Chimeric Antigen Receptor T Cell Immunotherapy for Tumor: A Review of Patent Literatures

Author(s): Manxue Fu, Liling Tang*

Journal Name: Recent Patents on Anti-Cancer Drug Discovery

Volume 14 , Issue 1 , 2019

Become EABM
Become Reviewer


Background: Chimeric Antigen Receptor (CAR) T cell immunotherapy, as an innovative method for tumor immunotherapy, acquires unprecedented clinical outcomes. Genetic modification not only provides T cells with the antigen-binding function but also endows T cells with better immunological functions both in solid and hematological cancer. However, the CAR T cell therapy is not perfect because of several reasons, such as tumor immune microenvironment, and autologous limiting factors of CAR T cells. Moreover, the safety of CAR T cells should be improved.

Objective: Recently many patents and publications have reported the importance of CAR T cell immunotherapy. Based on the patents about CAR T cell immunotherapy, we conclude some methods for designing the CAR which can provide information to readers.

Methods: In this review, we collect recent patents and publications, summarize some specific antigens for oncotherapy from patents and enumerate some approaches to conquering immunosuppression and reinforcing the immune response of CAR T cells. We also sum up some strategies for improving the safety of CAR T cell immunotherapy.

Results: CAR T cell immunotherapy as a neotype cellular immunotherapy has been proved effective in oncotherapy and authorized by FDA. Improvements in CAR designing enhance functions of CAR T cells.

Conclusion: This review, summarizing antigens and approaches to overcome defects of CAR T cell immunotherapy from patents and publications, might contribute to a broad readership.

Keywords: Antigen, CAR T cells, efficiency, immune checkpoints, immune therapy, safety.

