Engineering CAR-T Cells for Improved Function Against Solid Tumors

Appleman, 2002, CD28 costimulation mediates down-regulation of p27kip1 and cell cycle progression by activation of the PI3K/PKB signaling pathway in primary human T cells, J Immunol., 168, 2729, 10.4049/jimmunol.168.6.2729

Baer, 2017, Src-family kinases negatively regulate NFAT signaling in resting human T cells, PLoS ONE, 12, e0187123, 10.1371/journal.pone.0187123

Steffen, 1988, Simultaneous production of tumor necrosis factor-alpha and lymphotoxin by normal T cells after induction with IL-2 and anti-T3, J Immunol., 140, 2621, 10.4049/jimmunol.140.8.2621

Teixeira, 2005, IFN-gamma production by CD8+ T cells depends on NFAT1 transcription factor and regulates Th differentiation, J Immunol., 175, 5931, 10.4049/jimmunol.175.9.5931

Shahrara, 2009, IL-17 induces monocyte migration in rheumatoid arthritis, J Immunol., 182, 3884, 10.4049/jimmunol.0802246

Raphael, 2015, T cell subsets and their signature cytokines in autoimmune and inflammatory diseases, Cytokine, 74, 5, 10.1016/j.cyto.2014.09.011

Porter, 2011, Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia, N Engl J Med., 365, 725, 10.1056/NEJMoa1103849

Grupp, 2013, Chimeric antigen receptor-modified T cells for acute lymphoid leukemia, N Engl J Med., 368, 1509, 10.1056/NEJMoa1215134

Maude, 2014, Chimeric antigen receptor T cells for sustained remissions in leukemia, N Engl J Med., 371, 1507, 10.1056/NEJMoa1407222

Kochenderfer, 2015, Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor, J Clin Oncol., 33, 540, 10.1200/JCO.2014.56.2025

Ali, 2016, T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma, Blood, 128, 1688, 10.1182/blood-2016-04-711903

Guo, 2016, CD138-directed adoptive immunotherapy of chimeric antigen receptor (CAR)-modified T cells for multiple myeloma, J Cell Immunother, 2, 28, 10.1016/j.jocit.2014.11.001

Turtle, 2016, Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells, Sci Transl Med, 8, 355ra116, 10.1126/scitranslmed.aaf8621

Berdeja, 2017, Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated Results from a multicenter study of bb2121 Anti-Bcma CAR T cell therapy, Blood, 130, 740, 10.1182/blood.V130.Suppl_1.740.740

Kochenderfer, 2017, Lymphoma remissions caused by Anti-CD19 chimeric antigen receptor T Cells are associated with high serum interleukin-15 levels, J Clin Oncol., 35, 1803, 10.1200/JCO.2016.71.3024

Kochenderfer, 2017, Long-duration complete remissions of diffuse large b cell lymphoma after Anti-CD19 chimeric antigen receptor T cell therapy, Mol Ther., 25, 2245, 10.1016/j.ymthe.2017.07.004

Schuster, 2017, Chimeric antigen receptor T cells in refractory B-cell lymphomas, N Engl J Med., 10.1056/NEJMoa1708566

Brudno, 2018, T cells genetically modified to express an Anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma, J Clin Oncol., 36, 2267, 10.1200/JCO.2018.77.8084

Maude, 2018, Tisagenlecleucel in children and young adults with B-cell Lymphoblastic Leukemia, N Engl J Med., 378, 439, 10.1056/NEJMoa1709866

Park, 2018, Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia, N Engl J Med., 378, 449, 10.1056/NEJMoa1709919

Bingle, 2002, The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies, J Pathol., 196, 254, 10.1002/path.1027

Xu, 2014, LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses, Cancer Res., 74, 3418, 10.1158/0008-5472.CAN-13-2690

Kyi, 2016, Immune checkpoint inhibitor combinations in solid tumors: opportunities and challenges, Immunotherapy, 8, 821, 10.2217/imt-2016-0002

Wherry, 2015, Molecular and cellular insights into T cell exhaustion, Nat Rev Immunol., 15, 486, 10.1038/nri3862

Querfeld, 2018, Primary T cells from cutaneous T-cell lymphoma skin explants display an exhausted immune checkpoint profile, Cancer Immunol Res., 10.1158/2326-6066.CIR-17-0270

Granier, 2017, Tim-3 expression on tumor-infiltrating PD-1(+)CD8(+) T cells correlates with poor clinical outcome in renal cell carcinoma, Cancer Res., 77, 1075, 10.1158/0008-5472.CAN-16-0274

