Advances in cancer immunotherapy: Strategies and innovations strategies for adoptive immunotherapy of cancer

Document Type : Review Article

Authors

1 Aryogen Pharmed Biopharmaceutical Research Center, Alborz University of Medical Science, Karaj, Iran

2 Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

3 Student Research Committee, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran

4 Clinical Research Development Unit, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

10.22038/ijbms.2025.88384.19090

Abstract

Cancer immunotherapy has emerged as a transformative approach in oncology, offering alternatives beyond traditional treatments. This narrative review focuses on major innovations, including adoptive cell therapy (ACT), chimeric antigen receptor T-cells (CAR-T), T-cell receptor (TCR) engineering, monoclonal antibodies (mAbs), bispecific antibodies (BsAbs), and immune checkpoint inhibitors (ICIs). The central aim of this article is to analyze how these technologies improve antitumor responses and help overcome resistance in hematologic and solid tumors. This narrative review combines the latest findings from clinical and preclinical studies to highlight therapeutic potentials and challenges. Key observations include the clinical success of CAR-T cells in treating blood cancers, the expanding application of ICIs in solid tumors, and the evolving structure-function relationship of BsAbs in recruiting immune effectors. This paper concludes by evaluating the current limitations of these immunotherapeutic strategies and discusses future directions for integrating them into personalized cancer therapy.

Graphical Abstract

Advances in cancer immunotherapy: Strategies and innovations strategies for adoptive immunotherapy of cancer

