Engineering strategies to overcome the current roadblocks in CAR T cell therapy

Nature Reviews Clinical Oncology - Tập 17 Số 3 - Trang 147-167 - 2020
Sarwish Rafiq1, Christopher S. Hackett2, Renier J. Brentjens2
1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Tóm tắt

Từ khóa


Tài liệu tham khảo

Jackson, H. J., Rafiq, S. & Brentjens, R. J. Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 13, 370–383 (2016).

Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).

Park, J. H. et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378, 449–459 (2018).

Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

Schuster, S. J. et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 377, 2545–2554 (2017).

U.S. Food & Drug Administration. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. fda.gov https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumab-cytokine-release-syndrome (2017).

U.S. Food & Drug Administration. FDA approves axicabtagene ciloleucel for large B-cell lymphoma. fda.gov https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-axicabtagene-ciloleucel-large-b-cell-lymphoma (2017).

Ramello, M. C., Haura, E. B. & Abate-Daga, D. CAR-T cells and combination therapies: what's next in the immunotherapy revolution? Pharmacol. Res. 129, 194–203 (2018).

Bailey, S. R. & Maus, M. V. Gene editing for immune cell therapies. Nat. Biotechnol. https://doi.org/10.1038/s41587-019-0137-8 (2019).

Dwivedi, A., Karulkar, A., Ghosh, S., Rafiq, A. & Purwar, R. Lymphocytes in cellular therapy: functional regulation of CAR T cells. Front. Immunol. 9, 3180 (2019).

Zhang, G. et al. Anti-melanoma activity of T cells redirected with a TCR-like chimeric antigen receptor. Sci. Rep. 4, 3571 (2014).

Oren, R. et al. Functional comparison of engineered T cells carrying a native TCR versus TCR-like antibody-based chimeric antigen receptors indicates affinity/avidity thresholds. J. Immunol. 193, 5733–5743 (2014).

Inaguma, Y. et al. Construction and molecular characterization of a T-cell receptor-like antibody and CAR-T cells specific for minor histocompatibility antigen HA-1H. Gene Ther. 21, 575–584 (2014).

Rafiq, S. et al. Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms tumor 1 antigen. Leukemia 31, 1788–1797 (2017).

Chang, Z. L. et al. Rewiring T-cell responses to soluble factors with chimeric antigen receptors. Nat. Chem. Biol. 14, 317–324 (2018).

Xie, Y. J. et al. Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc. Natl Acad. Sci. USA 116, 7624–7631 (2019).

Smith, E. L. et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci. Transl. Med. 11, eaau7746 (2019).

Smith, E. L. et al. Development and evaluation of an optimal human single-chain variable fragment-derived BCMA-targeted CAR T cell vector. Mol. Ther. 26, 1447–1456 (2018).

Chailyan, A., Marcatili, P. & Tramontano, A. The association of heavy and light chain variable domains in antibodies: implications for antigen specificity. FEBS J. 278, 2858–2866 (2011).

Hudecek, M. et al. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin. Cancer Res. 19, 3153–3164 (2013).

Lynn, R. C. et al. High-affinity FRβ-specific CAR T cells eradicate AML and normal myeloid lineage without HSC toxicity. Leukemia 30, 1355–1364 (2016).

Liu, X. et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. 75, 3596–3607 (2015).

Caruso, H. G. et al. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res. 75, 3505–3518 (2015).

Watanabe, K. et al. Excessively high-affinity single-chain fragment variable region in a chimeric antigen receptor can counteract T-cell proliferation. Blood 124, 4799–4799 (2014).

Ghorashian, S. et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat. Med. 25, 1408–1414 (2019).

Ajina, A. & Maher, J. Strategies to address chimeric antigen receptor tonic signaling. Mol. Cancer Ther. 17, 1795–1815 (2018).

Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375, 2561–2569 (2016).

Lee, L. et al. An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma. Blood 131, 746–758 (2018).

Wang, Y. et al. Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells. J. Hematol. Oncol. 11, 60 (2018).

Nakazawa, Y. et al. Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34+ cells of juvenile myelomonocytic leukemia. J. Hematol. Oncol. 9, 27 (2016).

Baumeister, S. H. et al. Phase I trial of autologous CAR T cells targeting NKG2D ligands in patients with AML/MDS and multiple myeloma. Cancer Immunol. Res. 7, 100–112 (2019).

