Muhammad AH Khoiruddin, Yusi Windya Febriyanti, Nafia Amalia


Uveal Melanoma (UM) is the primary intraocular tumor most commonly found in adults. The combination of therapy, Brachytherapy, surgery, Tranpupillary Thermal Therapy (TTT), Proton Beam Theraphy has not produced satisfactory results. The discovery of HER2 receptors expressed by UM cells can be used as a specific antigen target for the treatment of CAR T-celss. However, the effectiveness of CAR T-cell immunotherapy in tumors results in immunosuppressive T cells caused by an increase in Programmed cell Death Ligand-1 (PD-L1). This literature review demonstrates the success of HER2-specific CART T Cells as UM therapeutic efforts capable of eliminating tumor cells. In addition, CRSPR / Cas9 PD-1 / PD-L1-blocking modified HER2-specific CAR T cells can be a gene innovation in UM sufferers. Further clinical trials are needed to prove the effectiveness of CRISPR / Cas9 PD-1 / PD-L1-Blocking modified HER2-specific CAR T Cells in the treatment of UM patients.

KeywordsUveal melanoma, CAR T cell, reseptor HER

Full Text:



Kranz B A, Dave N,Komatsubara K M, Marr B P, Carvajal R D. Uveal Melanoma : Epidemiology, Etiology, and Treatment of Primary Disease.Clinical Ophthalmology. 2017. 11:279-289

Singh A D, Turell M E, Topham A K. Uveal Melanoma : trends in incidence, treatment, and survival. Ophtalmology.2011.118:1881-1885

Damato E M, Damato B E. Detection and time to treatment uveal melanoma in United Kingdom : an Evaluation of 2.384 patients.Ophtalmology.2012.119(8): 1582-1589

Damato B. Progress in management of patients with Uveal Melanoma: the 2012 ashton lecturer.eye(land). 2012.26(9).1157-1172

Komatsubara K M. Carvajal R D. Immunotherapy for the treatment uveal melanoma : current status and emerging therapies.Curr Oncol Rep.2017.19:45

Park S J. Oh C M. Kim B W. Woo S J. Coo H. Park K H. National wide incidence of ocular melanoma in south korea by using the National Cancer Registry Database ( 1999-2011).Invest Opthalmol Vis Sci. 2015.56(8):4719-4724

Shields C L. Kaliki S. Livesey M. Association of ocular and oculodermal melanocytosis with the rate of uveal melanoma metastasis : analysis of 7872 consecutive eye. JAMA Ophtalmol. 2013.131(8):993-1003

Turell M, Saunthararajah Y, Triozi P. Recent advances in prognostication for uveal melanoma. Ophtalmol Int. 2012:45-48

Kuk D, Shoushtari A N, Barker C A. Prognosis of mucosal, uveal, acral, con acral cutaneous and unknown primary melanoma from the first metastasis.Oncologist. 2016. 21(7) : 848-854

Blum E S, Yang J, Komatsubara K M, Carvajal R D. Clinical management of uveal and conjuctival melanoma. Oncology .2016. 30:29-48

Mariani P, Piperno-Neumann S, Servois V. Surgical management of liver matastases from uveal melanoma : 16 years experience at the institute curie. Eur J Surg Oncol. 2009.35: 1192-1197

Shields C L, Kaliki S, Furuta M, Fulco E, Alarcon C, Shields J A. American Joint committee on cancer classification of uveal melanoma ( anatomic stage ) predict prognosis in 7.731 patients :the 2013 zimmerman lecturer. Ophtalmology. 2013.122(6):1180-1186

Kaliki S, Shields C L. Uveal Melanoma: relatively rare but deadly cancer. Eye 2016.:1-17

Moriarty J P, Borah B J, Foote R L, Pulido J S,Shah N D. Cost-Effectiveness of Proton Beam Therapy for Intraocular Melanoma.Plos One.2015. 10(5):1-14

Morgan RA, Johnson LA, Davis JL, Zheng Z, Woolard KD. Recognition of Glioma Stem Cells by Genetically Modified T Cells Targeting EGFRvIII and Development of Adoptive Cell Therapy for Glioma. Hum Gene Ther. 2012. 23:1043-1053

Forsberg E M V, Linberg M F, Jespersen H, Alsen S, Bagge R O, Donia M, Svane I M, Nilsson O, Ny L, Nilsson L M,Nilsson J A. HER2 CAR T cells eradicate uveal melanoma and T cells therapy-resistant human melanoma in Interleukin-2( IL-2 ) transgenic NOD/SCID Il-2 receptor knockout mice.American Association for Cancer Research Journal.2019