Keywords

Main Subjects


1. Zhang C-L, Huang T, Wu B-L, He W-X, Liu D. Stem cells in cancer therapy: Opportunities and challenges. Oncotarget 2017; 8:75756-75766.
2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68:394-424.
3. Oh C-M, Won Y-J, Jung K-W, Kong H-J, Cho H, Lee J-K, et al. Cancer statistics in Korea: Incidence, mortality, survival, and prevalence in 2013. Cancer Res Treat 2016; 48:436-450.
4. Colak S, Medema JP. Cancer stem cells–important players in tumor therapy resistance. FEBS J 2014; 281:4779-4791.
5. Wang J, Zheng Y, Zhao M. Exosome-based cancer therapy: Implication for targeting cancer stem cells. Front Pharmacol. 2017; 7:533-543.
6. Huehls AM, Coupet TA, Sentman CL. Bispecific T-cell engagers for cancer immunotherapy. Immunol Cell Biol 2015; 93:290-296.
7. Lee HY, Hong IS. Double‐edged sword of mesenchymal stem cells: cancer‐promoting versus therapeutic potential. Cancer science 2017; 108:1939-1946.
8.Wargo JA, Reuben A, Cooper ZA, Oh KS, Sullivan RJ, editors. Immune effects of chemotherapy, radiation, and targeted therapy and opportunities for combination with immunotherapy. Semin Oncol; 2015 ;42:601-616. 
9. Hughes PE, Caenepeel S, Wu LC. Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer. Trends Immunol 2016; 37:462-476.
10. Tang H, Qiao J, Fu Y-X. Immunotherapy and tumor microenvironment. Cancer Lett 2016; 370:85-90.
11. Kuroki M, Miyamoto S, Morisaki T, Yotsumoto F, Shirasu N, Taniguchi Y, et al. Biological response modifiers used in cancer biotherapy. Anticancer Res 2012; 32:2229-2233.
12. Suryadevara CM, Gedeon PC, Sanchez-Perez L, Verla T, Alvarez-Breckenridge C, Choi BD, et al. Are BiTEs the “missing link” in cancer therapy? Oncoimmunology 2015; 4:e1008339.
13. Stieglmaier J, Benjamin J, Nagorsen D. Utilizing the BiTE (bispecific T-cell engager) platform for immunotherapy of cancer. Expert Opin Biol Ther 2015; 15:1093-1099.
14. Swartz MA, Iida N, Roberts EW, Sangaletti S, Wong MH, Yull FE, et al. Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Res 2012; 72:2473-2480.
15. Li MY, Ye W, Luo KW. Immunotherapies targeting tumor-associated macrophages (TAMs) in cancer. Pharmaceutics 2024; 16:865-892.
16. Olejarz W, Sadowski K, Szulczyk D, Basak G. Advancements in personalized CAR-T therapy: Comprehensive overview of biomarkers and therapeutic targets in hematological malignancies. Int J Mol Sci 2024; 25:7743-7765.
17. Dvir K, Giordano S, Leone JP. Immunotherapy in breast cancer. Int J Mol Sci 2024; 25:7517-7532.
18. Bai R, Cui J. Development of immunotherapy strategies targeting tumor microenvironment is fiercely ongoing. Front Immunol 2022; 13:890166.
19. Golonko A, Pienkowski T, Swislocka R, Orzechowska S, Marszalek K, Szczerbinski L, et al. Dietary factors and their influence on immunotherapy strategies in oncology: A comprehensive review. Cell Death Dis 2024; 15:254-269.
20. Verhaert MAM, Aspeslagh S. Immunotherapy efficacy and toxicity: Reviewing the evidence behind patient implementable strategies. Eur J Cancer 2024; 209:114235.
21. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015; 348:62-68.
22. Liao S-K, Oldham RK. Immunotherapy of cancer is a part of biotherapy. J Cancer Metastasis Treat 2018; 4:3-10
23. Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics 2016; 3:16011-16017.
24. Lin B, Du L, Li H, Zhu X, Cui L, Li X. Tumor-infiltrating lymphocytes: Warriors fight against tumors powerfully. Biomed Pharmacother 2020; 132:110873.
25. Weber EW, Maus MV, Mackall CL. The emerging landscape of immune cell therapies. Cell 2020; 181:46-62.
26. Wang S, Sun J, Chen K, Ma P, Lei Q, Xing S, et al. Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors. BMC Med 2021; 19:140-146.
27. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: A clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008; 8:299-308.
28. Jiang T, Zhou C. The past, present and future of immunotherapy against tumor. Transl Lung Cancer Res 2015; 4:253-264.
