Driving CARs on the uneven road of antigen heterogeneity in solid tumors

Sadelain, 2013, The basic principles of chimeric antigen receptor design, Cancer Discov, 3, 388, 10.1158/2159-8290.CD-12-0548 Thistlethwaite, 2017, The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity, Cancer Immunol Immunother, 10.1007/s00262-017-2034-7 Zhong, 2010, Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication, Mol Ther, 18, 413, 10.1038/mt.2009.210 Zhang, 2013, Inhibition of TGF-beta signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy, Gene Ther, 20, 575, 10.1038/gt.2012.75 Cherkassky, 2016, Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition, J Clin Invest, 126, 3130, 10.1172/JCI83092 Fedorov, 2013, PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses, Sci Transl Med, 5, 215ra172, 10.1126/scitranslmed.3006597 Hegde, 2016, Tandem CAR T cells targeting HER2 and IL13Ralpha2 mitigate tumor antigen escape, J Clin Invest, 126, 3036, 10.1172/JCI83416 Rodgers, 2016, Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies, Proc Natl Acad Sci U S A, 113, E459, 10.1073/pnas.1524155113 Ma, 2016, Versatile strategy for controlling the specificity and activity of engineered T cells, Proc Natl Acad Sci U S A, 113, E450, 10.1073/pnas.1524193113 Morello, 2016, Mesothelin-targeted CARs: driving T cells to solid tumors, Cancer Discov, 6, 133, 10.1158/2159-8290.CD-15-0583 Kiesgen, 2017, Chimeric antigen receptor (CAR) T-cell therapy for thoracic malignancies, J Thorac Oncol Suzuki, 2013, Clinical impact of immune microenvironment in stage I lung adenocarcinoma: tumor interleukin-12 receptor beta2 (IL-12Rbeta2), IL-7R, and stromal FoxP3/CD3 ratio are independent predictors of recurrence, J Clin Oncol, 31, 490, 10.1200/JCO.2012.45.2052 Kadota, 2015, Prognostic impact of immune microenvironment in lung squamous cell carcinoma: tumor-infiltrating CD10+ neutrophil/CD20+ lymphocyte ratio as an independent prognostic factor, J Thorac Oncol, 10, 1301, 10.1097/JTO.0000000000000617 Zeltsman, 2017, CAR T-cell therapy for lung cancer and malignant pleural mesothelioma, Transl Res, 187, 1, 10.1016/j.trsl.2017.04.004 DeSelm, 2017, CAR T-cell therapy for pancreatic cancer, J Surg Oncol, 116, 63, 10.1002/jso.24627 Smith, 2017, Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors, J Clin Invest, 127, 2176, 10.1172/JCI87624 Lo, 2015, Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells, Cancer Res, 75, 2800, 10.1158/0008-5472.CAN-14-3041 Caruana, 2015, Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes, Nat Med, 21, 524, 10.1038/nm.3833 Wang, 2017, Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors, Clin Cancer Res Stromnes, 2015, T cells engineered against a native antigen can surmount immunologic and physical barriers to treat pancreatic ductal adenocarcinoma, Cancer Cell, 28, 638, 10.1016/j.ccell.2015.09.022 Mohammed, 2017, Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer, Mol Ther, 25, 249, 10.1016/j.ymthe.2016.10.016 Feng, 2016, Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer, Sci China Life Sci, 59, 468, 10.1007/s11427-016-5023-8 Beatty, 2014, Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce antitumor activity in solid malignancies, Cancer Immunol Res, 10.1158/2326-6066.CIR-13-0170 Feng, 2017, Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers, Protein Cell Kachala, 2014, Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma, Clin Cancer Res, 20, 1020, 10.1158/1078-0432.CCR-13-1862 Heinmoller, 2003, HER2 status in non-small cell lung cancer: results from patient screening for enrollment to a phase II study of herceptin, Clin Cancer Res, 9, 5238 Situ, 2011, Expression and prognostic relevance of MUC1 in stage IB non-small cell lung cancer, Med Oncol, 28, S596, 10.1007/s12032-010-9752-4 Kawaguchi, 2010, Clinical