Immunotherapy and gene therapy as novel treatments for cancer
AbstractThe immune system interacts closely with tumors during the disease development and progression to metastasis. This complex communication between the immune system and the tumor cells can prevent or promote tumor growth. New therapeutic approaches harnessing protective immunological mechanisms have recently shown very promising results. This is performed by blocking inhibitory signals or by activating immunological effector cells directly. Immune checkpoint blockade with monoclonal antibodies directed against the inhibitory immune receptors CTLA-4 and PD-1 has emerged as a successful treatment approach for patients with advanced melanoma. Ipilimumab is an anti-CTLA-4 antibody which demonstrated good results when administered to patients with melanoma. Gene therapy has also shown promising results in clinical trials, particularly, Herpes simplex virus (HSV)-mediated delivery of the HSV thymidine kinase (TK) gene to tumor cells in combination with ganciclovir (GCV) may provide an effective suicide gene therapy for destruction of glioblastomas, prostate tumors and other neoplasias by recruiting tumor-infiltrating lymphocytes into the tumor. Development of new treatment strategies or combination of available innovative therapies to improve cell cytotoxic T lymphocytes trafficking into the tumor mass and the production of inhibitory molecules blocking tumor tissue immunotolerance are crucial to improve the efficacy of cancer therapy.
- monoclonal antibody
- regulatory T cells
- gene therapy
Dzivenu OK, O’Donnell TJ. Cancer and the immune system: the vital connection. Cancer Research Institute: New York; 2003. Accesed: 30 September 2016. Available from: https://www.cancerresearch.org/patients/answers-and-support/vital-connection.
Finn O. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012; 23(Suppl 8): viii6-9.
Sathyanarayanan V, Neelapu S. Cancer immunotherapy: Strategies for personalization and combinatorial approaches. Mol Oncol. 2015; 9(10): 2043-53.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12(4): 252-64.
Amer MH. Gene therapy for cancer: present status and future perspective. Mol Cell Ther. 2014; 2: 27.
Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015; 35 (Suppl): S185-98.
Pennock GK, Chow LQ. The evolving role of immune checkpoint inhibitors in cancer treatment. Oncologist. 2015; 20(7): 812-22.
Jacobs J, Smits E, Lardon F, Pauwels P, Deschoolmeester V. Immune checkpoint modulation in colorectal cancer: What's new and what to expect. J Immunol Res. 2015; 2015: 158038.
Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape. Curr Opin Immunol. 2014; 27: 16-25.
Pandya PH, Murray ME, Pollok KE, Renbarger JL. The immune system in cancer pathogenesis: Potential therapeutic approaches. J Immunol Res. 2016; 2016:4273943.
Grivennikov SI1, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010; 140(6): 883-99.
Messerschmidt JL, Prendergast GC, Messerschmidt GL. How cancers escape immune destruction and mechanisms of action for the new significantly active immune therapies: Helping nonimmunologists decipher recent advances. Oncologist. 2016; 21(2): 233-43.
Palucka AK, Coussens LM. The basis of oncoimmunology. Cell. 2016; 164(6): 1233-47.
Zou W. Regulatory T cells, tumor immunity and immunotherapy. Nat Rev Immunol. 2006; 6(4): 295-07.
Takeuchi Y, Nishikawa H. Roles of regulatory T cells in cancer immunity. Int Immunol. 2016; 28(8): 401-09.
Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol. 2014; 27: 1-7.
Oleinika K, Nibbs RJ, Graham GJ, Fraser AR. Suppression, subversion and escape: The role of regulatory T cells in cancer progression. Clin Exp Immunol. 2013; 171(1): 36-45.
Pernot S, Terme M, Voron T, Colussi O, Marcheteau E, Tartour E, et al. Colorectal cancer and immunity: What we know and perspectives. World J Gastroenterol. 2014; 20(14): 3738-50.
Amin M, Lockhart AC. The potential role of immunotherapy to treat colorectal cancer. Expert Opin Investig Drugs. 2015; 24(3): 329-44.
Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008; 8(7): 523-32.