29. Mohammadi M, Moradi Hasan-Abad A, Ghasemi A. Evaluation of the antitumor activity of moronecidin (Piscidin)-like peptide in combination with anti-PD-1 antibody against melanoma tumor. Iran J Basic Med Sci 2023; 26:1061-1067.
30. Ghasemi A, Ghavimi R, Momenzadeh N, Hajian S, Mohammadi M. Characterization of antitumor activity of a synthetic moronecidin-like peptide computationally predicted from the tiger tail seahorse hippocampus comes in tumor-bearing mice. Int J Pept Res Ther 2021; 27:2391-2401.
31. Kuroki M, Miyamoto S, Morisaki T, Yotsumoto F, Shirasu N, Taniguchi Y, et al. Biological response modifiers used in cancer biotherapy. Anticancer Res 2012; 32:2229-2233.
32. Sharma A, Campbell M, Yee C, Goswami S, Sharma P. Immunotherapy of cancer. Clinical Immunology: Elsevier; 2019. p. 1033-1048. e1031.
33. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015; 348:62-68.
34. Kong Y, Li J, Zhao X, Wu Y, Chen L. CAR-T cell therapy: Developments, challenges and expanded applications from cancer to autoimmunity. Front Immunol 2025 ;15:1519671. 
35. Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics 2016; 3:16011-16017.
36. Robat-Jazi B, Mahalleh M, Dashti M, Nejati N, Ahmadpour M, Alinejad E, et al. A systematic review and meta-analysis on the safety and efficacy of CAR T cell therapy targeting GPRC5D in patients with multiple myeloma: A new insight in cancer immunotherapy. Anticancer Agents Med Chem 2025; 25:1017-1028.
37. Lin B, Du L, Li H, Zhu X, Cui L, Li X. Tumor-infiltrating lymphocytes: Warriors fight against tumors powerfully. Biomed Pharmacother 2020; 132:110873.
38. Wang S, Sun J, Chen K, Ma P, Lei Q, Xing S, et al. Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors. BMC Med 2021; 19:1-7.
39. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: A clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008; 8:299-308.
40. Jiang T, Zhou C. The past, present and future of immunotherapy against tumor. Transl Lung Cancer Res 2015; 4:253-264.
41. Juárez-Salcedo LM, Sandoval-Sus J, Sokol L, Chavez JC, Dalia S. The role of anti-PD-1 and anti-PD-L1 agents in the treatment of diffuse large B-cell lymphoma: The future is now. Crit Rev Oncol Hematol 2017; 113:52-62.
42. Yu S, Li A, Liu Q, Li T, Yuan X, Han X, et al. Chimeric antigen receptor T cells: A novel therapy for solid tumors. J Hematol Oncol 2017; 10:78-90.
43. Tian Y, Li Y, Shao Y, Zhang Y. Gene modification strategies for next-generation CAR T cells against solid cancers. J Hematol Oncol 2020; 13:1-16.
44. Al-Haideri M, Tondok SB, Safa SH, Rostami S, Jalil AT, Al-Gazally ME, et al. CAR-T cell combination therapy: The next revolution in cancer treatment. Cancer Cell Int 2022; 22:1-26.
45. Figueroa JA, Reidy A, Mirandola L, Trotter K, Suvorava N, Figueroa A, et al. Chimeric antigen receptor engineering: A right step in the evolution of adoptive cellular immunotherapy. Int Rev Immunol 2015; 34:154-187.
46. Lim WA, June CH. The principles of engineering immune cells to treat cancer. Cell 2017; 168:724-740.
47. Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res 2017; 23:2255-2266.
48. Maalej KM, Merhi M, Inchakalody VP, Mestiri S, Alam M, Maccalli C, et al. CAR-cell therapy in the era of solid tumor treatment: Current challenges and emerging therapeutic advances. Mol Cancer 2023; 22:20-73.
49. Miliotou AN, Papadopoulou LC. CAR T-cell therapy: A new era in cancer immunotherapy. Curr Pharm Biotechnol 2018; 19:5-18.
50. Shen S, Xu N, Yang S, O’Brien T, Dolnikov A. Stem cell approach to generate chimeric antigen receptor modified immune effector cells to treat cancer. Cytotherapy 2016; 18:S101.
51. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2019; 380:45-56.
52. Myers JA, Miller JS. Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol 2021; 18:85-100.
53. Ong MZ, Kimberly SA, Lee WH, Ling M, Lee M, Tan KW, et al. FDA-approved CAR T-cell Therapy: A Decade of Progress and Challenges. Curr Pharm Biotechnol 2024; 25:1377-1393.
54. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: From T cell basic science to clinical practice. Nat Rev Immunol 2020; 20:651-668.
