Immunotherapy: the Mega Weapon to Cure Cancer
,
Abstract
Objective: Cancer is one of the most complex genomic diseases that can gain abilities to resist different therapies. These capabilities, known as the hallmark of cancer, allow specific and personalised therapies such as immunotherapy.
Materials and methods: This review paper discusses how different immunotherapies, such as immune checkpoint blockade, chimeric antigen receptor (CAR) T-cell, and Oncolytic viral therapy, which are currently being used and researched to overcome cancer cell capabilities by using the patient’s immune system.
Results: Immune checkpoint blockade therapy is used to block immune inhibitory pathways using anti-PD-1 receptor and anti-CTLA-4 receptor antibodies, which make lymphocytes more responsive towards cancer cells. Then, it is discussed how CAR T-cells are designed to make cancer antigens more easily identified by T-cells for a more specific immune response. Furthermore, it is shown that oncolytic viruses directly destroy cancer cells and, indirectly, make them more vulnerable to the immune system.
Conclusion: It is proposed that oncolytic viral therapy is a bridge between Immune checkpoint and CAR T-cell therapies for a more effective and more specific immune response towards cancer.
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4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
5. van Middendorp JJ, Sanchez GM, Burridge AL. The Edwin Smith papyrus: a clinical reappraisal of the oldest known document on spinal injuries. Eur Spine J. 2010;19(11):1815-23.
6. Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The Different Mechanisms of Cancer Drug Resistance: A Brief Review. Adv Pharm Bull. 2017;7(3):339-48.
7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74.
8. Hanahan D,Hallmarks of cancer—Then and now, and beyond. Cell. 2026;189(8): 2254-2277.
9. Kiyotani K, Toyoshima Y, Nakamura Y. Personalized immunotherapy in cancer precision medicine. Cancer Biol Med. 2021;18(4):955–65.
10. Xing X, Zhao Q, Zhou J, Zhou R, Liu Y, Qin X, Zhang M, Zhong Y, Wang J, Tian M, Zhang H. Positron emission tomography molecular imaging to monitor anti-tumor systemic response for immune checkpoint inhibitor therapy. Eur J Nucl Med Mol Imaging. 2023;50(6):1671-1688.
11. Baldanzi G. Immune Checkpoint Receptors Signaling in T Cells. Int J Mol Sci. 2022;23(7):3529.
12. Kythreotou A, Siddique A, Mauri FA, Bower M, Pinato DJ. PD-L1. J Clin Pathol. 2018 ;71(3):189-194.
13. Antonia SJ, Muñoz-Antonia T, Soldevila G, Miller J, Flavell RA. B7-1 expression by a non-antigen presenting cell-derived tumor. Cancer Res. 1995;55(11):2253-6.
14. Hannani D, Vétizou M, Enot D, Rusakiewicz S, Chaput N, Klatzmann D, et al. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. Cell Res. 2015;25(2):208-24.
15. Gong Q, Wang C, Zhang W, Iqbal J, Hu Y, Greiner TC, et al. Assessment of T-cell receptor repertoire and clonal expansion in peripheral T-cell lymphoma using RNA-seq data. Sci Rep. 2017;7(1):11301.
16. Bekoz H, Ozbalak M, Karadurmus N, Paydas S, Turker A, Toptas T, et al. Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience. Ann Hematol. 2020;99(11):2565-76.
17. Levy B, Paz-Ares L, Bennouna J, Felip E, Abreu DR, Isla D, et al. Afatinib With Pembrolizumab for Treatment of Patients With Locally Advanced/Metastatic Squamous Cell Carcinoma of the Lung: The LUX-Lung IO/KEYNOTE 497 Study Protocol. Clin Lung Cancer. 2019;20(3):e407-e412.
18. Migden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2018;379(4):341-51.
19. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017;377(14):1345-56.
20. Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res. 2019;38(1):255.
21. Toulmonde M, Penel N, Adam J, Chevreau C, Blay JY, Le Cesne A, et al. Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in Sarcomas: A Phase 2 Clinical Trial. JAMA Oncol. 2018;4(1):93-7.
22. Ariyan CE, Brady MS, Siegelbaum RH, Hu J, Bello DM, Rand J, et al. Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade. Cancer Immunol Res. 2018;6(2):189-200.
23. Johnson DB, Beckermann KE, Wang DY. Immune Checkpoint Inhibitor Therapy in Patients With Autoimmune Disease. Oncology (Williston Park). 2018;32(4):190-4.