Guzmán-Flores JM, Portales-Pérez DP. Mecanismos de supresión de las células T reguladoras (Treg). Gac Med Mex. 2013; 149: 630-8.
Ren X, Ye F, Jiang Z, Chu Y, Xiong S, Wang Y. Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4+CD25+ regulatory T cells. Cell Death Differ. 2007; 14: 2076-84.
Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015; 33(17): 1974-82.
Iwai Y, Hamanishi J, Chamoto K, Honjo T. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci. 2017; 24(1): 26.
Ceeraz S, Nowak EC, Burns CM, Noelle RJ. Immune checkpoint receptors in regulating immune reactivity in rheumatic disease. Arthritis Res Ther. 2014; 16: 469.
Dyck L, Mills KHG. Immune checkpoints and their inhibition in cancer and infectious diseases. Eur J Immunol. 2017; 47(5):765-779.
27. Yuan J, Hegde PS, Clynes R, Foukas PG, Harari A, Kleen TO, et al. Novel technologies and emerging biomarkers for personalized cancer immunotherapy. J Immunother Cancer. 2016; 4:3-3.
28. Wolchok JD, Saenger Y. The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation. Oncologist. 2008; 13(Suppl l4): 2-9.
Gelao L, Criscitiello C, Esposito A, Goldhirsch A, Curigliano G. Immune checkpoint blockade in cancer treatment: A double-edged sword cross-targeting the host as an “Innocent bystander”. Toxins. 2014; 6(3): 914-33.
Grosso JF, Jure-Kunkel MN. CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun. 2013; 13:5.
Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol. 2001; 1(3): 220-28.
Pico YC, Choudhury A, Kiessling R. Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system. Trends Mol Med. 2015; 21(8): 482-91.
Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell. 2015; 27(4): 450-61.
Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PDL1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013; 19(19): 524-35.
Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: Similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016; 39(1): 98-106.
Callahan MK, Postow MA, Wolchok JD. Targeting T cell co-receptors for cancer therapy. Immunity. 2016; 44(5): 1069-78.
Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015; 33(10): 1191-6.
Hamanishi J, Mandai M, Matsumura N, Abiko K, Baba T, Konishi I. PD-1/PD-L1 blockade in cancer treatment: perspectives and issues. Int J Clin Oncol. 2016; 21: 462-73.
Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated Melanoma. N Engl J Med. 2015; 373(13): 1270-1.
Andrews A. Treating with checkpoint inhibitor. Figure $1 million per patient. Am Health Drug Benefits. 2015; 8: 9.
Blagosklonny MV. Prospective strategies to enforce selectively cell death in cancer cells. Oncogene. 2004; 23(16): 2967-75.
Karjoo Z, Chen X, Hatefi A. Progress and problems with the use of suicide genes for targeted cancer therapy. Adv Drug Deliv Rev. 2016; 99(Pt A): 113-128.
Wirth T, Yla-Herttuala S. Gene therapy used in cancer treatment. Biomedicines. 2014; 2(2): 149-62
Rooseboom M, Commandeur JN, Vermeulen NP. Enzyme-catalyzed activation of anticancer prodrugs. Pharmacol Rev. 2004; 56(1): 53-02.
Smee DF, Martin JC, Verheyden JP, and Matthews TR. Anti-herpesvirus activity of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine. Antimicrob Agents Chemother. 1983; 23(5): 676-82.
Ingemarsdotter CK, Poddar C, Mercier C, Patzel V, Lever AM. Expression of Herpes Simplex Virus thymidine kinase/ganciclovir by RNA trans-splicing induces selective killing of HIV-producing cells. Mol Ther Nucleic Acids. 2017; 7: 140-154.
Rojas-Martinez A, Wyde PR, Montgomery CA, Chen SH, Woo SL, Aguilar-Cordova E. Distribution, persistency, toxicity, and lack of replication of an E1A-deficient adenoviral vector after intracardiac delivery in the cotton rat. Cancer Gene Ther. 1998; 5(6): 365-70.