55. Luo F, Wang Y, Liu J, Chu Y. BiTE-T cell: A novel design for solid tumor. Cancer Res 2019 ;79(13_Supplement):2328.
56. Tao R, Han X, Bai X, Yu J, Ma Y, Chen W, et al. Revolutionizing cancer treatment: Enhancing CAR-T cell therapy with CRISPR/Cas9 gene editing technology. Front Immunol 2024; 15:1354825.
57. Dimitri A, Herbst F, Fraietta JA. Engineering the next-generation of CAR T-cells with CRISPR-Cas9 gene editing. Mol Cancer 2022; 21:78-90.
58. Wei W, Chen ZN, Wang K. CRISPR/Cas9: A powerful strategy to improve CAR-T cell persistence. Int J Mol Sci 2023; 24:12317-12334.
59. Rezvani K. Adoptive cell therapy using engineered natural killer cells. Bone Marrow Transplant 2019; 54:785-788.
60. Liu E, Tong Y, Dotti G, Shaim H, Savoldo B, Mukherjee M, et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia 2018; 32:520-531.
61. Li Y, Hermanson DL, Moriarity BS, Kaufman DS. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance antitumor activity. Cell stem cell 2018; 23:181-192.e5.
62. Lutterbuese R, Raum T, Kischel R, Hoffmann P, Mangold S, Rattel B, et al. T cell-engaging BiTE antibodies specific for EGFR potently eliminate KRAS-and BRAF-mutated colorectal cancer cells. Proc Natl Acad Sci U S A 2010; 107:12605-12610.
63. Dos Reis FD, Saidani Y, Martín-Rubio P, Sanz-Pamplona R, Stojanovic A, Correia MP. CAR-NK cells: Harnessing the power of natural killers for advanced cancer therapy. Front Immunol 2025; 16:1603757.
64. Guo JH, Afzal A, Ahmad S, Saeed G, Rehman A, Saddozai UAK, et al. Novel strategies to overcome tumor immunotherapy resistance using CAR NK cells. Front Immunol 2025; 16:1550652.
65. Von Behring E, Kitasato S. The mechanism of diphtheria immunity and tetanus immunity in animals. 1890. Mol Immunol 1991; 28:1317-1320.
66. Schroeder Jr HW, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol 2010; 125:S41-S52.
67. Sedykh SE, Prinz VV, Buneva VN, Nevinsky GA. Bispecific antibodies: design, therapy, perspectives. Drug Des Devel Ther 2018; 12:195-208.
68. Holzlöhner P, Hanack K. Generation of murine monoclonal antibodies by hybridoma technology. J Vis Exp 2017; 119:54832-54838.
69. Donini C, D’Ambrosio L, Grignani G, Aglietta M, Sangiolo D. Next generation immune-checkpoints for cancer therapy. J Thorac Dis 2018; 10:S1581-S1601.
70. Ocvirk J, Rebersek M, Boc M. Bevacizumab in first-line therapy of metastatic colorectal cancer: a retrospective comparison of FOLFIRI and XELIRI. Anticancer Res 2011; 31:1777-1782.
71. Rampino M, Bacigalupo A, Russi E, Schena M, Lastrucci L, Iotti C, et al. Efficacy and feasibility of induction chemotherapy and radiotherapy plus cetuximab in head and neck cancer. Anticancer Res 2012; 32:195-199.
72. Fan G, Wang Z, Hao M, Li J. Bispecific antibodies and their applications. J Hematol Oncol 2015; 8:130-143.
73. Baker JHE, Kyle AH, Reinsberg SA, Moosvi F, Patrick HM, Cran J, et al. Heterogeneous distribution of trastuzumab in HER2-positive xenografts and metastases: role of the tumor microenvironment. Clin Exp Metastasis 2018; 35:691-705.
74. Pallasch CP, Leskov I, Braun CJ, Vorholt D, Drake A, Soto-Feliciano YM, et al. Sensitizing protective tumor microenvironments to antibody-mediated therapy. Cell 2014; 156:590-602.
75. Cruz E, Kayser V. Monoclonal antibody therapy of solid tumors: clinical limitations and novel strategies to enhance treatment efficacy. Biologics 2019; 13:33-51. 
76. Elgundi Z, Reslan M, Cruz E, Sifniotis V, Kayser V. The state-of-play and future of antibody therapeutics. Adv Drug Deliv Rev 2017; 122:2-19.
77. Chung J. Special issue on therapeutic antibodies and biopharmaceuticals. Exp Mol Med 2017; 49:e304.
78. Khan M, Maker AV, Jain S. The evolution of cancer immunotherapy. Vaccines 2021; 9:614-624.
79. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012.
80. Wu J, Fu J, Zhang M, Liu D. Bispecific T cell engagers: An emerging therapy for management of hematologic malignancies. J Hematol Oncol. 2021;14:75-92.
81. Dhimolea E, Reichert JM. World Bispecific Antibody Summit, September 27-28, 2011, Boston, MA. MAbs 2012; 4:4-13.