24. Xia A, Zhang Y, Xu J, Yin T, Lu XJ. T Cell Dysfunction in Cancer Immunity and Immunotherapy. Front Immunol. 2019;10:1719.
25. Hossen MM, Ma Y, Yin Z, Xia Y, Du J, Huang JY, et al. Current understanding of CTLA-4: from mechanism to autoimmune diseases. Front Immunol. 2023;14:1198365.
26. Tokarew N, Ogonek J, Endres S, von Bergwelt-Baildon M, Kobold S. Teaching an old dog new tricks:
next-generation CAR T cells. Br J Cancer. 2019;120(1):26-37.
27. Lehner M, Götz G, Proff J, Schaft N, Dörrie J, Full F, et al. Redirecting T cells to Ewing's sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection. PLoS One. 2012;7(2):e31210.
28. Abreu TR, Fonseca NA, Gonçalves N, Moreira JN. Current challenges and emerging opportunities of CAR-T cell therapies. J Control Release. 2020;319:246-61.
29. You F, Jiang L, Zhang B, Lu Q, Zhou Q, Liao X, et al. Phase 1 clinical trial demonstrated that MUC1 positive metastatic seminal vesicle cancer can be effectively eradicated by modified Anti-MUC1 chimeric antigen receptor transduced T cells. Sci China Life Sci. 2016;59(4):386-97.
30. Anagnostou T, Riaz IB, Hashmi SK, Murad MH, Kenderian SS. Anti-CD19 chimeric antigen receptor
T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis. Lancet Haematol. 2020 ;7(11):e816-e826.
31. Li D, Li X, Zhou WL, Huang Y, Liang X, Jiang L, et al. Genetically engineered T cells for cancer immunotherapy. Signal Transduct Target Ther. 2019;4:35.
32. Zhang X, Lu XA, Yang J, Zhang G, Li J, Song L, et al. Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features. Blood Adv. 2020;4(10):2325-38.
33. Zheng M, Huang J, Tong A, Yang H. Oncolytic Viruses for Cancer Therapy: Barriers and Recent Advances. Mol Ther Oncolytics. 2019;15:234-247.
34. Shafren DR, Dorahy DJ, Ingham RA, Burns GF, Barry RD. Coxsackievirus A21 binds to decay-accelerating factor but requires intercellular adhesion molecule 1 for cell entry. J Virol. 1997;71(6):4736-43.
35. Bommareddy PK, Shettigar M, Kaufman HL. Integrating oncolytic viruses in combination cancer immunotherapy. Nat Rev Immunol. 2018;18(8):498-513.
36. Huang H, Liu Y, Liao W, Cao Y, Liu Q, Guo Y, et al. Oncolytic adenovirus programmed by synthetic gene circuit for cancer immunotherapy. Nat Commun. 2019;10(1):4801.
37. Lv SQ, Ye ZL, Liu PY, Huang Y, Li LF, Liu H, et al. 11R-P53 and GM-CSF Expressing Oncolytic Adenovirus Target Cancer Stem Cells with Enhanced Synergistic Activity. J Cancer. 2017;8(2):199-206.
38. Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017;170(6):1109-1119.e10.
39. Wang G, Kang X, Chen KS, Jehng T, Jones L, Chen J, et al. An engineered oncolytic virus expressing PD-L1 inhibitors activates tumor neoantigen-specific T cell responses. Nat Commun. 2020;11(1):1395.
40. Fujii K, Kurozumi K, Ichikawa T, Onishi M, Shimazu Y, Ishida J, et al. The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus. Cancer Gene Ther. 2013;20(8):437-44.
41. Yamada S, Kuroda T, Fuchs BC, He X, Supko JG, Schmitt A, et al. Oncolytic herpes simplex virus expressing yeast cytosine deaminase: relationship between viral replication, transgene expression, prodrug bioactivation. Cancer Gene Ther. 2012;19(3):160-70.
42. Ge Y, Wang H, Ren J, Liu W, Chen L, Chen H, et al. Oncolytic vaccinia virus delivering tethered IL-12 enhances antitumor effects with improved safety. J Immunother Cancer. 2020;8(1):e000710.
43. Qu H, Jin Q, Quan C. CLDN6: From Traditional Barrier Function to Emerging Roles in Cancers. Int J Mol Sci. 2021;22(24):13416.
44. Kaur B, Brat DJ, Devi NS, Van Meir EG. Vasculostatin, a proteolytic fragment of brain angiogenesis inhibitor 1, is an antiangiogenic and antitumorigenic factor. Oncogene. 2005;24(22):3632-42.