Hammill, J. A. et al. Designed ankyrin repeat proteins are effective targeting elements for chimeric antigen receptors. J. Immunother. Cancer 3, 55 (2015).

Siegler, E., Li, S., Kim, Y. J. & Wang, P. Designed ankyrin repeat proteins as Her2 targeting domains in chimeric antigen receptor-engineered T cells. Hum. Gene Ther. 28, 726–736 (2017).

Han, X. et al. Adnectin-based design of chimeric antigen receptor for T cell engineering. Mol. Ther. 25, 2466–2476 (2017).

Jensen, M. C. & Riddell, S. R. Designing chimeric antigen receptors to effectively and safely target tumors. Curr. Opin. Immunol. 33, 9–15 (2015).

Alabanza, L. et al. Function of novel anti-CD19 chimeric antigen receptors with human variable regions is affected by hinge and transmembrane domains. Mol. Ther. 25, 2452–2465 (2017).

James, S. E. et al. Antigen sensitivity of CD22-specific chimeric TCR is modulated by target epitope distance from the cell membrane. J. Immunol. 180, 7028–7038 (2008).

Haso, W. et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 121, 1165–1174 (2013).

Qin, L., Zhao, R. & Li, P. Incorporation of functional elements enhances the antitumor capacity of CAR T cells. Exp. Hematol. Oncol. 6, 28 (2017).

Watanabe, N. et al. Fine-tuning the CAR spacer improves T-cell potency. Oncoimmunology 5, e1253656 (2016).

Guest, R. D. et al. The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens. J. Immunother. 28, 203–211 (2005).

Hudecek, M. et al. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol. Res. 3, 125–135 (2015).

Hombach, A., Hombach, A. A. & Abken, H. Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc 'spacer' domain in the extracellular moiety of chimeric antigen receptors avoids 'off-target' activation and unintended initiation of an innate immune response. Gene Ther. 17, 1206–1213 (2010).

Jonnalagadda, M. et al. Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding and improve T cell persistence and antitumor efficacy. Mol. Ther. 23, 757–768 (2015).

Bridgeman, J. S. et al. The optimal antigen response of chimeric antigen receptors harboring the CD3ζ transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J. Immunol. 184, 6938–6949 (2010).

Guedan, S. et al. Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. JCI Insight 3, 96976 (2018).

Dotti, G., Gottschalk, S., Savoldo, B. & Brenner, M. K. Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol. Rev. 257, 107–126 (2014).

Brocker, T. & Karjalainen, K. Signals through T cell receptor-ζ chain alone are insufficient to prime resting T lymphocytes. J. Exp. Med. 181, 1653–1659 (1995).

Maher, J., Brentjens, R. J., Gunset, G., Riviere, I. & Sadelain, M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002).

Sadelain, M., Riviere, I. & Riddell, S. Therapeutic T cell engineering. Nature 545, 423–431 (2017).

Kawalekar, O. U. et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44, 712 (2016).

Mata, M. et al. Inducible activation of MyD88 and CD40 in CAR T cells results in controllable and potent antitumor activity in preclinical solid tumor models. Cancer Discov. 7, 1306–1319 (2017).

Hombach, A. A., Heiders, J., Foppe, M., Chmielewski, M. & Abken, H. OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells. Oncoimmunology 1, 458–466 (2012).

Hombach, A. A., Chmielewski, M., Rappl, G. & Abken, H. Adoptive immunotherapy with redirected T cells produces CCR7- cells that are trapped in the periphery and benefit from combined CD28-OX40 costimulation. Hum. Gene Ther. 24, 259–269 (2013).

Guedan, S. et al. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 124, 1070–1080 (2014).

Song, D. G. & Powell, D. J. Pro-survival signaling via CD27 costimulation drives effective CAR T-cell therapy. Oncoimmunology 1, 547–549 (2012).

Duong, C. P. et al. Engineering T cell function using chimeric antigen receptors identified using a DNA library approach. PLOS ONE 8, e63037 (2013).

Wang, E. et al. Generation of potent T-cell immunotherapy for cancer using DAP12-based, multichain, chimeric immunoreceptors. Cancer Immunol. Res. 3, 815–826 (2015).