82. Weisser NE, Hall JC. Applications of single-chain variable fragment antibodies in therapeutics and diagnostics. Biotechnol Adv 2009; 27:502-520.
83. Goulet DR, Atkins WM. Considerations for the Design of Antibody-Based Therapeutics. J Pharm Sci 2020; 109:74-103.
84. May C, Sapra P, Gerber HP. Advances in bispecific biotherapeutics for the treatment of cancer. Biochem Pharmacol 2012; 84:1105-1112.
85. Morecki S, Lindhofer H, Yacovlev E, Gelfand Y, Slavin S. Use of trifunctional bispecific antibodies to prevent graft versus host disease induced by allogeneic lymphocytes. Blood 2006; 107:1564-1569.
86. Krishnamurthy A, Jimeno A. Bispecific antibodies for cancer therapy: A review. Pharmacol Ther 2018; 185:122-134.
87. Manis JP, Feldweg AM. Overview of therapeutic monoclonal antibodies. US Pharm 2019; 44:31.
88. Huang S, van Duijnhoven SMJ, Sijts A, van Elsas A. Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy. J Cancer Res Clin Oncol 2020; 146:3111-3122.
89. Spiess C, Zhai Q, Carter PJ. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol 2015; 67:95-106.
90. Grugan KD, Dorn K, Jarantow SW, Bushey BS, Pardinas JR, Laquerre S, et al. Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells. MAbs 2017; 9:114-126.
91. Zhang X, Yang Y, Fan D, Xiong D. The development of bispecific antibodies and their applications in tumor immune escape. Exp Hematol Oncol 2017; 6:12.
92. Regales L, Gong Y, Shen R, de Stanchina E, Vivanco I, Goel A, et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest 2009; 119:3000-3010.
93. Li J, Stagg NJ, Johnston J, Harris MJ, Menzies SA, DiCara D, et al. Membrane-proximal epitope facilitates efficient T cell synapse formation by Anti-FcRH5/CD3 and is a requirement for myeloma cell killing. Cancer Cell 2017; 31:383-395.
94. Thakur A, Huang M, Lum LG. Bispecific antibody based therapeutics: Strengths and challenges. Blood Rev 2018; 32:339-347.
95. Brinkmann U, Kontermann RE. The making of bispecific antibodies. MAbs 2017; 9:182-212.
96. Kontermann RE. Strategies for extended serum half-life of protein therapeutics. Curr Opin Biotechnol 2011; 22:868-876.
97. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017; 376:836-847.
98. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 1970; 3:393-403.
99. Aldoss I, Bargou RC, Nagorsen D, Friberg GR, Baeuerle PA, Forman SJ. Redirecting T cells to eradicate B-cell acute lymphoblastic leukemia: Bispecific T-cell engagers and chimeric antigen receptors. Leukemia 2017; 31:777-787.
100. Xing J, Lin L, Li J, Liu J, Zhou C, Pan H, et al. BiHC, a T-cell-engaging bispecific recombinant antibody, has potent cytotoxic activity against Her2 tumor cells. Transl Oncol 2017; 10:780-785.
101. Lim K, Zhu XS, Zhou D, Ren S, Phipps A. Clinical pharmacology strategies for bispecific antibody development: learnings from FDA-approved bispecific antibodies in oncology. Clin Pharmacol Ther 2024; 116:315-327.
102. Goéré D, Flament C, Rusakiewicz S, Poirier-Colame V, Kepp O, Martins I, et al. Potent immunomodulatory effects of the trifunctional antibody catumaxomab. Cancer Res 2013; 73:4663-4673.
103. Zhang J, Medeiros LJ, Young KH. Cancer immunotherapy in diffuse large B-cell lymphoma. Front Oncol 2018; 8:351-362.
104. Köhnke T, Krupka C, Tischer J, Knösel T, Subklewe M. Increase of PD-L1 expressing B-precursor ALL cells in a patient resistant to the CD19/CD3-bispecific T cell engager antibody blinatumomab. J Hematol Oncol 2015; 8:111-115.
105. Lyons KU, Gore L. Bispecific T-cell engagers in childhood B-acute lymphoblastic leukemia. Haematologica 2024; 109:1668-1676.
106. Ribera JM. Efficacy and safety of bispecific T-cell engager blinatumomab and the potential to improve leukemia-free survival in B-cell acute lymphoblastic leukemia. Expert Rev Hematol 2017; 10:1057-1067.
107. Simão DC, Zarrabi KK, Mendes JL, Luz R, Garcia JA, Kelly WK, et al. Bispecific T-cell engagers therapies in solid tumors: Focusing on prostate cancer. Cancers (Basel) 2023; 15:1412-1434.