45. Altanerova U, Jakubechova J, Benejova K, Priscakova P, Repiska V, Babelova A, et al. Intracellular prodrug gene therapy for cancer mediated by tumor cell suicide gene exosomes. Int J Cancer. 2021;148(1):128-39.
2. Klein CA. Cancer progression and the invisible phase of metastatic colonization. Nat Rev Cancer. 2020; 20(11):681-694.
3. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100(1):57-70.
4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
5. van Middendorp JJ, Sanchez GM, Burridge AL. The Edwin Smith papyrus: a clinical reappraisal of the oldest known document on spinal injuries. Eur Spine J. 2010;19(11):1815-23.
6. Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The Different Mechanisms of Cancer Drug Resistance: A Brief Review. Adv Pharm Bull. 2017;7(3):339-48.
7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74.
8. Hanahan D,Hallmarks of cancer—Then and now, and beyond. Cell. 2026;189(8): 2254-2277.
9. Kiyotani K, Toyoshima Y, Nakamura Y. Personalized immunotherapy in cancer precision medicine. Cancer Biol Med. 2021;18(4):955–65.
10. Xing X, Zhao Q, Zhou J, Zhou R, Liu Y, Qin X, Zhang M, Zhong Y, Wang J, Tian M, Zhang H. Positron emission tomography molecular imaging to monitor anti-tumor systemic response for immune checkpoint inhibitor therapy. Eur J Nucl Med Mol Imaging. 2023;50(6):1671-1688.
11. Baldanzi G. Immune Checkpoint Receptors Signaling in T Cells. Int J Mol Sci. 2022;23(7):3529.
12. Kythreotou A, Siddique A, Mauri FA, Bower M, Pinato DJ. PD-L1. J Clin Pathol. 2018 ;71(3):189-194.
13. Antonia SJ, Muñoz-Antonia T, Soldevila G, Miller J, Flavell RA. B7-1 expression by a non-antigen presenting cell-derived tumor. Cancer Res. 1995;55(11):2253-6.
14. Hannani D, Vétizou M, Enot D, Rusakiewicz S, Chaput N, Klatzmann D, et al. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. Cell Res. 2015;25(2):208-24.
15. Gong Q, Wang C, Zhang W, Iqbal J, Hu Y, Greiner TC, et al. Assessment of T-cell receptor repertoire and clonal expansion in peripheral T-cell lymphoma using RNA-seq data. Sci Rep. 2017;7(1):11301.
16. Bekoz H, Ozbalak M, Karadurmus N, Paydas S, Turker A, Toptas T, et al. Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience. Ann Hematol. 2020;99(11):2565-76.
17. Levy B, Paz-Ares L, Bennouna J, Felip E, Abreu DR, Isla D, et al. Afatinib With Pembrolizumab for Treatment of Patients With Locally Advanced/Metastatic Squamous Cell Carcinoma of the Lung: The LUX-Lung IO/KEYNOTE 497 Study Protocol. Clin Lung Cancer. 2019;20(3):e407-e412.
18. Migden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2018;379(4):341-51.
19. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017;377(14):1345-56.
20. Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res. 2019;38(1):255.
21. Toulmonde M, Penel N, Adam J, Chevreau C, Blay JY, Le Cesne A, et al. Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in Sarcomas: A Phase 2 Clinical Trial. JAMA Oncol. 2018;4(1):93-7.
22. Ariyan CE, Brady MS, Siegelbaum RH, Hu J, Bello DM, Rand J, et al. Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade. Cancer Immunol Res. 2018;6(2):189-200.
23. Johnson DB, Beckermann KE, Wang DY. Immune Checkpoint Inhibitor Therapy in Patients With Autoimmune Disease. Oncology (Williston Park). 2018;32(4):190-4.
24. Xia A, Zhang Y, Xu J, Yin T, Lu XJ. T Cell Dysfunction in Cancer Immunity and Immunotherapy. Front Immunol. 2019;10:1719.
25. Hossen MM, Ma Y, Yin Z, Xia Y, Du J, Huang JY, et al. Current understanding of CTLA-4: from mechanism to autoimmune diseases. Front Immunol. 2023;14:1198365.
26. Tokarew N, Ogonek J, Endres S, von Bergwelt-Baildon M, Kobold S. Teaching an old dog new tricks:
next-generation CAR T cells. Br J Cancer. 2019;120(1):26-37.
27. Lehner M, Götz G, Proff J, Schaft N, Dörrie J, Full F, et al. Redirecting T cells to Ewing's sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection. PLoS One. 2012;7(2):e31210.