Brudno, J. N. & Kochenderfer, J. N. Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management. Blood Rev. 34, 45–55 (2019).

Lee, D. W. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. 25, 625–638 (2019).

Santomasso, B. D. et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 8, 958–971 (2018).

Hay, K. A. et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood 130, 2295–2306 (2017).

Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra138 (2013).

Milone, M. C. & Bhoj, V. G. The pharmacology of T cell therapies. Mol. Ther. Methods Clin. Dev. 8, 210–221 (2018).

van der Stegen, S. J., Hamieh, M. & Sadelain, M. The pharmacology of second-generation chimeric antigen receptors. Nat. Rev. Drug Discov. 14, 499–509 (2015).

Salter, A. I. et al. Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function. Sci. Signal. 11, eaat6753 (2018).

Ying, Z. et al. A safe and potent anti-CD19 CAR T cell therapy. Nat. Med. 25, 947–953 (2019).

Sommermeyer, D. et al. Fully human CD19-specific chimeric antigen receptors for T-cell therapy. Leukemia 31, 2191-2199 (2017).

Sterner, R. M. et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood 133, 697–709 (2019).

Sachdeva, M., Duchateau, P., Depil, S., Poirot, L. & Valton, J. Granulocyte-macrophage colony-stimulating factor inactivation in CAR T-cells prevents monocyte-dependent release of key cytokine release syndrome mediators. J. Biol. Chem. 294, 5430–5437 (2019).

Giavridis, T. et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat. Med. 24, 731–738 (2018).

Norelli, M. et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat. Med. 24, 739–748 (2018).

Staedtke, V. et al. Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome. Nature 564, 273–277 (2018).

Lee, Y. G. et al. Regulation of CAR T cell-mediated cytokine release syndrome-like toxicity using low molecular weight adapters. Nat. Commun. 10, 2681 (2019).

Rodgers, D. T. et al. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. Proc. Natl Acad. Sci. USA 113, E459–E468 (2016).

Serafini, M. et al. Characterization of CD20-transduced T lymphocytes as an alternative suicide gene therapy approach for the treatment of graft-versus-host disease. Hum. Gene Ther. 15, 63–76 (2004).

Griffioen, M. et al. Retroviral transfer of human CD20 as a suicide gene for adoptive T-cell therapy. Haematologica 94, 1316–1320 (2009).

Philip, B. et al. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood 124, 1277–1287 (2014).

Wang, X. et al. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood 118, 1255–1263 (2011).

Di Stasi, A. et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011).

Juillerat, A. et al. Modulation of chimeric antigen receptor surface expression by a small molecule switch. BMC Biotechnol. 19, 44 (2019).

Mestermann, K. et al. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci. Transl. Med. 11, eaau5907 (2019).

Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011).

Lamers, C. H. J. et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol. Ther. 21, 904–912 (2013).

Morgan, R. A. et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol. Ther. 18, 843–851 (2010).

Seidman, A. et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J. Clin. Oncol. 20, 1215–1221 (2002).

Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015).

Goff, S. L. et al. Pilot trial of adoptive transfer of chimeric antigen receptor-transduced T cells targeting EGFRvIII in patients with glioblastoma. J. Immunother. 42, 126–135 (2019).

Thistlethwaite, F. C. et al. 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. 66, 1425–1436 (2017).

Caruso, H. G., Heimberger, A. B. & Cooper, L. J. N. Steering CAR T cells to distinguish friend from foe. Oncoimmunology 8, e1271857 (2018).

Liu, K. et al. Retargeted human avidin-CAR T cells for adoptive immunotherapy of EGFRvIII expressing gliomas and their evaluation via optical imaging. Oncotarget 6, 23735–23747 (2015).

Song, D.-G. et al. A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity. Oncotarget 6, 21533–21546 (2015).

Richman, S. A. et al. High-affinity GD2-specific CAR T cells induce fatal encephalitis in a preclinical neuroblastoma model. Cancer Immunol. Res. 6, 36–46 (2018).

Roybal, KoleT. et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779 (2016).

Srivastava, S. et al. Logic-gated ROR1 chimeric antigen receptor expression rescues T cell-mediated toxicity to normal tissues and enables selective tumor targeting. Cancer Cell 35, 489–503.e8 (2019).

