Efficacy of Anti-Cancer Immune Responses Elicited Using Tumor-Targeted IL-2 Cytokine and Its Derivatives in Combined Preclinical Therapies
Effective cancer therapies must address the tumor microenvironment (TME), a complex network of tumor cells and stromal components, including endothelial, immune, and mesenchymal cells. Durable outcomes require targeting both tumor cells and the TME while minimizing systemic toxicity. Interleukin-2 (...
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2025-01-01
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| author | Sahar Balkhi Giorgia Bilato Andrea De Lerma Barbaro Paola Orecchia Alessandro Poggi Lorenzo Mortara |
| author_facet | Sahar Balkhi Giorgia Bilato Andrea De Lerma Barbaro Paola Orecchia Alessandro Poggi Lorenzo Mortara |
| author_sort | Sahar Balkhi |
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| description | Effective cancer therapies must address the tumor microenvironment (TME), a complex network of tumor cells and stromal components, including endothelial, immune, and mesenchymal cells. Durable outcomes require targeting both tumor cells and the TME while minimizing systemic toxicity. Interleukin-2 (IL-2)-based therapies have shown efficacy in cancers such as metastatic melanoma and renal cell carcinoma but are limited by severe side effects. Innovative IL-2-based immunotherapeutic approaches include immunotoxins, such as antibody–drug conjugates, immunocytokines, and antibody–cytokine fusion proteins that enhance tumor-specific delivery. These strategies activate cytotoxic CD8<sup>+</sup> T lymphocytes and natural killer (NK) cells, eliciting a potent Th1-mediated anti-tumor response. Modified IL-2 variants with reduced Treg cell activity further improve specificity and reduce immunosuppression. Additionally, IL-2 conjugates with peptides or anti-angiogenic agents offer improved therapeutic profiles. Combining IL-2-based therapies with immune checkpoint inhibitors (ICIs), anti-angiogenic agents, or radiotherapy has demonstrated synergistic potential. Preclinical and clinical studies highlight reduced toxicity and enhanced anti-tumor efficacy, overcoming TME-driven immune suppression. These approaches mitigate the limitations of high-dose soluble IL-2 therapy, promoting immune activation and minimizing adverse effects. This review critically explores advances in IL-2-based therapies, focusing on immunotoxins, immunocytokines, and IL-2 derivatives. Emphasis is placed on their role in combination strategies, showcasing their potential to target the TME and improve clinical outcomes effectively. Also, the use of IL-2 immunocytokines in “in situ” vaccination to relieve the immunosuppression of the TME is discussed. |
| format | Article |
| id | doaj-art-2856dc800fe8483f9a84fc487735d26e |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Vaccines |
| spelling | doaj-art-2856dc800fe8483f9a84fc487735d26e2025-01-24T13:51:50ZengMDPI AGVaccines2076-393X2025-01-011316910.3390/vaccines13010069Efficacy of Anti-Cancer Immune Responses Elicited Using Tumor-Targeted IL-2 Cytokine and Its Derivatives in Combined Preclinical TherapiesSahar Balkhi0Giorgia Bilato1Andrea De Lerma Barbaro2Paola Orecchia3Alessandro Poggi4Lorenzo Mortara5Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, ItalyLaboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, ItalyLaboratory of Comparative Physiopathology, Department of Biotechnology and Life Sciences, University of Insubria, 20145 Varese, ItalyPathology and Experimental Immunology Operative Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, ItalySSD Oncologia Molecolare e Angiogenesi, IRCCS Ospedale Policlinico San Martino, 16132 Genova, ItalyLaboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, ItalyEffective cancer therapies must address the tumor microenvironment (TME), a complex network of tumor cells and stromal components, including endothelial, immune, and mesenchymal cells. Durable outcomes require targeting both tumor cells and the TME while minimizing systemic toxicity. Interleukin-2 (IL-2)-based therapies have shown efficacy in cancers such as metastatic melanoma and renal cell carcinoma but are limited by severe side effects. Innovative IL-2-based immunotherapeutic approaches include immunotoxins, such as antibody–drug conjugates, immunocytokines, and antibody–cytokine fusion proteins that enhance tumor-specific delivery. These strategies activate cytotoxic CD8<sup>+</sup> T lymphocytes and natural killer (NK) cells, eliciting a potent Th1-mediated anti-tumor response. Modified IL-2 variants with reduced Treg cell activity further improve specificity and reduce immunosuppression. Additionally, IL-2 conjugates with peptides or anti-angiogenic agents offer improved therapeutic profiles. Combining IL-2-based therapies with immune checkpoint inhibitors (ICIs), anti-angiogenic agents, or radiotherapy has demonstrated synergistic potential. Preclinical and clinical studies highlight reduced toxicity and enhanced anti-tumor efficacy, overcoming TME-driven immune suppression. These approaches mitigate the limitations of high-dose soluble IL-2 therapy, promoting immune activation and minimizing adverse effects. This review critically explores advances in IL-2-based therapies, focusing on immunotoxins, immunocytokines, and IL-2 derivatives. Emphasis is placed on their role in combination strategies, showcasing their potential to target the TME and improve clinical outcomes effectively. Also, the use of IL-2 immunocytokines in “in situ” vaccination to relieve the immunosuppression of the TME is discussed.https://www.mdpi.com/2076-393X/13/1/69IL-2immunotoxinsimmunocytokines |
| spellingShingle | Sahar Balkhi Giorgia Bilato Andrea De Lerma Barbaro Paola Orecchia Alessandro Poggi Lorenzo Mortara Efficacy of Anti-Cancer Immune Responses Elicited Using Tumor-Targeted IL-2 Cytokine and Its Derivatives in Combined Preclinical Therapies Vaccines IL-2 immunotoxins immunocytokines |
| title | Efficacy of Anti-Cancer Immune Responses Elicited Using Tumor-Targeted IL-2 Cytokine and Its Derivatives in Combined Preclinical Therapies |
| title_full | Efficacy of Anti-Cancer Immune Responses Elicited Using Tumor-Targeted IL-2 Cytokine and Its Derivatives in Combined Preclinical Therapies |
| title_fullStr | Efficacy of Anti-Cancer Immune Responses Elicited Using Tumor-Targeted IL-2 Cytokine and Its Derivatives in Combined Preclinical Therapies |
| title_full_unstemmed | Efficacy of Anti-Cancer Immune Responses Elicited Using Tumor-Targeted IL-2 Cytokine and Its Derivatives in Combined Preclinical Therapies |
| title_short | Efficacy of Anti-Cancer Immune Responses Elicited Using Tumor-Targeted IL-2 Cytokine and Its Derivatives in Combined Preclinical Therapies |
| title_sort | efficacy of anti cancer immune responses elicited using tumor targeted il 2 cytokine and its derivatives in combined preclinical therapies |
| topic | IL-2 immunotoxins immunocytokines |
| url | https://www.mdpi.com/2076-393X/13/1/69 |
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