Marcq, 2017, Abundant expression of TIM-3, LAG-3, PD-1 and PD-L1 as immunotherapy checkpoint targets in effusions of mesothelioma patients, Oncotarget, 8, 89722, 10.18632/oncotarget.21113

Singer, 2002, MMP-2 and MMP-9 expression in breast cancer-derived human fibroblasts is differentially regulated by stromal-epithelial interactions, Breast Cancer Res Treat, 72, 69, 10.1023/A:1014918512569

Zhao, 2012, Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer, Oncoimmunology, 1, 152, 10.4161/onci.1.2.18480

Feig, 2013, Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer, Proc Natl Acad Sci USA., 110, 20212, 10.1073/pnas.1320318110

Ligtenberg, 2016, Coexpressed catalase protects chimeric antigen receptor-redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity, J Immunol., 196, 759, 10.4049/jimmunol.1401710

Fleming, 2018, Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression, Front Immunol., 9, 398, 10.3389/fimmu.2018.00398

Liao, 2009, Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model, PLoS ONE, 4, e7965, 10.1371/journal.pone.0007965

Xing, 2010, Cancer associated fibroblasts (CAFs) in tumor microenvironment, Front Biosci., 15, 166, 10.2741/3613

Orimo, 2005, Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion, Cell, 121, 335, 10.1016/j.cell.2005.02.034

Wald, 2011, Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: role in non-small cell lung cancer tumor proliferation, J Thorac Cardiovasc Surg., 141, 1503, 10.1016/j.jtcvs.2010.11.056

Thomas, 2008, The chemokine receptor CXCR4 is expressed in pancreatic intraepithelial neoplasia, Gut, 57, 1555, 10.1136/gut.2007.143941

Iwasa, 2009, Expression of CXCR4 and its ligand SDF-1 in intestinal-type gastric cancer is associated with lymph node and liver metastasis, Anticancer Res., 29, 4751

Liu, 2009, Increased expression of SDF-1/CXCR4 is associated with lymph node metastasis of invasive micropapillary carcinoma of the breast, Histopathology, 54, 741, 10.1111/j.1365-2559.2009.03289.x

Liang, 2010, High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma, Cancer Epidemiol Biomarkers Prev., 19, 2598, 10.1158/1055-9965.EPI-10-0405

Meng, 2010, Expression of CXCR4 in oral squamous cell carcinoma: correlations with clinicopathology and pivotal role of proliferation, J Oral Pathol Med, 39, 63, 10.1111/j.1600-0714.2009.00801.x

Guo, 2011, Chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 correlate with lymph node metastasis in epithelial ovarian carcinoma, Chin J Cancer, 30, 336, 10.5732/cjc.010.10490

Huang, 2013, Expression of the CXCL12/CXCR4 and CXCL16/CXCR6 axes in cervical intraepithelial neoplasia and cervical cancer, Chin J Cancer, 32, 289, 10.5732/cjc.012.10063

Yu, 2014, Stromal cell-derived factor-1 (SDF-1)/CXCR4 axis enhances cellular invasion in ovarian carcinoma cells via integrin beta1 and beta3 expressions, Oncol Res., 21, 217, 10.3727/096504014X13907540404879

Guo, 2016, CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks, Oncogene, 35, 816, 10.1038/onc.2015.139

Oweida, 2018, Resistance to radiotherapy and PD-L1 blockade is mediated by TIM-3 upregulation and regulatory T-cell infiltration, Clin Cancer Res., 10.1158/1078-0432.CCR-18-1038

Kloss, 2018, Dominant-negative TGF-beta receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication, Mol Ther., 26, 1855, 10.1016/j.ymthe.2018.05.003

Deng, 2018, mTOR-mediated glycolysis contributes to the enhanced suppressive function of murine tumor-infiltrating monocytic myeloid-derived suppressor cells, Cancer Immunol Immunother., 67, 1355, 10.1007/s00262-018-2177-1

Lee, 2018, Matrix metalloproteinase-9 in monocytic myeloid-derived suppressor cells correlate with early infections and clinical outcomes in allogeneic hematopoietic stem cell transplantation, Biol Blood Marrow Transplant., 24, 32, 10.1016/j.bbmt.2017.08.017

Nenu, 2017, Lactate - A new frontier in the immunology and therapy of prostate cancer, J Cancer Res Ther., 13, 406, 10.4103/0973-1482.163692

Dolan, 2014, PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy, Cancer Control., 21, 231, 10.1177/107327481402100308

Noguchi, 2017, Temporally distinct PD-L1 expression by tumor and host cells contributes to immune escape, Cancer Immunol Res., 5, 106, 10.1158/2326-6066.CIR-16-0391