Kloss, C. C., Condomines, M., Cartellieri, M., Bachmann, M. & Sadelain, M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat. Biotechnol. 31, 71–75 (2013).

Wilkie, S. et al. Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling. J. Clin. Immunol. 32, 1059–1070 (2012).

Lanitis, E. et al. Chimeric antigen receptor T cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo. Cancer Immunol. Res. 1, 43–53 (2013).

Leen, A. M. et al. Reversal of tumor immune inhibition using a chimeric cytokine receptor. Mol. Ther. 22, 1211–1220 (2014).

Fedorov, V. D., Themeli, M. & Sadelain, M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci. Transl. Med. 5, 215ra172 (2013).

Juillerat, A. et al. An oxygen sensitive self-decision making engineered CAR T-cell. Sci. Rep. 7, 39833 (2017).

Tchou, J. et al. Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer. Cancer Immunol. Res. 5, 1152–1161 (2017).

Wu, C. Y., Roybal, K. T., Puchner, E. M., Onuffer, J. & Lim, W. A. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350, aab4077 (2015).

Juillerat, A. et al. Design of chimeric antigen receptors with integrated controllable transient functions. Sci. Rep. 6, 18950 (2016).

Fisher, J. & Anderson, J. Engineering approaches in human gamma delta T cells for cancer immunotherapy. Front. Immunol. 9, 1409 (2018).

Fisher, J. et al. Avoidance of on-target off-tumor activation using a co-stimulation-only chimeric antigen receptor. Mol. Ther. 25, 1234–1247 (2017).

Kim, M. Y. et al. Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T cell immunotherapy for acute myeloid leukemia. Cell 173, 1439–1453.e19 (2018).

Majzner, R. G. & Mackall, C. L. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 8, 1219–1226 (2018).

Rafiq, S. & Brentjens, R. J. Tumors evading CARs — the chase is on. Nat. Med. 24, 1492–1493 (2018).

Pan, J. et al. CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia. Leukemia 33, 2854–2866 (2019).

Shah, N. N. et al. Results of a phase I study of bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) modified T cells for relapsed, refractory, non-Hodgkin lymphoma. J. Clin. Oncol. 37, 2510–2510 (2019).

Mahadeo, K. M. et al. Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy. Nat. Rev. Clin. Oncol. 16, 45–63 (2019).

Kantarjian, H. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 376, 836–847 (2017).

Choi, B. D. et al. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat. Biotechnol. 37, 1049–1058 (2019).

Curran, K. J. et al. Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol. Ther. 23, 769–778 (2015).

Kuhn, N. F. et al. CD40 ligand-modified chimeric antigen receptor T cells enhance antitumor function by eliciting an endogenous antitumor response. Cancer Cell 35, 473–488.e6 (2019).

Boice, M. et al. Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T cells. Cell 167, 405–418.e13 (2016).

Busch, D. H., Fräßle, S. P., Sommermeyer, D., Buchholz, V. R. & Riddell, S. R. Role of memory T cell subsets for adoptive immunotherapy. Semin. Immunol. 28, 28–34 (2016).

Morgan, M. A. & Schambach, A. Engineering CAR-T cells for improved function against solid tumors. Front. Immunol. 9, 2493 (2018).

Petersen, C. T. et al. Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists. Blood Adv. 2, 210–223 (2018).

Turtle, C. J. et al. CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Invest. 126, 2123–2138 (2016).

Turtle, C. J. et al. 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 (2016).

Sabatino, M. et al. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood 128, 519–528 (2016).

Kochenderfer, J. N., Yu, Z., Frasheri, D., Restifo, N. P. & Rosenberg, S. A. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood 116, 3875–3886 (2010).

Boucher, J. C. et al. Mutation of the CD28 costimulatory domain confers increased CAR T cell persistence and decreased exhaustion. J. Immunol. 200, 57.28 (2018).

Feucht, J. et al. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat. Med. 25, 82–88 (2019).

Zhao, Z. et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 28, 415–428 (2015).

Park, J. H. et al. A phase I first-in-human clinical trial of CD19-targeted 19-28z/4-1BBL "armored" CAR T cells in patients with relapsed or refractory NHL and CLL including Richter's transformation. Blood 132, 224 (2018).

