Chemoimmunotherapy as a Novel Cancer Therapy

Document Type: Review article


1 Department of Immunology, Faculty of Medical Sciences Tarbiat Modares University, Tehran, Iran.

2 Immunoregulation Research Center, Shahed University, Tehran, Iran.


Over the past decade, it was widely accepted that some chemotherapeutic drugs can be combined with immunotherapeutic drugs in treatment of cancer. Chemotherapeutic drugs can induce apoptosis in the tumor cell and at the same time stimulate the immune response. Several reports support the use   immunomodulators in treatment of cancers through regulating the immune response and boosting the microenvironments toward T helper (Th1) cells. At the same time these molecule attach to transferrin-Fe2+ and circulate in the blood vessels until they find transferin receptors which are highly detected in tumor cells and induce apoptosis in tumor cells.


World Health Organization. Cancer. Geneva: World Health Organization; 2018.
Shahrokhi S, Zuhair MH, Mohagheghi MA, Ghazanfari T, Askarian Sh, Sheikhian A, et al. [The effect of oral consumption of shark cartilage on the cellular immune responses of cancer patients (Persian)]. Yafteh. 2006; 8(3):15-21.
Nickels S, Truong T, Hein R, Stevens K, Buck K, Behrens S, et al. Evidence of gene–environment interactions between common breast cancer susceptibility loci and established environmental risk factors. PLOS. 2013; 9(3):e1003284. [DOI:10.1371/journal.pgen.1003284]
Payne SR, Kemp CJ. Tumor suppressor genetics. Carcinogenesis. 2005; 26(12):2031–45.[DOI:10.1093/carcin/bgi223] [PMID]
Chabncr BA. The role of drugs in cancer treatment. In: Chabner BA, editor. Pharmacologie Principles of Cancer Treatment. Philadelphia: Saunders; 1982.
McDonald CJ. The uses of systemic chemotherapeutic agents in psoriasis. Pharmacology & Therapeutics. 1981; 14(1):1-24. [DOI:10.1016/0163-7258(81)90008-5]
Kieseier BC, Jeffery DR. Chemotherapeutics in the treatment of multiple sclerosis. Therapeutic Advances in Neurological Disorders. 2010; 3(5):277–91. [DOI:10.1177/1756285610379885]
Traynor AE, Schroeder J, Rosa RM, Cheng D, Stefka J, Mujais S, et al. Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: A phase I study. Lancet. 2000; 356(9231):701-7. [DOI:10.1016/S0140-6736(00)02627-1]
Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. The Lancet. 2007; 370(9605):2103–11. [DOI:10.1016/S0140-6736(07)61904-7]
Larkin J. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. New England Journal of Medicine. New England Journal of Medicine. 2015; 373(13):1270–1. [DOI:10.1056/NEJMoa1504030] [PMID] [PMCID]
Robak T. Alemtuzumab for B-cell chronic lymphocytic leukemia. Expert Review of Anticancer Therapy. 2008; 8(7):1033–51. [DOI:10.1586/14737140.8.7.1033] A phase II Study of atezolizumab in combination with cisplatin+gemcitabine before surgery to remove the bladder cancer. 2018; Identifier: NCT02989584.
Savoia P, Astrua C, Fava P. Ipilimumab (Anti-Ctla-4 Mab) in the treatment of metastatic melanoma: Effectiveness and toxicity management. Human Vaccines & Immunotherapeutics. 2016; 12(5):1092–101. [DOI:10.1080/21645515.2015.1129478] [PMID] [PMCID]
Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, et al. Ofatumumab as single-agent cd20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. Journal of Clinical Oncology. 2010; 28(10):1749–55. [DOI:10.1200/jco.2009.25.3187]
Guo L, Zhang H, Chen B. Nivolumab as Programmed Death-1 (PD-1) inhibitor for targeted immunotherapy in tumor. Journal of Cancer. 2017; 8(3):410–6. [DOI:10.7150/jca.17144]
Sui X, Ma J, Han W, Wang X, Fang Y, Li D, et al. The anticancer immune response of anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients. Oncotarget. 2015; 6(23): 19393–404. [DOI:10.18632/oncotarget.5107]
Dotan E, Aggarwal C, Smith MR. Impact of rituximab (Rituxan) on the treatment of B-cell Non-hodgkin's lymphoma. Journal of Orthopaedic & Sports Physical Therapy. 2010; 35(3):148–57. [PMID] [PMCID]
Summers J, Cohen MH, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab plus interferon for advanced renal cell carcinoma. The Oncologist. 2010; 15(1):104–11. [DOI:10.1634/theoncologist.2009-0250]
Hazarika M, Chuk MK, Theoret MR, Mushti S, He K, Weis SL, et al. U.S. FDA approval summary: Nivolumab for treatment of unresectable or metastatic melanoma following progression on ipilimumab. Clinical Cancer Research. 2017; 23(14):3484–8. [DOI:10.1158/1078-0432.CCR-16-0712] Safety study of anti-LAG-3 with and without anti-PD-1 in the treatment of solid tumors. 2018; Identifier: NCT02966548