Perrotta, 2018, Nitric oxide generated by tumor-associated macrophages is responsible for cancer resistance to cisplatin and correlated with syntaxin 4 and acid sphingomyelinase inhibition, Front Immunol., 9, 1186, 10.3389/fimmu.2018.01186

Giavridis, 2018, CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade, Nat Med., 24, 731, 10.1038/s41591-018-0041-7

Sallusto, 2004, Central memory and effector memory T cell subsets: function, generation, and maintenance, Annu Rev Immunol., 22, 745, 10.1146/annurev.immunol.22.012703.104702

Gattinoni, 2017, T memory stem cells in health and disease, Nat Med., 23, 18, 10.1038/nm.4241

Sommermeyer, 2016, Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo, Leukemia, 30, 492, 10.1038/leu.2015.247

Priesner, 2016, Automated enrichment, transduction, and expansion of clinical-scale CD62L(+) T cells for manufacturing of gene therapy medicinal products, Hum Gene Ther., 27, 860, 10.1089/hum.2016.091

Sabatino, 2018, Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies, Blood, 128, 519, 10.1182/blood-2015-11-683847

Blaeschke, 2018, Induction of a central memory and stem cell memory phenotype in functionally active CD4(+) and CD8(+) CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19(+) acute lymphoblastic leukemia, Cancer Immunol Immunother., 67, 1053, 10.1007/s00262-018-2155-7

Zheng, 2018, PI3K orchestration of the in vivo persistence of chimeric antigen receptor-modified T cells, Leukemia, 32, 1157, 10.1038/s41375-017-0008-6

Araki, 2009, mTOR regulates memory CD8 T-cell differentiation, Nature, 460, 108, 10.1038/nature08155

Kim, 2012, Signal integration by Akt regulates CD8 T cell effector and memory differentiation, J Immunol., 188, 4305, 10.4049/jimmunol.1103568

Urak, 2017, Ex vivo Akt inhibition promotes the generation of potent CD19CAR T cells for adoptive immunotherapy, J Immunother Cancer, 5, 26, 10.1186/s40425-017-0227-4

Granier, 2017, Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer, ESMO Open, 2, e000213, 10.1136/esmoopen-2017-000213

Chen, 2013, Oncology meets immunology: the cancer-immunity cycle, Immunity, 39, 1, 10.1016/j.immuni.2013.07.012

Ferris, 2015, Immunology and immunotherapy of head and neck cancer, J Clin Oncol., 33, 3293, 10.1200/JCO.2015.61.1509

Ryser, 2017, High affinity anti-TIM-3 and anti-KIR monoclonal antibodies cloned from healthy human individuals, PLoS ONE, 12, e0181464, 10.1371/journal.pone.0181464

Kondo, 2018, Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway, Leukemia, 32, 960, 10.1038/leu.2017.304

Parry, 2005, CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms, Mol Cell Biol., 25, 9543, 10.1128/MCB.25.21.9543-9553.2005

Vidyarthi, 2018, TLR-3 stimulation skews M2 macrophages to M1 through IFN-alphabeta Signaling and restricts tumor progression, Front Immunol., 9, 1650, 10.3389/fimmu.2018.01650

Kuramitsu, 2015, Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses, Cancer Gene Ther., 22, 487, 10.1038/cgt.2015.47

Shaim, 2018, The CXCR4-STAT3-IL-10 leukemia and is modulated by lenalidomide, Front Immunol., 8, 1773, 10.3389/fimmu.2017.01773

Righi, 2011, CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer, Cancer Res., 71, 5522, 10.1158/0008-5472.CAN-10-3143

Li, 2018, AMD3100 augments the efficacy of mesothelin-targeted, immune-activating VIC-008 in mesothelioma by modulating intratumoral immunosuppression, Cancer Immunol Res., 6, 539, 10.1158/2326-6066.CIR-17-0530

Chen, 2015, CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice, Hepatology, 61, 1591, 10.1002/hep.27665

Zboralski, 2017, Increasing Tumor-Infiltrating T Cells through Inhibition of CXCL12 with NOX-A12 Synergizes with PD-1 Blockade, Cancer Immunol Res., 5, 950, 10.1158/2326-6066.CIR-16-0303

Long, 2016, Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas, Cancer Immunol Res., 4, 869, 10.1158/2326-6066.CIR-15-0230

Chuang, 2014, Serial low doses of sorafenib enhance therapeutic efficacy of adoptive T cell therapy in a murine model by improving tumor microenvironment, PLoS ONE, 9, e109992, 10.1371/journal.pone.0109992

Akbay, 2013, Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors, Cancer Discov., 3, 1355, 10.1158/2159-8290.CD-13-0310

Chen, 2015, Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation, J Thorac Oncol., 10, 910, 10.1097/JTO.0000000000000500