Centers for Disease Control and Prevention. United States Cancer Statistics: Data Visualizations https://www.cdc.gov/cancer/dataviz (2019).

Junttila, M. R. & de Sauvage, F. J. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501, 346–354 (2013).

Wing, A. et al. Improving CART-cell therapy of solid tumors with oncolytic virus-driven production of a bispecific T-cell engager. Cancer Immunol. Res. 6, 605–616 (2018).

Urbanska, K. et al. A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Res. 72, 1844–1852 (2012).

Lohmueller, J. J., Ham, J. D., Kvorjak, M. & Finn, O. J. mSA2 affinity-enhanced biotin-binding CAR T cells for universal tumor targeting. Oncoimmunology 7, e1368604 (2017).

Tamada, K. et al. Redirecting gene-modified T cells toward various cancer types using tagged antibodies. Clin. Cancer Res. 18, 6436–6445 (2012).

Kim, M. S. et al. Redirection of genetically engineered CAR-T cells using bifunctional small molecules. J. Am. Chem. Soc. 137, 2832–2835 (2015).

Ma, J. S. Y. et al. Versatile strategy for controlling the specificity and activity of engineered T cells. Proc. Natl Acad. Sci. USA 113, E450–E458 (2016).

Lee, Y. G. et al. Use of a single CAR T cell and several bispecific adapters facilitates eradication of multiple antigenically different solid tumors. Cancer Res. 79, 387–396 (2019).

Kudo, K. et al. T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res. 74, 93–103 (2014).

Cho, J. H., Collins, J. J. & Wong, W. W. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 173, 1426–1438.e11 (2018).

Beatty, G. L. et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol. Res. 2, 112–120 (2014).

Katz, S. C. et al. Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA+ liver metastases. Clin. Cancer Res. 21, 3149–3159 (2015).

Hardaway, J. C., Prince, E., Arepally, A. & Katz, S. C. Regional infusion of chimeric antigen receptor T cells to overcome barriers for solid tumor immunotherapy. J. Vasc. Interv. Radiol. 29, 1017–1021.e1 (2018).

Sridhar, P. & Petrocca, F. Regional delivery of chimeric antigen receptor (CAR) T-cells for cancer therapy. Cancers 9, E92 (2017).

Nagarsheth, N., Wicha, M. S. & Zou, W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat. Rev. Immunol. 17, 559–572 (2017).

Lo, A. S. et al. Harnessing the tumour-derived cytokine, CSF-1, to co-stimulate T-cell growth and activation. Mol. Immunol. 45, 1276–1287 (2008).

Di Stasi, A. et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113, 6392–6402 (2009).

Craddock, J. A. et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J. Immunother. 33, 780–788 (2010).

Moon, E. K. et al. Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin. Cancer Res. 17, 4719–4730 (2011).

Tran, E. et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J. Exp. Med. 210, 1125–1135 (2013).

Wang, L. C. et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol. Res. 2, 154–166 (2014).

Caruana, I. et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat. Med. 21, 524–529 (2015).

Mardomi, A. & Abediankenari, S. Matrix metalloproteinase 8: could it benefit the CAR-T cell therapy of solid tumors? - a- Commentary on therapeutic potential. Cancer Microenviron. 11, 93–96 (2018).

Ramanathan, R. K. et al. Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J. Clin. Oncol. 37, 1062–1069 (2019).

Hingorani, S. R. et al. HALO 202: Randomized phase II study of PEGPH20 plus Nab-paclitaxel/gemcitabine versus Nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J. Clin. Oncol. 36, 359–366 (2018).

Postow, M. A., Callahan, M. K. & Wolchok, J. D. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33, 1974–1982 (2015).

Moon, E. K. et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin. Cancer Res. 20, 4262–4273 (2014).

Yoon, D. H., Osborn, M. J., Tolar, J. & Kim, C. J. Incorporation of immune checkpoint blockade into chimeric antigen receptor T cells (CAR-Ts): combination or built-in CAR-T. Int. J. Mol. Sci. 19, E340 (2018).

Li, A. M. et al. Checkpoint inhibitors augment CD19-directed chimeric antigen receptor (CAR) T cell therapy in relapsed B-cell acute lymphoblastic leukemia. Blood 132, 556 (2018).