Topalian S L. Safety, Activity, and immune correlates of Anti-PD-1 antibody in cancer.The New England Journal of Medicine.2012.366:2443-2554

Su S. CRISPR-Cas9 mediated efficient PD-1 distruption on human primary T-Cells from cancer patient. Sci rep.2016

Chew W L. Immunity to CRISPR-Cas9 and Cas12 Therapeutic. Wiley interdiscip rev syst boil Med. 2018.10

Woodman S E. Metastatic Uveal Melanoma: Biology and Emerging Treatments.National Institure of health. 2012

Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Molecular biology Int. 2014

Yu S, Li A, Liu Q, Li T. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol.2017.10(1):78

Magee M S, Snook A E. Challenges to chimeric antigen receptor (CAR)-T cell Therapy for cancer. Discov Med.2014.18(100):265-271

Scholler J, Brady T L, Binder-Scholl G, Hwang W T. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells.sci transl Med.2012.4(132)

Park JH, Geyer MB, Brentjens RJ. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood. 2016; 127(26):33120-20.

Wang Z, Wu Z, Liu Y, Han W. New development in CAR-T cell therapy. J Hematol Oncol. 2017; 10(1):53.

Curran KJ, Seinstra BA, Nikhamin Y, Yeh R, et al. Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol Ther. 2015; 23(4):769-78.

Kerkar SP, Muranski P, Kaiser A, Boni A, et al. Tumor-specific CD8+ T cells expressing IL-12 eradicate established cancers in lymphodepleted hosts. Cancer Res. 2010; 70(17):6725- 6734

Textor A, Listopad JJ, Perez C, et al. Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNγ. Cancer Res. 2014; 74(23):6796-805.

L. Porter, B.L. Levine, M. Kalos,A Bagg, C.H. June, Chimeric antigen receptor modified T cells in chronic lymphoid leukemia, N. Engl. J. Med. 2011. 365 (8). 725–733.

J.N. Kochenderfer, W.H. Wilson, J.E. Janik, M.E. Dudley, M. Stetler- Stevenson, S.A. Feldman, et al., Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19, Blood 11. 2010. 4099–4102.

Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. Therapeutics and Clinical Risk Management. 2019:15 323–335 .

Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366: 2443-54.

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: 6580-7.

Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal. 2012; 5: ra46.

Sheppard K A, Fitz L J, Lee J M, Benander C, George J A, Wooters J, Qiu Y, Jussif J M, Carter L, Wood C R, Chaudhary D. PD-1 inhibits T- cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004; 574: 37-41

Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2015; 25: 9543-53.

Hu J, Sun C, Bernatchez C, et al. T cell homing therapy for reducing regulatory T cells and preserving effector T cell function in large solid tumors. Clin Cancer Res. 2018.

Oestreich KJ, Yoon H, Ahmed R, Boss JM. NFATc1 regulates PD-1 expression upon T cell activation. J Immunol. 2008; 181: 4832-9.

Fuguo jiang and Jennifer A. Doudna. CRISPR/Cas9 Structures and Mechanisms. 2017. Annu. Rev. Biophys. 46:505-29.

Garneau JE, Dupuis M` E, Villion M, Romero DA, Barrangou R, et al. 2010. The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA. Nature 468(7320):67–71

Gasiunas G, Barrangou R, Horvath P, Siksnys V. 2012. Cas9–crRNA ribonucleoprotein complex medi-ates specific DNA cleavage for adaptive immunity in bacteria. PNAS 109(39):E2579–86

Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. 2012. A programmable dualRNA– guided DNA endonuclease in adaptive bacterial immunity. Science 337(6096):816–21

Chen H, Choi J, Bailey S. 2014. Cut site selection by the two nuclease domains of the Cas9 RNA- guidedendonuclease. J. Biol. Chem. 289(19):13284–94

Zhang C, Peng Y, Hublitz P. Genetic abrogation of immune checkpoints in antigen-specific cytotoxic T- lymphocyte as a potential alternative to blockade immunotherapy. Scientific Repors. 2018. 8:5549.

Rupp LJ, Schumann K, Roybal K T, et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Scientific Reports. 2017. 7

DOI: https://doi.org/10.26618/aimj.v3i1.2745


  • There are currently no refbacks.

Copyright (c) 2019 Muhammad AH Khoiruddin, Yusi Windya Febriyanti, Nafia Amalia

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Flag Counter