Sanmamed MF, Rodriguez I, Oñate C, Azpilikueta A, Rodriguez-Ruiz ME, Morales-Kastresana A, et al. Abstract 261: Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2Rγnull immunodeficient mice. Cancer Research. 2015; 75(15 Supplement):261–261. [DOI:10.1158/0008-5472.CAN-14-3510] [PMID]
Jeffrey R. Infante Combining Atezolizumab With OX40 Agonist Shows Promise in Solid Tumors Community Practice Connections™. Paper presented at: 12th Annual International Symposium on Melanoma and Other Cutaneous Malignancies. 20 February 2016; Miami, USA. A study of GDC-0919 and atezolizumab combination treatment in participants with locally advanced or metastatic solid tumors. 2018; Identifier: NCT02471846.
Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. The Lancet Oncology. 2016; 17(3):299-308. [DOI:10.1016/S1470-2045(15)00544-6.][PMID] [PMCID]
Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. The Lancet Oncology. 2016; 17(11):1558–68. [DOI:10.1016/s1470-2045(16)30366-7] Study of pembrolizumab (MK-3475) as first-line Monotherapy and combination therapy for treatment of advanced gastric or gastroesophageal junction adenocarcinoma (MK-3475-062/KEYNOTE-062); 2015. Identifier: NCT02494583
Kocoglu M, Badros A. The role of immunotherapy in multiple myeloma. Pharmaceuticals. 2016; 9(1):3. [DOI:10.3390/ph9010003]
Cheng ML, Fong L. Beyond sipuleucel-T: Immune approaches to treating prostate cancer. Current Treatment Options in Oncology. 2014; 15(1):115–26. [DOI:10.1007/s11864-013-0267-z]
Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non–small-cell lung cancer. Journal of Clinical Oncology. 2016; 34(25):2969–79. [DOI:10.1200/jco.2016.66.9861]
Shikanov S, Shikanov A, Gofrit O, Nyska A, Corn B, Domb AJ. Intratumoral delivery of paclitaxel for treatment of orthotopic prostate cancer. Journal of Pharmaceutical Sciences. 2009; 98(3):1005–14. [DOI:10.1002/jps.21492]
Hortobágyi GN. Anthracyclines in the treatment of cancer. Drugs. 1997; 54(4):1-7. [DOI:10.2165/00003495-199700544-00003] [PMID]
Noori S, Taghikhani M, Hassan ZM, Allameha A, Mostafaei A. Tehranolide molecule modulates the immune response, reduce regulatory T cell and inhibits tumor growth in vivo. Molecular Immunology. 2010; 47(7-8):1579–84. [DOI:10.1016/j.molimm.2010.01.007]
Hassan ZM, Feyzi R, Sheikhian A, Bargahi A, Mostafaie A, Mansouri K, et al. Low molecular weight fraction of shark cartilage can modulate immune responses and abolish angiogenesis. International Immunopharmacology. 2005; 5(6):961–70. [DOI:10.1016/j.intimp.2005.01.006] [PMID]
Safari E, Hassan ZM, Moazzeni SM. Shark cartilage 14 kDa protein as a dendritic cells activator. Immunopharmacology and Immunotoxicology. 2015; 37(2):165-70. [DOI:10.3109/08923973.2015.1006370]
Feyzi R, Hassan ZM, Mostafaie A. Modulation of CD4+ and CD8+ tumor infiltrating lymphocytes by a fraction isolated from shark cartilage: Shark cartilage modulates anti-tumor immunity. International Immunopharmacology. 2003; 3(7):921–6.[DOI:10.1016/S1567-5769(02)00255-2]
Shahrokhi S, Zuhair MH, Mohagheghi MA, Ghazanfari T, Ebtekar M. Shark cartilage modulates immune responses in stage III breast cancer patients. International Journal of Hematology-Oncology and Stem Cell Research. 2009; 3(3):21-8.
O’Dwyer PJ, Duffy MJ, O’Sullivan F, McDermott E, Losty P, O’Higgins NJ. CEA and CA 15-3 in primary and recurrent breast cancer. World Journal of Surgery. 1990; 14(5):562–5. [DOI:10.1007/BF01658788] [PMID]
Jäger W, Kissing A, Cilaci S, Melsheimer R, Lang N. Is an increase in CA 125 in breast cancer patients an indicator of pleural metastases? British Journal of Cancer. 1994; 70(3):493–5. [DOI:10.1038/bjc.1994.333] [PMID] [PMCID]
Papantoniou V, Tsiouris S, Koutsikos J, Ptohis N, Lazaris D, Zerva C. Increased serum carbohydrate antigen 19-9 in relapsed ductal breast carcinoma. Hellenic Journal of Nuclear Medicine. 2006; 9(1):36-8. [PMID]
Sarraf A, Ghazanfari T, Gharib B, Sedaghtsayar S, Shirvanian F, Faghihzadeh S , et al. Evaluation shark cartilage effect on Treated Invasive Ductal Carcinoma Patients (Unpublished).
Crespo-Ortiz MP, Wei MQ. Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug. Journal of Biomedicine and Biotechnology. 2012; 2012:1–18. [DOI:10.1155/2012/247597]
Noori S, Hassan ZM. Dihydroartemisinin shift the immune response towards Th1, inhibit the tumor growth in vitro and in vivo. Cellular Immunology. 2011; 271(1):67–72.[DOI:10.1016/j.cellimm.2011.06.008] [PMID]