Chong, E. A. et al. Phase I/II study of pembrolizumab for progressive diffuse large B cell lymphoma after anti-CD19 directed chimeric antigen receptor modified T cell therapy. Blood 130, 4121 (2017).

Adusumilli P. S. et al. A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: safety and efficacy - a preliminary report. Presented at the American Society of Gene and Cell 21st Annual Meeting (2018).

Cherkassky, L. et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J. Clin. Invest. 126, 3130–3144 (2016).

Prosser, M. E., Brown, C. E., Shami, A. F., Forman, S. J. & Jensen, M. C. Tumor PD-L1 co-stimulates primary human CD8+ cytotoxic T cells modified to express a PD1:CD28 chimeric receptor. Mol. Immunol. 51, 263–272 (2012).

Ankri, C., Shamalov, K., Horovitz-Fried, M., Mauer, S. & Cohen, C. J. Human T cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity. J. Immunol. 191, 4121–4129 (2013).

Kobold, S. et al. Impact of a new fusion receptor on PD-1-mediated immunosuppression in adoptive T cell therapy. J. Natl Cancer Inst. 107, djv146 (2015).

Liu, X. et al. A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res. 76, 1578–1590 (2016).

Suarez, E. R. et al. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 7, 34341–34355 (2016).

Rafiq, S. et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat. Biotechnol. 36, 847–856 (2018).

Li, S. et al. Enhanced cancer immunotherapy by chimeric antigen receptor–modified T cells engineered to secrete checkpoint inhibitors. Clin. Cancer Res. 23, 6982–6992 (2017).

Rupp, L. J. et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci. Rep. 7, 737 (2017).

Simon, S. & Labarriere, N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology 7, e1364828 (2017).

Wei, J. et al. PD-1 silencing impairs the anti-tumor function of chimeric antigen receptor modified T cells by inhibiting proliferation activity. J. Immunother. Cancer 7, 209 (2019).

Condomines, M. et al. Tumor-targeted human T cells expressing CD28-based chimeric antigen receptors circumvent CTLA-4 inhibition. PLOS ONE 10, e0130518 (2015).

Newick, K. et al. Augmentation of CAR T-cell trafficking and antitumor efficacy by blocking protein kinase A localization. Cancer Immunol. Res. 4, 541–551 (2016).

Beavis, P. A. et al. Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J. Clin. Invest. 127, 929–941 (2017).

Siriwon, N. et al. CAR-T cells surface-engineered with drug-encapsulated nanoparticles can ameliorate intratumoral T-cell hypofunction. Cancer Immunol. Res. 6, 812–824 (2018).

Kloss, C. C. et al. Dominant-negative TGF-β receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol. Ther. 26, 1855–1866 (2018).

Mohammed, S. et al. Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol. Ther. 25, 249–258 (2017).

Wilkie, S. et al. Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. J. Biol. Chem. 285, 25538–25544 (2010).

Yamamoto, T. N. et al. T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy. J. Clin. Invest. 129, 1551–1565 (2019).

Xu, X., Gnanaprakasam, J. N. R., Sherman, J. & Wang, R. A metabolism toolbox for CAR T therapy. Front. Oncol. 9, 322 (2019).

Geiger, R. et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842.e13 (2016).

Vodnala, S. K. et al. T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science 363, eaau0135 (2019).

Ando, T. et al. Transduction with the antioxidant enzyme catalase protects human T cells against oxidative stress. J. Immunol. 181, 8382–8390 (2008).

Chmielewski, M., Hombach, A. A. & Abken, H. Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol. Rev. 257, 83–90 (2014).

Pegram, H. J. et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119, 4133–4141 (2012).

Koneru, M., Purdon, T. J., Spriggs, D., Koneru, S. & Brentjens, R. J. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology 4, e994446 (2015).

Yeku, O. O., Purdon, T. J., Koneru, M., Spriggs, D. & Brentjens, R. J. Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. Sci. Rep. 7, 10541 (2017).

Koneru, M., O’Cearbhaill, R., Pendharkar, S., Spriggs, D. R. & Brentjens, R. J. A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16ecto directed chimeric antigen receptors for recurrent ovarian cancer. J. Transl. Med. 13, 102 (2015).