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65(2): 87-108.
Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 2016; 66(4): 271-89.
Ansiaux R, Dewever J, Grégoire V, Feron O, Jordan BF, Gallez B. Decrease in tumor cell oxygen consumption after treatment with vandetanib (ZACTIMA; ZD6474) and its effect on response to radiotherapy. Radiat Res 2009; 172(5): 584-91.
Zhou QP, Guo JM, Gallo P. Impact of angiogenesis inhibition by sunitinib on tumor distribution of temozolomide. Clin Cancer Res 2008; 14(5): 1540-9.
Miller KD, Sweeney CJ, Sledge GW Jr. Redefining the target: Chemotherapeutics as antiangiogenics. J Clin Oncol 2001; 19(4): 1195-206.
Malissen B, P. Bongrand. Early T cell activation: Integrating biochemical, structural, and biophysical cues. Annu Rev Immunol 2015; 33: 539-61.
Ramos CA, Savoldo B, Dotti G. CD19-CAR trials. Cancer J 2014; 20(2): 112-8.
Sadelain M. CD19 CAR T Cells. Cell 2017; 171(7): 1471-8.
Zhang WY, Wang Y, Guo YL, Dai HR, Yang QM, Zhang YJ, et al. Treatment of CD20-directed Chimeric Antigen Receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: An early Phase IIa trial report. Signal Transduct Target Ther 2016; 1: 16002-9.
Lo AS, Xu C, Murakami A, Marasco WA. Regression of established renal cell carcinoma in nude mice using lentivirus-transduced human T cells expressing a human anti-CAIX chimeric antigen receptor. Mol Ther Oncolytics 2014; 1: 14003-8.
Sadelain M, Brentjens R, Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov 2013; 3(4): 388-98.
Kakarla S, Gottschalk S. CAR T cells for solid tumors: armed and ready to go? Cancer J 2014; 20(2): 151-5.
Epstein AL, Hu PS, Pinski JK. CAR T-cell therapy directed to LHR for the treatment of solid tumors. AU2016243124 (2017)
Li HS. Anti-robo1 CAR-T cell, and preparation and application thereof. WO2017181552 (2017)
Jiang JT, Lu BF, Chen YA, Chen LJ. CEA.CAR-T (carcinoembryonic antigen.chimeric antigen receptor-T) and preparation method and application thereof. CN107056952 (2017)
Rehm A, Höpken UE, Bluhm J, Uckert W, Kieback E, Marino S. Chimeric antigen receptor and CAR-T cells that bind BCMA. WO2017211900 (2017)
Balyasnikova IV, Lesniak MS, Gottschalk SMG. CAR Tcells recognizing cancer-specific IL13Rα2. WO2016123143 (2016)
Liu WB. Anti-MUC1 CAR-T cell and its preparation method and application. CN107227299 (2017)
Zeng XZ, Zhang Y. CAR-T cell as well as preparation method and application thereof. CN106047817 (2016)
Qi W, Yu L, Ou HG. Mesothelin-targeted replication-defective recombinant lentivirus CAR-T transgenic carrier as well as establishment method and application thereof. CN105969805 (2016)
Qi W, Yu L, Ou HG. CD 30-targeting replication-defective recombinant lentivirus CAR-T transgenic vector as well as construction method and applications thereof. CN105950663 (2016)
Zhou X. CAR-T cell preparation for treating prostatic cancer and preparation method thereof. CN105640991 (2016)
Liu WB. Anti AFP (alpha-fetoprotein) CAR-T (chimeric antigen receptor T) cell, preparation method thereof and application of cell. CN107254447 (2017)
Brogdon J, Gill S, Glass D, et al. Porter. D.L., Ruella, M., Wang, Yq., Wu, Q.L., Zhang, J.Q. Treatment of cancer using a CD123 chimeric antigen receptor. US 20160068601 In: (2016)
Ebersbach HE, Huber T, Jascur J, et al. Treatment of cancer using a CD33 chimeric antigen receptor. US20160096892 (2016)
Morgan RA, Rosenberg SA. Anti-epidermal growth factor receptor variant III chimeric antigen receptors and use of same for the treatment of cancer. US20160200819 (2016)
Rosenberg SA, Chinnasamy D. Anti-vascular endothelial growth factor receptor-2 chimeric antigen receptors and use of same for the treatment of cancer. US20130225668 (2013)
Leong SR, Liang WC, Wu Y, Crocker L, Cheng E, Sampath D, et al. An anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer. Mol Pharm 2015; 12(6): 1717-29.
Epstein AL, Hu PS. CAR T-cells for the treatment of B7-H4 expressing solid tumors. AU2016243126 (2017).
Loumagne L, Baudhuin J, Favier B, Montespan F, Carosella ED, Rouas-Freiss N. In vivo evidence that secretion of HLA-G by immunogenic tumor cells allows their evasion from immunosurveillance. Int J Cancer 2014; 135(9): 2107-17.