Duarte S, Carle G, Faneca H, de Lima MC, Pierrefite-Carle V. Suicide gene therapy in cancer: where do we stand now?. Cancer Lett. 2012; 324(2): 160-70.
Herman JR, Adler HL, Aguilar-Cordova E, Rojas-Martinez A, Woo S, Timme TL, et al. In situ gene therapy for adenocarcinoma of the prostate: a phase I clinical trial. Hum Gene Ther. 1999; 10(7): 1239-49.
Rojas-Martínez A, Manzanera AG, Sukin SW, Esteban-María J, González-Guerrero JF, Gomez-Guerra L, et al. Intraprostatic distribution and long term follow-up after AdV-tk + prodrug as neoadjuvant to surgery in patients with prostate cancer. Cancer Gene Ther. 2013; 20(11): 642-49.
Trask TW, Trask RP, Aguilar-Córdova E, Shine HD, Wyde PR, Goodman JC, et al. Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with recurrent malignant brain tumors. Mol Ther. 2000; 1(2): 195-03.
Zhao F, Tian J, An L, Yang K. Prognostic utility of gene therapy with herpes simplex virus thymidine kinase for patients with high-grade malignant gliomas: a systematic review and meta-analysis. J Neurooncol. 2014; 118(2): 239-46.
de Melo SM, Bittencourt S, Ferrazoli EG, da Silva CS, da Cunha FF, da Silva FH, et al. The anti-tumor effects of adipose tissue mesenchymal stem cell transduced with HSV-TK gene on U-87-driven brain tumor. PLoS One. 2015; 10(6): e0128922.
Hasenburg A, Fischer DC, Tong XW, Rojas-Martínez A, Nyberg-Hoffman C, Orlowska-Volk M, et al. Histologic and immunohistochemical analysis of tissue response to adenovirus-mediated herpes simplex thymidine kinase gene therapy of ovarian cancer. Int J Gynecol Cancer. 2002; 12(1): 66-73.
Rawlinson JW, Vaden K, Hunsaker J, Miller DF, Nephew KP. Adenoviral-delivered HE4-HSV-tk sensitizes ovarian cancer cells to ganciclovir. Gene Ther Mol Biol. 2013; 15: 120-130.
Tang W, He Y, Zhou S, Ma Y, Liu G. A novel Bifidobacterium infantis-mediated TK/GCV suicide gene therapy system exhibits antitumor activity in a rat model of bladder cancer. J Exp Clin Cancer Res. 2009; 28(1): 155.
Pan JG, Luo RQ, Zhou X, Han RF, Zeng GW. Potent antitumor activity of the combination of HSV-TK and endostatin by adeno-associated virus vector for bladder cancer in vivo. Clin Lab. 2013; 59(9-10): 1147-58.
Chen D, Tang Q. An experimental study on cervix cancer with combination of HSV-TK/GCV suicide gene therapy system and Co radiotherapy. BMC Cancer. 2010; 10: 609-20.
Abate DD, García LR, Sumoy L, Fillat C. Cell cycle control pathways act as conditioning factors for TK/GCV sensitivity in pancreatic cancer cells. Biochim Biophys Acta. 2010; 1803(10): 1175-85.
Aguilar LK, Shirley LA, Chung VM, Marsh CL, Walker J, Coyle W, et al. Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma. Cancer Immunol Immunother. 2015; 64(6): 727-36.
Zhu R, Chen D, Lin D, Lu F, Yin J, Li N. Adenovirus vector-mediated herpes simplex virus-thymidine kinase gene/ganciclovir system exhibits anti-tumor effects in an orthotopic hepatocellular carcinoma model. Pharmazie. 2014; 69(7): 547-52.
Ji N, Weng D, Liu C, Gu Z, Chen S, Guo Y, et al. Adenovirus-mediated delivery of herpes simplex virus thymidine kinase administration improves outcome of recurrent high-grade glioma. Oncotarget 2016; 7(4): 4369-4378.
Hassan W, Sanford MA, Woo SL, Chen SH, Hall SJ. Prospects for herpes-simplex-virus thymidine-kinase and cytokine gene transduction as immunomodulatory gene therapy for prostate cancer. World J Urol. 2000; 18(2): 130-35.