Chmielewski, M., Kopecky, C., Hombach, A. A. & Abken, H. 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, 5697–5706 (2011).

Chinnasamy, D. et al. Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin. Cancer Res. 18, 1672–1683 (2012).

Leonard, J. P. et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-γ production. Blood 90, 2541–2548 (1997).

Zhang, L. et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin. Cancer Res. 21, 2278–2288 (2015).

Mizuguchi, H., Xu, Z., Ishii-Watabe, A., Uchida, E. & Hayakawa, T. IRES-dependent second gene expression is significantly lower than Cap-dependent first gene expression in a bicistronic vector. Mol. Ther. 1, 376–382 (2000).

Zhang, L. et al. Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment. Mol. Ther. 19, 751–759 (2011).

Hoyos, V. et al. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 24, 1160–1170 (2010).

Krenciute, G. et al. Transgenic expression of IL15 improves antiglioma activity of IL13Rα2-CAR T cells but results in antigen loss variants. Cancer Immunol. Res. 5, 571–581 (2017).

Chen, Y. et al. Eradication of neuroblastoma by T cells redirected with an optimized GD2-specific chimeric antigen receptor and interleukin-15. Clin. Cancer Res. 25, 2915–2924 (2019).

Hurton, L. V. et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc. Natl Acad. Sci. USA 113, E7788–E7797 (2016).

Nair, S. et al. Functional improvement of chimeric antigen receptor through intrinsic interleukin-15Rα signaling. Curr. Gene Ther. 19, 40–53 (2019).

Hsu, C. et al. Cytokine-independent growth and clonal expansion of a primary human CD8+ T-cell clone following retroviral transduction with the IL-15 gene. Blood 109, 5168–5177 (2007).

Fehniger, T. A. et al. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J. Exp. Med. 193, 219–231 (2001).

Conlon, K. C. et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J. Clin. Oncol. 33, 74–82 (2015).

Tang, L. et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat. Biotechnol. 36, 707 (2018).

Carroll, R. G. et al. Distinct effects of IL-18 on the engraftment and function of human effector CD8 T cells and regulatory T cells. PLOS ONE 3, e3289 (2008).

Avanzi, M. P. et al. Engineered tumor-targeted T cells mediate enhanced anti-tumor efficacy both directly and through activation of the endogenous immune system. Cell Rep. 23, 2130–2141 (2018).

Chmielewski, M. & Abken, H. CAR T cells releasing IL-18 convert to T-Bethigh FoxO1low effectors that exhibit augmented activity against advanced solid tumors. Cell Rep. 21, 3205–3219 (2017).

Hu, B. et al. Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18. Cell Rep. 20, 3025–3033 (2017).

Robertson, M. J. et al. Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin. Cancer Res. 12, 4265–4273 (2006).

Sedimbi, S. K., Hagglof, T. & Karlsson, M. C. IL-18 in inflammatory and autoimmune disease. Cell. Mol. Life Sci. 70, 4795–4808 (2013).

Vidal-Vanaclocha, F. et al. Clinical and experimental approaches to the pathophysiology of interleukin-18 in cancer progression. Cancer Metastasis Rev. 25, 417–434 (2006).

Adachi, K. et al. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat. Biotechnol. 36, 346–351 (2018).

Chen, Y. & Lu, B. Guided delivery of the “alarming” cytokine IL-33 to tumor by chimeric antigen receptor T cells. J. Immunol. 198, 204.223 (2017).

Li, X. D., A., Lopez, A., Purdon, T. & Brentjens, R. Augmenting CAR T cell mediated antitumor efficacy through genetic modification to secrete a novel cytokine IL-36γ. Mol. Ther. 27, 432–433 (2019).

Singh, N., Perazzelli, J., Grupp, S. A. & Barrett, D. M. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Sci. Transl. Med. 8, 320ra323 (2016).

Das, R. K., Vernau, L., Grupp, S. A. & Barrett, D. M. Naïve T-cell deficits at diagnosis and after chemotherapy impair cell therapy potential in pediatric cancers. Cancer Discov. 9, 492–499 (2019).

Elavia, N. et al. Effects of starting cellular material composition on chimeric antigen receptor T-cell expansion and characteristics. Transfusion 59, 1755–1764 (2019).

Schietinger, A. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389–401 (2016).

