s):

Jiamin Zhou ◽

Yi Xiang ◽

Teizo Yoshimura ◽

Keqiang Chen ◽

Wanghua Gong ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Responses ◽

Tumor Cells ◽

Immune Cells ◽

Malignant Tumors ◽

G Protein Coupled Receptors ◽

Host Cells ◽

The Past ◽

G Protein Coupled

Chemoattractant receptors are a family of seven transmembrane G protein coupled receptors (GPCRs) initially found to mediate the chemotaxis and activation of immune cells. During the past decades, the functions of these GPCRs have been discovered to not only regulate leukocyte trafficking and promote immune responses, but also play important roles in homeostasis, development, angiogenesis, and tumor progression. Accumulating evidence indicates that chemoattractant GPCRs and their ligands promote the progression of malignant tumors based on their capacity to orchestrate the infiltration of the tumor microenvironment by immune cells, endothelial cells, fibroblasts, and mesenchymal cells. This facilitates the interaction of tumor cells with host cells, tumor cells with tumor cells, and host cells with host cells to provide a basis for the expansion of established tumors and development of distant metastasis. In addition, many malignant tumors of the nonhematopoietic origin express multiple chemoattractant GPCRs that increase the invasiveness and metastasis of tumor cells. Therefore, GPCRs and their ligands constitute targets for the development of novel antitumor therapeutics.

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753 InhibigenTM administration promotes aberrant T cell responses in cancer but may be beneficial for amelioration of autoimmune disease

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.753 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A787-A787

Author(s):

Victoria DeVault ◽

Hanna Starobinets ◽

Julie Arnold ◽

Stephanie Rinaldi ◽

Charley Hubbard ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Tumor Growth ◽

Cancer Immunotherapy ◽

T Cell Responses ◽

Cell Responses ◽

Tumor Bearing ◽

Melanoma Model ◽

Cancer Immunotherapies

BackgroundSelecting neoantigens that generate robust anti-tumor T cell responses remains a challenge for cancer immunotherapy design. The ATLASTM platform, a functional recall assay using patient autologous cells, identifies both stimulatory and inhibitory (Inhibigen) neoantigens via up- or downregulation of T cell cytokine secretion.1 We propose that stimulatory neoantigens are ideal targets for cancer vaccines and T cell therapies. In contrast, data suggest that Inhibigens be excluded, due to their association with accelerated tumor growth and dampened immunity in a murine melanoma model.2 While detrimental to cancer immunotherapy, the Inhibigen-associated downregulation of cytokine production may be beneficial in the context of autoimmunity.MethodsATLAS screens were performed as previously described.1 2 Peptide vaccines containing tumor-specific neoantigens ± Inhibigens were evaluated in prophylactic and therapeutic B16F10 melanoma tumor models for immunogenicity and efficacy. RNAseq analysis was performed on T cells sorted from draining lymph nodes of vaccinated tumor-bearing mice. For experimental autoimmune encephalomyelitis (EAE) studies, mice were administered a vaccine containing MOG peptide ± the melanoma MMP9FS Inhibigen. Immune responses and phenotypic analyses for both models were measured by flow cytometry, ELISPOT, and immunohistochemistry.ResultsIn the melanoma model, inclusion of the Inhibigen MMP9FS accelerated tumor growth in a non-dose dependent manner and abrogated immune responses. RNAseq of T cells from tumor-bearing mice vaccinated with MMP9FS showed a higher level of differentially expressed genes (adjusted P value of <0.05) in TCR-signaling regulation and suppressor GO pathways (>5 distinct pathways/gene) as compared to stimulatory controls, indicating Inhibigen-specific effects on T cells. In the EAE model of autoimmunity, animals treated with MOG peptide + MMP9FS exhibited dampened anti-MOG immune responses, delayed disease onset, reduced disease incidence and scoring (average 1 vs. 3) and decreased spinal cord immune infiltration as compared to control vaccination. These data indicate that Inhibigen administration has the potential to ameliorate autoimmune sequelae, independent of cognate antigen expression.ConclusionsFunctional identification and exclusion of Inhibigens from cancer immunotherapies may be critical to protective immunity since their inclusion can result in quelling of otherwise beneficial immune responses. Conversely, Inhibigen-specific responses can dampen destructive autoimmune sequelae. Mechanistic studies show altered T cell signaling pathways in the context of therapeutic Inhibigen vaccination. These data suggest that Inhibigen-specific responses, while detrimental for the treatment of cancer, may have a therapeutic benefit in other disease contexts.ReferencesNogueira C, Kaufmann JK, Lam H, Flechtner JB. Improving cancer immunotherapies through empirical neoantigen selection. Trends in Cancer 2018;4(2):97–100.Lam H, et al. An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor response or drive tumor growth. Cancer Discovery 2021;11(3):696–713.Ethics ApprovalAll animal studies were undertaken in conformity with the Cambridge, MA Ordinance 1086 of the city's Municipal Code and in accordance with the policies and protocols approved by Genocea's Institutional Animal Care and Use Committee (IACUC).

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Engineering Therapeutic Strategies in Cancer Immunotherapy via Exogenous Delivery of Toll-like Receptor Agonists

Pharmaceutics ◽

10.3390/pharmaceutics13091374 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1374

Author(s):

Sehwan Jeong ◽

Yunyoung Choi ◽

Kyobum Kim

Keyword(s):

T Cells ◽

Immune Responses ◽

Cancer Immunotherapy ◽

Cell Activation ◽

The Body ◽

Toll Like Receptor ◽

Tlr Agonists ◽

Cytokines And Chemokines ◽

Adaptive Immune Cells ◽

Delivery Strategies

As a currently spotlighted method for cancer treatment, cancer immunotherapy has made a lot of progress in recent years. Among tremendous cancer immunotherapy boosters available nowadays, Toll-like receptor (TLR) agonists were specifically selected, because of their effective activation of innate and adaptive immune cells, such as dendritic cells (DCs), T cells, and macrophages. TLR agonists can activate signaling pathways of DCs to express CD80 and CD86 molecules, and secrete various cytokines and chemokines. The maturation of DCs stimulates naïve T cells to differentiate into functional cells, and induces B cell activation. Although TLR agonists have anti-tumor ability by activating the immune system of the host, their drawbacks, which include poor efficiency and remarkably short retention time in the body, must be overcome. In this review, we classify and summarize the recently reported delivery strategies using (1) exogenous TLR agonists to maintain the biological and physiological signaling activities of cargo agonists, (2) usage of multiple TLR agonists for synergistic immune responses, and (3) co-delivery using the combination with other immunomodulators or stimulants. In contrast to naked TLR agonists, these exogenous TLR delivery strategies successfully facilitated immune responses and subsequently mediated anti-tumor efficacy.

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