Epstein AL, Hu PS. HLA-G as a novel target for CAR T-cell immunotherapy. CA2981166 (2016)
Pulé M, Anderson J, Thomas S. Chimeric antigen receptor. WO2015132604 (2018)
Tamada K, Sakoda Y, Ishizaki H. Chimeric antigen receptor. WO2018181207 (2018)
Bicknell R, Lee S, Mount N, Sharpe M. Chimeric antigen receptor. AU2017232431 (2018)
Dai HJ, Zhang Z, Li XL, Zhou J, Zhao XD, Xiong B. Specific chimeric antigen receptor targeting NKG2DL and CAR-T cell thereof and use thereof. WO2018165913 (2018)
Dotti G, Ferrone S. CSGP4-specific chimeric antigen receptor for cancer. US2018251568 (2018)
Yao YH, Huang JQ, Zhu SG, et al. Construction of chimeric antigen receptor targeting cd20 antigen and activity identification of engineered t cells thereof. WO2018145649 (2018)
Yang L, Zhang P. Targeted CSF1R chimeric antigen receptor modified NK92MI cell, T cell, and preparation method and application of cells. CN108276495 (2018)
Wang YS, Wei YQ, Guo FC, Wang W. Chimeric antigen receptor modified lymphocyte capable of expressing CXCR4, and preparation method and applications thereof. CN108277205 (2018)
Mamonkin M, Brenner MK. CD5 chimeric antigen receptor for adoptive T cell therapy. US2018104308 (2018)
Muta H, Podack ER. CD30: From basic research to cancer therapy. Immunol Res 2013; 57(1-3): 151-8.
Wang CM, Wu ZQ, Wang Y, Guo YL, Dai HR, Wang XH, et al. Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory hodgkin lymphoma: An open-label Phase I trial. Clin Cancer Res 2017; 23(5): 1156-66.
Ao JY, Chai ZT, Zhang YY, Zhu XD, Kong LQ, Zhang N, et al. Robo1 promotes angiogenesis in hepatocellular carcinoma through the Rho family of guanosine triphosphatases signaling pathway. Tumour Biol 2015; 36(11): 8413-24.
Liang AB, Liu J, Sun Y, et al. Multi-target combined CAR (chimeric antigen receptor)-T cell preparation and preparation method. CN106822184 (2017).
Zhu FL, Liu XM. Transformation, multiplication culture and preservation method for T cell for expressing CD19 and CD20 antibody gene CAR (chimeric antigen receptor). CN106701827 (2017).
Zhou X. CAR-T cell preparation for treating breast cancer and preparation method thereof. CN105640990 (2016).
O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 2017; 9(399)
Ghoneim HE, Zamora AE, Thomas PG, Youngblood BA. Cell-intrinsic barriers of T cell-based immunotherapy. Trends Mol Med 2016; 22(12): 1000-11.
Boussiotis VA, Chatterjee P, Li L. Biochemical signaling of PD-1 on T cells and its functional implications. Cancer J 2014; 20(4): 265-71.
Serganova I, Moroz E, Cohen I, Moroz M, Mane M, Zurita J, et al. Enhancement of PSMA-directed CAR adoptive immunotherapy by PD-1/PD-L1 Blockade. Mol Ther Oncolytics 2017; 4: 41-54.
Hyun TL, Ju YL, Heejin L, Sang HL, Yu JM, Hyo JP, et al. Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab. Sci Rep 2017; 7(1): 5532.
Condomines M, Arnason J, Benjamin R, Gunset G, Plotkin J, Sadelain M. Tumor-targeted human T cells expressing CD28-based chimeric antigen receptors circumvent CTLA-4 inhibition. PLoS One 2015; 10(6): e0130518.
Shang XY, Zhang LL, Li G. Preparation of PD-1 knocked-out CD19 CAR (Chimeric Antigen Receptor)-T cell. CN107119021 (2017).
Rupp LJ, Schumann K, Roybal KT, Gate RE, Ye CJ, Lim WA, et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci Rep 2017; 7(1): 75-86.
Dai HJ, Li XL, Sun B, Zhang Z, Zhao XD, Xiong B. Method for knocking out PD-1 gene by utilizing CRISPR/Cas9 technology to construct MSLN-targeted novel CAR-T cell and application of method. CN106480097 (2017)
Li HS. PD-1 CAR-T cell, preparation method therefor, and application thereof. WO2017177575 (2017)
Shi WX, Yang CX, Du Y, Fang YS. Anti-PD-L1-CAR-T, and preparation method and application thereof. CN106350533 (2016)
Xin BC. Application of CAR-T cell carrying PD-L1 and CTLA-4 antibody genes in tumor immunology. CN105796597 (2017)
Suarez ER, Chang K, Sun J, Sui J, Freeman GJ, Signoretti S, et al. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 2016; 7(23): 34341-55.