Kubo M, Satoh T, Tabata KI, Tsumura H, Iwamura M, Baba S, et al. Enhanced central memory cluster of differentiation 8+ and tumor antigen-specific T cells in prostate cancer patients receiving repeated in situ adenovirus-mediated suicide gene therapy. Mol Clin Oncol. 2015; 3(3): 515-21.
Barba D, Hardin J, Sadelain M, Gage, FH. Development of anti-tumor immunity following thymidine kinase-mediated killing of experimental brain tumors. Proc Natl Acad Sci U S A. 1994; 91(10): 348-52.
Cho HS, Lee HR, Kim MK. Bystander-mediated regression of murine neuroblastoma via retroviral transfer of the HSV-TK gene. J Korean Med Sci. 2004; 19(1): 107-12.
Aguilar LK, Guzik BW, Aguilar-Cordova E. Cytotoxic immunotherapy strategies for cancer: mechanisms and clinical development. J Cell Biochem. 2011; 112: 1969-77.
Wheeler LA, Manzanera AG, Bell SD, Cavaliere R, McGregor JM, Grecula JC, et al. Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma. Neuro Oncol. 2016; 18(8): 1137-45.
Ayala G, Satoh T, Li R, Shalev M, Gdor Y, Aguilar-Cordova E, et al. Biological response determinants in HSV-tk + ganciclovir gene therapy for prostate cancer. Mol Ther. 2006; 13(4): 716-28.
Gregory SM, Nazir SA, Metcalf JP. Implications of the innate immune response to adenovirus and adenoviral vectors. Future Virol. 2011; 6(3): 357-74.
Higashi K, Hazama S, Araki A, Yoshimura K, Iizuka N, Yoshino S, et al. A novel cancer vaccine strategy with combined IL-18 and HSV-TK gene therapy driven by the hTERT promoter in a murine colorectal cancer model. Int J Oncol. 2014; 45(4): 1412-20.
Boieri M, Ulvmoen A, Sudworth A, Lendrem C, Collin M, Dickinson AM, et al. IL-12, IL-15, and IL-18 pre-activated NK cells target resistant T cell acute lymphoblastic leukemia and delay leukemia development in vivo. Oncoimmunology. 2017; 6(3): e1274478.
Vile RG, Castleden S, Marshall J, Camplejohn R, Upton C, Chong H. Generation of an anti-tumour immune response in a non-immunogenic tumour: HSVtk killing in vivo stimulates a mononuclear cell infiltrate and a Th1-like profile of intratumoural cytokine expression. Int J Cancer. 1997; 71(2): 267-74.
Satoh T, Irie A, Egawa S, Baba S. In situ gene therapy for prostate cancer. Curr Gene Ther. 2005; 5(1): 111-9.
Gao Q, Chen C, Ji T, Wu P, Han Z, Fang H, et al. A systematic comparison of the anti-tumoural activity and toxicity of the three Adv-TKs. PLoS One. 2014; 9(4): e94050.
Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet. 2003; 4: 346-58
Shin SP, Seo HH, Shin JH, Park HB, Lim DP, Eom HS, et al. Adenovirus expressing both thymidine kinase and soluble PD1 enhances antitumor immunity by strengthening CD8 T-cell response. Mol Ther. 2013; 21(3): 688-95.
Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013; 13(4): 227-42.
Nirschl CJ, Drake CG. Molecular pathways: co-expression of immune checkpoint molecules: signaling pathways and implications for cancer immunotherapy. Clin Cancer Res. 2013; 19(18): 4917-24.
ClinicalTrials.gov. Disponible en http://clinicaltrials.gov. 2017. Accesed: Abril 2017..
The copy rights of the articles published in Colombia Médica belong to the Universidad del Valle. The contents of the articles that appear in the Journal are exclusively the responsibility of the authors and do not necessarily reflect the opinions of the Editorial Committee of the Journal. It is allowed to reproduce the material published in Colombia Médica without prior authorization for non-commercial use