Azuma, 2014, Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer, Ann Oncol., 25, 1935, 10.1093/annonc/mdu242

Yasui, 2002, SATB1 targets chromatin remodelling to regulate genes over long distances, Nature, 419, 641, 10.1038/nature01084

Stephen, 2017, SATB1 expression governs epigenetic repression of PD-1 in tumor-reactive T cells, Immunity, 46, 51, 10.1016/j.immuni.2016.12.015

Bae, 2018, Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors, Leukemia, 10.1038/s41375-018-0062-8

Vo, 2009, Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824, Cancer Res., 69, 8693, 10.1158/0008-5472.CAN-09-1456

Hudecek, 2015, The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity, Cancer Immunol Res., 3, 125, 10.1158/2326-6066.CIR-14-0127

Watanabe, 2016, Fine-tuning the CAR spacer improves T-cell potency, Oncoimmunology, 5, e1253656, 10.1080/2162402X.2016.1253656

Guedan, 2018, Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation, JCI Insight, 10.1172/jci.insight.96976

Kebriaei, 2016, Phase I trialls using Sleeping Beauty to generate CD19-specific CAR T cells, J Clin Invest., 126, 3363, 10.1172/JCI86721

Engels, 2003, Retroviral vectors for high-level transgene expression in T lymphocytes, Hum Gene Ther., 14, 1155, 10.1089/104303403322167993

Gomes-Silva, 2017, Tonic 4-1BB costimulation in chimeric antigen receptors impedes T Cell survival and is vector-dependent, Cell Rep., 21, 17, 10.1016/j.celrep.2017.09.015

Long, 2015, 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors, Nat Med., 21, 581, 10.1038/nm.3838

Dull, 1998, A third-generation lentivirus vector with a conditional packaging system, J Virol., 72, 8463, 10.1128/JVI.72.11.8463-8471.1998

Schambach, 2000, Context dependence of different modules for posttranscriptional enhancement of gene expression from retroviral vectors, Mol Ther., 2, 435, 10.1006/mthe.2000.0191

Schambach, 2006, Equal potency of gammaretroviral and lentiviral SIN vectors for expression of O-6-methylguanine-DNA methyltransferase in hematopoietic cells, Mol Ther., 13, 391, 10.1016/j.ymthe.2005.08.012

Gentner, 2012, Exploiting microRNA regulation for genetic engineering, Tissue Antigens, 80, 393, 10.1111/tan.12002

Wu, 2015, Remote control of therapeutic T cells through a small molecule-gated chimeric receptor, Science, 350, aab4077, 10.1126/science.aab4077

Newick, 2016, Augmentation of CAR T-cell trafficking and antitumor efficacy by blocking protein kinase a localization, Cancer Immunol Res., 4, 541, 10.1158/2326-6066.CIR-15-0263

Hale, 2017, Homology-directed recombination for enhanced engineering of chimeric antigen receptor T cells, Mol Ther Methods Clin Dev., 4, 192, 10.1016/j.omtm.2016.12.008

Qasim, 2017, Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells, Sci Transl Med., 9, eaaj2013, 10.1126/scitranslmed.aaj2013

Ren, 2017, A versatile system for rapid multiplex genome-edited CAR T cell generation, Oncotarget, 8, 17002, 10.18632/oncotarget.15218

Hou, 2015, Genome editing of CXCR4 by CRISPR/cas9 confers cells resistant to HIV-1 infection, Sci Rep, 5, 15577, 10.1038/srep15577

Schumann, 2015, Generation of knock-in primary human T cells using Cas9 ribonucleoproteins, Proc Natl Acad Sci USA., 112, 10437, 10.1073/pnas.1512503112

Chmielewski, 2011, IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively Muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression, Cancer Res., 71, 5697, 10.1158/0008-5472.CAN-11-0103

Chmielewski, 2015, TRUCKs: the fourth generation of CARs, Expert Opin Biol Ther, 15, 1145, 10.1517/14712598.2015.1046430

Carroll, 2008, Distinct effects of IL-18 on the engraftment and function of human effector CD8 T cells and regulatory T cells, PLoS ONE, 3, e3289, 10.1371/journal.pone.0003289

Hu, 2017, Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18, Cell Rep., 20, 3025, 10.1016/j.celrep.2017.09.002

Chmielewski, 2017, CAR T Cells Releasing IL-18 Convert to T-Bet(high) FoxO1(low) effectors that exhibit augmented activity against advanced solid tumors, Cell Rep., 21, 3205, 10.1016/j.celrep.2017.11.063

Liu, 2016, A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T Cells in advanced solid tumors, Cancer Res., 76, 1578, 10.1158/0008-5472.CAN-15-2524