Qi W, Yu L, Kang LQ, Lin GW, Yu Z. OCTS-CAR doubletargeting chimeric antigen receptor, coding gene, recombinant expression vector and establishment and application of OCTS-CAR double-targeting chimeric antigen receptor, coding gene and recombinant expression vector. CN107337736 (2017)
Qi W, Yu L, Kang LQ, Lin GW, Yu Z. OCTS technologybased prostatic cancer CAR-T therapy vector and construction method and application thereof. CN107164410 (2017)
Qi W, Yu L, Kang LQ, Lin GW, Yu Z. PSCA (prostate stem cell antigen) and PD-L1 targeted CAR based on OCTS (one CAR with two ScFvs)-CAR (chimeric antigen receptor), encoding gene and expression vector. CN107325185 (2017)
Qi W, Yu L, Kang LQ, Lin GW, Yu Z. OCTS (One CAR (Chimeric Antigen Receptor) with two ScFvs (Single-chain variable Fragments)) technique based CAR-T (Chimeric Antigen Receptor- T cell immunotherapy) therapeutic vector for glioblastoma and construction method and application thereof CN107267555 (2017)
Qi W, Yu L, Kang LQ, Lin GW, Yu Z. Lymphoblastic leukemia CAR-T (chimeric antigen receptor T cell immunotherapy) therapy carrier based on OCTS (One CAR with Two SeFvs) technology as well as constructing method and application of lymphoblastic leukemia CAR-T therapy carrier CN107245500 (2017)
Qi W, Yu L, Kang LQ, Lin GW, Yu Z. Myeloid leukemia CAR-T treatment carrier based on OCTS technology and construction method and application of myeloid leukemia CAR-T treatment carrier. CN107177632 (2017)
Qi W, Yu L, Kang LQ, Lin GW, Yu Z. OCTS technology-based pancreatic cancer and malignant mesothelioma CAR-T therapy vector, as well as construction method and application thereof CN107299110 (2017).
Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 2015; 15(8): 486-99.
Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 2015; 21(6): 581-90.
Chang ZL, Chen YY. CARs: Synthetic Immunoreceptors for Cancer Therapy and Beyond. Trends Mol Med 2017; 23(5): 430-50.
Barrett DM, Singh N, Porter DL, Grupp SA, June CH. Chimeric antigen receptor therapy for cancer. Annu Rev Med 2014; 65: 333-47.
Zhao YB, Shedlock D, June CH, Liu XJ. Enhanced antigen presenting ability of RNA CAR T cells by co-introduction of costimulatory molecules. US2016340406 (2016)
Jensen MC, Riddell SR. Designing chimeric antigen receptors to effectively and safely target tumors. Curr Opin Immunol 2015; 33: 9-15.
Natsume A, Kuramitsu S, Ohno M. Uses of lenalidomide and CAR T-cells. WO2017176289 (2017)
Qi W, Yu Z, Kang LQ, Yu L. CAR-T cells with inhibited sterol o-acyltransferase 1 (SOAT1) as well as preparation method and application of CAR-T (Chimeric Antigen Receptor-T-cell Immunotherapy) cells. CN107058232 (2017)
Ichiyama K, Chen T, Wang X, Yan X, Kim BS, Tanaka S, et al. The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity 2015; 42(4): 613-26.
Motz G, Bushman FD, Fraietta JA, et al. CAR T cell therapies with enhanced efficacy. WO2017049166 (2017)
Sahin U, Reinhard K, Simon P, Mroz KA, Hobohm K. Enhancing the effect of CAR-engineered T cells by means of nucleic acid vaccination. CA2985156 (2016)
Tamada K, Sakoda Y, Adachi K. CAR expression vector and car-expressing t cells. PH12017500596 (2017)
Berdel W, Rossig C, Schliemann C, Altvater B, Kailayangiri S. Combination therapy comprising an inflammatory immunocytokine and a chimeric antigen receptor (CAR)-T cell. AU2017249694 (2017)
Shang XY. Preparation method of CD19 CAR-T cell secreting IL- 12. CN106916789 (2017)
Sun XL, Li X. CAR-T cytotoxicity indicating vector. CN106086078 (2016)
Zhang QX, Wang H, Du X, Chen WH. TaqMan real-time fluorescent quantitative PCR kit for detecting peripheral blood CAR (Chimeric Antigen Receptor)-T cells. CN106399550 (2017)
Lu XA, He T, Ma L. Capture probe for detecting CAR-T cell, method for detecting cell content, and application. WO2017133222 (2017)
Liu DF. Quality of immunological synapse predicts effectiveness of chimeric antigen receptor (CAR) T cells. US2018231523 (2018)
Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 2012; 119(12): 2709-20.
Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 2014; 6(224): 224-9.