108. Zhou S, Liu M, Ren F, Meng X, Yu J. The landscape of bispecific T cell engager in cancer treatment. Biomark Res 2021; 9:38-60.
109. Velasquez MP, Bonifant CL, Gottschalk S. Redirecting T cells to hematological malignancies with bispecific antibodies. Blood 2018; 131:30-38.
110. Aliperta R, Cartellieri M, Feldmann A, Arndt C, Koristka S, Michalk I, et al. Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts. Blood Cancer J 2015; 5:e348.
111. Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med 2016; 8:328rv324.
112. Bryan LJ, Gordon LI. Releasing the brake on the immune system: The PD-1 strategy for hematologic malignancies. Oncology (Williston Park) 2015; 29:431-439.
113. Brodská B, Otevřelová P, Kuželová K. Correlation of PD-L1 surface expression on leukemia cells with the ratio of PD-L1 mRNA variants and with electrophoretic mobility. Cancer Immunol Res 2016; 4:815-819.
114. Sehgal A, Whiteside TL, Boyiadzis M. Programmed death-1 checkpoint blockade in acute myeloid leukemia. Expert Opin Biol Ther 2015; 15:1191-1203.
115. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014; 124:687-695.
116. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010; 107:4275-4280.
117. Rotte A, Jin JY, Lemaire V. Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann Oncol 2018; 29:71-83.
118. Disis ML, Taylor MH, Kelly K, Beck JT, Gordon M, Moore KM, et al. Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: Phase 1b results from the javelin solid tumor trial. JAMA Oncol 2019; 5:393-401.
119. Ye H, Liao W, Pan J, Shi Y, Wang Q. Immune checkpoint blockade for cancer therapy: Current progress and perspectives. J Zhejiang Univ Sci B 2025; 26:203-226.
120. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: The beginning of the end of cancer? BMC Med 2016; 14:1-18.
121. Ribas A. Adaptive immune resistance: How cancer protects from immune attack. Cancer Discov 2015; 5:915-919.
122. Du X, Tang F, Liu M, Su J, Zhang Y, Wu W, et al. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res 2018; 28:416-432.
123. Nelson MA, Ngamcherdtrakul W, Luoh S-W, Yantasee W. Prognostic and therapeutic role of tumor-infiltrating lymphocyte subtypes in breast cancer. Cancer Metastasis Rev 2021; 40:519-536.
124. Ward FJ, Kennedy PT, Al-Fatyan F, Dahal LN, Abu-Eid R. CTLA-4-two pathways to anti-tumour immunity? Immunother Adv 2025; 5:ltaf008.
125. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell 2015; 27:450-461.
126. Schreiner J, Thommen DS, Herzig P, Bacac M, Klein C, Roller A, et al. Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor. Oncoimmunology 2015; 5:e1062969.
127. Krupka C, Kufer P, Kischel R, Zugmaier G, Lichtenegger FS, Köhnke T, et al. Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism. Leukemia 2016; 30:484-491.
128. Topp MS, Borchmann P, Wagner-Johnston ND, Provencio M, Cordoba R, Papadopoulos K, et al. Safety and preliminary antitumor activity of the anti-PD-1 monoclonal antibody REGN2810 alone or in combination with REGN1979, an anti-CD20 x anti-CD3 bispecific antibody, in patients with B-lymphoid malignancies. Blood 2017; 130:1495.
129. Segal N, Saro J, Melero Ia, Ros W, Argiles G, Marabelle A, et al. Phase I studies of the novel carcinoembryonic antigen T-cell bispecific (CEA-CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients (pts) with metastatic colorectal cancer (mCRC). Ann Oncol 2017; 28:v134.
130. Kil SH, Estephan R, Sanchez J, Zain JM, Kadin ME, Young JW, et al. PD-L1 is regulated by interferon gamma and interleukin 6 through STAT1 and STAT3 signaling in cutaneous T-cell lymphoma. Blood 2017; 130:1458-1458.
131. Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3—potential mechanisms of action. Nat Rev Immunol 2015; 15:45-56.
132. Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3--potential mechanisms of action. Nat Rev Immunol 2015; 15:45-56.
133. Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med 2015; 21:24-33.
134. Hawkes EA, Grigg A, Chong G. Programmed cell death-1 inhibition in lymphoma. Lancet Oncol 2015; 16:e234-245.
135. Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 2009; 10:1185-1192.
136. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 2009; 206:3015-3029.
137. Ross SL, Sherman M, McElroy PL, Lofgren JA, Moody G, Baeuerle PA, et al. Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing. PLoS One 2017; 12:e0183390.
138. Juárez-Salcedo LM, Sandoval-Sus J, Sokol L, Chavez JC, Dalia S. The role of anti-PD-1 and anti-PD-L1 agents in the treatment of diffuse large B-cell lymphoma: The future is now. Crit Rev Oncol Hematol 2017; 113:52-62.
139. Cruz E, Kayser V. Monoclonal antibody therapy of solid tumors: Clinical limitations and novel strategies to enhance treatment efficacy. Biologics 2019; 13:33-51.
140. Carter LL, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, et al. PD‐1: PD‐L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL‐2. Eur J Immunol 2002; 32:634-643.
141. Chen DS, Irving BA, Hodi FS. Molecular pathways: Next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 2012; 18:6580-6587.
142. Osada T, Patel SP, Hammond SA, Osada K, Morse MA, Lyerly HK. CEA/CD3-bispecific T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1. Cancer Immunol Immunother 2015; 64:677-688.
143. Giannopoulos K. Targeting immune signaling checkpoints in acute myeloid leukemia. J Clin Med 2019; 8:236-246.
144. Li H, Er Saw P, Song E. Challenges and strategies for next-generation bispecific antibody-based antitumor therapeutics. Cell Mol Immunol 2020; 17:451-461.
145. Horn LA, Ciavattone NG, Atkinson R, Woldergerima N, Wolf J, Clements VK, et al. CD3xPDL1 bi-specific T cell engager (BiTE) simultaneously activates T cells and NKT cells , kills PDL1 + tumor cells , and extends the survival of tumor-bearing humanized mice.Oncotarget  2017; 8:57964-57980.
146. Moody J, Barker PJ, Sciasci J, Pauley JL, Bragg A, McMillan C, et al. Blinatumomab infusion interruptions in pediatric patients rarely lead to readmission. Pediatr Blood Cancer 2024;71:e31223.
147. Huang J, Shi B, Yu S, Xue M, Wang L, Jiang J, et al. Efficacy of blinatumomab as maintenance therapy for B-lineage acute lymphoblastic leukemia/lymphoma following allogeneic hematopoietic cell transplantation. Blood Cancer J 2024; 14:109.
148. Guo Y, Quijano Cardé NA, Kang L, Verona R, Banerjee A, Kobos R, et al. Teclistamab: Mechanism of action, clinical, and translational science. Clin Transl Sci 2024; 17:e13717.
149. Mohan M, Monge J, Shah N, Luan D, Forsberg M, Bhatlapenumarthi V, et al. Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study. Blood Cancer J 2024; 14:35-40.
150. Riedhammer C, Bassermann F, Besemer B, Bewarder M, Brunner F, Carpinteiro A, et al. Real-world analysis of teclistamab in 123 RRMM patients from Germany. Leukemia 2024; 38:365-371.
151. Howlett S, Carter TJ, Shaw HM, Nathan PD. Tebentafusp: A first-in-class treatment for metastatic uveal melanoma. Ther Adv Med Oncol 2023; 15:17588359231160140.
152. Khushboo B, Kumar JR. Perils and problems in bispecific T-cell engager antibodies. Curr Drug Saf 2025; 20:85-88.
153. Said SS, Ibrahim WN. Cancer resistance to immunotherapy: Comprehensive insights with future perspectives. Pharmaceutics 2023; 15:1143-1173.
154. Bai R, Chen N, Li L, Du N, Bai L, Lv Z, et al. Mechanisms of cancer resistance to immunotherapy. Front Oncol 2020; 10:1290-1301.
155. Vu SH, Vetrivel P, Kim J, Lee M-S. Cancer resistance to immunotherapy: molecular mechanisms and tackling strategies. Int J Mol Sci 2022; 23:10906-10927.
156. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017; 168:707-723.
157. de Miguel M, Umana P, Gomes de Morais AL, Moreno V, Calvo E. T-cell–engaging therapy for solid tumorsT-cell–engaging therapy for solid tumors. Clin Cancer Res 2021; 27:1595-1603.
158. Moon D, Tae N, Park Y, Lee S-W, Kim DH. Development of bispecific antibody for cancer immunotherapy: focus on T cell engaging antibody. Immune Netw 2022; 22:e4.
159. Sterner RC, Sterner RM. CAR-T cell therapy: Current limitations and potential strategies. Blood Cancer J 2021; 11:1-11.