28. Abreu TR, Fonseca NA, Gonçalves N, Moreira JN. Current challenges and emerging opportunities of CAR-T cell therapies. J Control Release. 2020;319:246-61.
29. You F, Jiang L, Zhang B, Lu Q, Zhou Q, Liao X, et al. Phase 1 clinical trial demonstrated that MUC1 positive metastatic seminal vesicle cancer can be effectively eradicated by modified Anti-MUC1 chimeric antigen receptor transduced T cells. Sci China Life Sci. 2016;59(4):386-97.
30. Anagnostou T, Riaz IB, Hashmi SK, Murad MH, Kenderian SS. Anti-CD19 chimeric antigen receptor
T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis. Lancet Haematol. 2020 ;7(11):e816-e826.
31. Li D, Li X, Zhou WL, Huang Y, Liang X, Jiang L, et al. Genetically engineered T cells for cancer immunotherapy. Signal Transduct Target Ther. 2019;4:35.
32. Zhang X, Lu XA, Yang J, Zhang G, Li J, Song L, et al. Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features. Blood Adv. 2020;4(10):2325-38.
33. Zheng M, Huang J, Tong A, Yang H. Oncolytic Viruses for Cancer Therapy: Barriers and Recent Advances. Mol Ther Oncolytics. 2019;15:234-247.
34. Shafren DR, Dorahy DJ, Ingham RA, Burns GF, Barry RD. Coxsackievirus A21 binds to decay-accelerating factor but requires intercellular adhesion molecule 1 for cell entry. J Virol. 1997;71(6):4736-43.
35. Bommareddy PK, Shettigar M, Kaufman HL. Integrating oncolytic viruses in combination cancer immunotherapy. Nat Rev Immunol. 2018;18(8):498-513.
36. Huang H, Liu Y, Liao W, Cao Y, Liu Q, Guo Y, et al. Oncolytic adenovirus programmed by synthetic gene circuit for cancer immunotherapy. Nat Commun. 2019;10(1):4801.
37. Lv SQ, Ye ZL, Liu PY, Huang Y, Li LF, Liu H, et al. 11R-P53 and GM-CSF Expressing Oncolytic Adenovirus Target Cancer Stem Cells with Enhanced Synergistic Activity. J Cancer. 2017;8(2):199-206.
38. Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017;170(6):1109-1119.e10.
39. Wang G, Kang X, Chen KS, Jehng T, Jones L, Chen J, et al. An engineered oncolytic virus expressing PD-L1 inhibitors activates tumor neoantigen-specific T cell responses. Nat Commun. 2020;11(1):1395.
40. Fujii K, Kurozumi K, Ichikawa T, Onishi M, Shimazu Y, Ishida J, et al. The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus. Cancer Gene Ther. 2013;20(8):437-44.
41. Yamada S, Kuroda T, Fuchs BC, He X, Supko JG, Schmitt A, et al. Oncolytic herpes simplex virus expressing yeast cytosine deaminase: relationship between viral replication, transgene expression, prodrug bioactivation. Cancer Gene Ther. 2012;19(3):160-70.
42. Ge Y, Wang H, Ren J, Liu W, Chen L, Chen H, et al. Oncolytic vaccinia virus delivering tethered IL-12 enhances antitumor effects with improved safety. J Immunother Cancer. 2020;8(1):e000710.
43. Qu H, Jin Q, Quan C. CLDN6: From Traditional Barrier Function to Emerging Roles in Cancers. Int J Mol Sci. 2021;22(24):13416.
44. Kaur B, Brat DJ, Devi NS, Van Meir EG. Vasculostatin, a proteolytic fragment of brain angiogenesis inhibitor 1, is an antiangiogenic and antitumorigenic factor. Oncogene. 2005;24(22):3632-42.
45. Altanerova U, Jakubechova J, Benejova K, Priscakova P, Repiska V, Babelova A, et al. Intracellular prodrug gene therapy for cancer mediated by tumor cell suicide gene exosomes. Int J Cancer. 2021;148(1):128-39.
| Files | ||
| Issue | Vol 20, No 1 (March 2026) | |
| Section | Review Articles | |
| Keywords | ||
| Immunotherapy Cancer Immune Checkpoint Blockade Viral Therapy | ||
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How to Cite
1.
Rostamitehrani Z, Jafarabadi M, Rezayof E. Immunotherapy: the Mega Weapon to Cure Cancer. J Family Reprod Health. 2026;20(1):1-9.