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124(2): 188-95.
Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: Recognition and management. Blood 2016; 127(26): 3321-30.
Wu LJ, Golubovskaya V, Lewis M, Zhou H. FLAG tagged CD19-CAR-T cells. WO2017172952 (2017)
Qi W, Kang LQ, Yu L, Xia RH. siRNA of humanized interleukin 6, recombination expression carrier CAR-T and construction method and application of recombination expression carrier CART. CN106636090 (2017)
Zhou X. CAR-T cell preparation for treating breast cancer and preparation method thereof. CN105640990 (2016)
Zhang YD, Li XG, Xie HT. Preparation method of universal heterologous CAR-T cells and application. CN106591363 (2017)
He T, Lu XA, You YN, Hu XL. Universal type CAR-T cell, and preparation method and application thereof. CN106544321 (2017)
Dong J, Yang Y, Liu YZ, Xiong W, Cai M. Do you detect car T cell IFN paper ELISA kit of gamma release? CN205861688 (2017).
Dong J, Yang Y, Liu YZ, Xiong W, Cai M. Do you detect car T cell IL 2 ELISA kit of release? CN205786667 (2016)
Low PS, Chu HY, Lee YGU. Methods and compositions for CAR T cell therapy. WO2017177149 (2017)
Anderson J, Fisher J, Pule M, Gustafsson K. T cell which expresses a gamma-delta T cell receptor (TCR) and a chimeric antigen receptor (CAR). CA2982532 (2016)
Jiang S, Ji XL, Yun Z, Luo CX. Double chimeric antigen receptor (CAR) modified T lymphocyte and preparation method thereof. CN105087495 (2015)
Stassinopoulos A, Greenman WM. Compositions and methods for improved car-t cell therapies. US2017354724 (2017)
Choi K, Park H, Lee JE, et al. Chimeric antigen receptor to which anti-cotinine antibody is linked, and use thereof. US2018256744 (2018)
Tan Y, Zhang HH. CD19-CAR-T cell carrying iCasp9 suicide gene and use thereof. CN107365798 (2017)
Qian QJ, Jin HJ, Li LF, et al. Molecular brake for rapidly stopping killing effect of CAR-T (T cell engineered with chimeric antigen receptors) and application of molecular brake. CN105330750 (2016)
Terakura S, Yamamoto TN, Gardner RA, Turtle CJ, Jensen MC, Riddell SR. Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. Blood 2012; 119(1): 72-82.
Zhang WF, Wu FL, Shao HW, Wang T, Huang XT, Li WL, et al. Chimeric adenoviral vector Ad5F35L containing the Ad5 natural long-shaft exhibits efficient gene transfer into human T lymphocytes. J Virol Methods 2013; 194(1-2): 52-9.
John LB, Chee TM, Gilham DE, Darcy PK. Genetic modification of mouse effector and helper T lymphocytes expressing a chimeric antigen receptor. Methods Mol Biol 2014; 1139: 177-87.
Sun XL, Li X, Xu H. Method for qualitatively detecting pollution of VSVG sequence in CAR-T product. CN106086235 (2016)
Xiong B. Method for preparing CAR-T cell by CRISPR/Cas9. CN104894068 (2015)
Zhang C, Zhang Y, Liu XM, Zhang YL. Method for sitespecific integration of CAR gene to AAVS1 site of T cell based on double-strand micro carrier. CN105524943 (2016)
Kelly K, Slukvin I. Method for treating a side effect of chimeric antigen receptor (CAR) T cell therapy. WO2018184074 (2016)
Blazar B, Flynn RP, Pennell CA. Chimeric antigen receptor (CAR) T cells as therapeutic interventions for auto- and alloimmunity. US2018264038 (2018)
Wagner T, Scharenberg AM, Rawlings DJ, Sather B, Sahni J. Ccr5 disruption of cells expressing anti-hiv chimeric antigen receptor (CAR) derived from broadly neutralizing antibodies. US2017044240 (2017)
Zhang TC, Hu G, Gu CJ, et al. Recombinant gene construction of chimeric antigen receptor (CAR) for treating HIV (human immunodeficiency virus) infection and application of chimeric antigen receptor. CN107098969 (2017)
Zhen A, Peterson CW, Carrillo MA, Reddy SS, Youn CS, Lam BB, et al. Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV / AIDS. PLoS Pathog 2017; 13(12): e1006753.
MacDonald KG, Hoeppli RE, Huang Q, Gillies J, Luciani DS, Orban PC, et al. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J Clin Invest 2016; 126(4): 1413-24.

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 13 March, 2019
Page: [60 - 69]
Pages: 10
DOI: 10.2174/1574892814666190111120908

Article Metrics

PDF: 95
HTML: 22
PRC: 3