significance of prostate stem cell antigen expression in non-small cell lung cancer, Jpn J Clin Oncol, 40, 319, 10.1093/jjco/hyp181 Ali, 2014, Expression of KOC, S100P, mesothelin and MUC1 in pancreatico-biliary adenocarcinomas: development and utility of a potential diagnostic immunohistochemistry panel, BMC Clin Pathol, 14, 35, 10.1186/1472-6890-14-35 Argani, 2001, Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE), Clin Cancer Res, 7, 3862 Pak, 2012, Significance of EpCAM and TROP2 expression in non-small cell lung cancer, World J Surg Oncol, 10, 53, 10.1186/1477-7819-10-53 Anurathapan, 2014, Kinetics of tumor destruction by chimeric antigen receptor-modified T cells, Mol Ther, 22, 623, 10.1038/mt.2013.262 Song, 2016, Effective adoptive immunotherapy of triple-negative breast cancer by folate receptor-alpha redirected CAR T cells is influenced by surface antigen expression level, J Hematol Oncol, 9, 56, 10.1186/s13045-016-0285-y Chen, 2013, Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation, Sci Rep, 3, 1870, 10.1038/srep01870 Valitutti, 1995, Serial triggering of many T-cell receptors by a few peptide-MHC complexes, Nature, 375, 148, 10.1038/375148a0 Alvarez-Vallina, 1999, Efficient discrimination between different densities of target antigen by tetracycline-regulatable T bodies, Hum Gene Ther, 10, 559, 10.1089/10430349950018634 Watanabe, 2015, Target antigen density governs the efficacy of anti-CD20-CD28-CD3 zeta chimeric antigen receptor-modified effector CD8+ T cells, J Immunol, 194, 911, 10.4049/jimmunol.1402346 Chmielewski, 2011, CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack, Gene Ther, 18, 62, 10.1038/gt.2010.127 Eyquem, 2017, Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection, Nature, 543, 113, 10.1038/nature21405 Frigault, 2015, Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells, Cancer Immunol Res, 3, 356, 10.1158/2326-6066.CIR-14-0186 Walker, 2017, Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase, Mol Ther, 25, 2189, 10.1016/j.ymthe.2017.06.008 Davenport, 2015, CAR-T cells inflict sequential killing of multiple tumor target cells, Cancer Immunol Res, 3, 483, 10.1158/2326-6066.CIR-15-0048 Kalos, 2011, T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia, Sci Transl Med, 3, 95ra73, 10.1126/scitranslmed.3002842 Arcangeli, 2017, Balance of anti-CD123 chimeric antigen receptor binding affinity and density for the targeting of acute myeloid leukemia, Mol Ther, 25, 1933, 10.1016/j.ymthe.2017.04.017 Morgan, 2010, Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2, Mol Ther, 18, 843, 10.1038/mt.2010.24 Caruso, 2015, Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity, Cancer Res, 75, 3505, 10.1158/0008-5472.CAN-15-0139 Liu, 2015, Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice, Cancer Res, 75, 3596, 10.1158/0008-5472.CAN-15-0159 Drent, 2017, A rational strategy for reducing on-target off-tumor effects of CD38-chimeric antigen receptors by affinity optimization, Mol Ther, 25, 1946, 10.1016/j.ymthe.2017.04.024 Ruella, 2016, Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies, J Clin Invest, 126, 3814, 10.1172/JCI87366 Genssler, 2016, Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival, Oncoimmunology, 5, e1119354, 10.1080/2162402X.2015.1119354 Wei, 2017, PSCA and MUC1 in non-small-cell lung cancer as targets of chimeric antigen receptor T cells, Oncoimmunology, 6, e1284722, 10.1080/2162402X.2017.1284722 Feng, 2017, Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma, J Hematol Oncol, 10, 4, 10.1186/s13045-016-0378-7 Grada, 2013, TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy, Mol Ther Nucleic Acids, 2, e105, 10.1038/mtna.2013.32 Zah, 2016, T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells, Cancer Immunol Res, 4, 498, 10.1158/2326-6066.CIR-15-0231