Totterman, T., Carlsson, M., Simonsson, B., Bengtsson, M. & Nilsson, K. T-cell activation and subset patterns are altered in B-CLL and correlate with the stage of the disease. Blood 74, 786–792 (1989).

Fraietta, J. A. et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 24, 563–571 (2018).

Philip, M. et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545, 452 (2017).

Kochenderfer, J. N. et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122, 4129–4139 (2013).

Kebriaei, P. et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J. Clin. Invest. 126, 3363–3376 (2016).

Brudno, J. N. et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J. Clin. Oncol. 34, 1112–1121 (2016).

Ghosh, A. et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat. Med. 23, 242 (2017).

Cruz, C. R. Y. et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 122, 2965–2973 (2013).

Rotolo, R. et al. CAR-based strategies beyond T lymphocytes: integrative opportunities for cancer adoptive immunotherapy. Int. J. Mol. Sci. 20, 2839 (2019).

Hu, W., Wang, G., Huang, D., Sui, M. & Xu, Y. Cancer immunotherapy based on natural killer cells: current progress and new opportunities. Front. Immunol. 10, 1205 (2019).

Osborn, M. J. et al. Evaluation of TCR gene editing achieved by TALENs, CRISPR/Cas9, and megaTAL nucleases. Mol. Ther. 24, 570–581 (2016).

Torikai, H. et al. A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood 119, 5697–5705 (2012).

Torikai, H. et al. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 122, 1341–1349 (2013).

Ren, J. et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin. Cancer Res. 23, 2255–2266 (2017).

Poirot, L. et al. Multiplex genome-edited T-cell manufacturing platform for “off-the-shelf” adoptive T-cell immunotherapies. Cancer Res. 75, 3853–3864 (2015).

Qasim, W. et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci. Transl. Med. 9, eaaj2013 (2017).

Georgiadis, C. et al. Long terminal repeat CRISPR-CAR-coupled “universal” T cells mediate potent anti-leukemic effects. Mol. Ther. 26, 1215–1227 (2018).

Liu, X. et al. CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells. Cell Res. 27, 154–157 (2017).

Ren, J. et al. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 8, 17002–17011 (2017).

Barnett, B. Manufacture of allogeneic “Universal Donor” CAR-T therapies using piggyBac™ and Cas-CLOVER in CAR-TCR Summit, Boston MA https://poseida.com/wp-content/uploads/2018-CAR-TCR-Summit.P-BCMA-ALLO1-1.pdf (2018).

Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113 (2017).

MacLeod, D. T. et al. Integration of a CD19 CAR into the TCR alpha chain locus streamlines production of allogeneic gene-edited CAR T cells. Mol. Ther. 25, 949–961 (2017).

Kamiya, T., Wong, D., Png, Y. T. & Campana, D. A novel method to generate T-cell receptor–deficient chimeric antigen receptor T cells. Blood Adv. 2, 517–528 (2018).

Graham, C., Jozwik, A., Pepper, A. & Benjamin, R. Allogeneic CAR-T cells: more than ease of access? Cells 7, 155 (2018).

Iriguchi, S. & Kaneko, S. Toward the development of true "off-the-shelf" synthetic T-cell immunotherapy. Cancer Sci. 110, 16–22 (2019).

Zakrzewski, J. L. et al. Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors. Nat. Biotechnol. 26, 453 (2008).

Papapetrou, E. P., Kovalovsky, D., Beloeil, L., Sant’angelo, D. & Sadelain, M. Harnessing endogenous miR-181a to segregate transgenic antigen receptor expression in developing versus post-thymic T cells in murine hematopoietic chimeras. J. Clin. Invest. 119, 157–168 (2009).

Themeli, M. et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat. Biotechnol. 31, 928 (2013).

van der Stegen, S. et al. Generation of clonal antigen specific CD8αβ+ cytotoxic T lymphocytes from renewable pluripotent stem cells for off-the-shelf T cell therapeutics. Blood 130 (Suppl. 1), 163 (2017).

Clarke, R. L. et al. Abstract LB-108: Generation of off-the-shelf TCR-less CAR-targeted cytotoxic T cells from renewable pluripotent cells for cancer immunotherapy. Cancer Res. 78, LB-108 (2018).

Fraietta, J. A. et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312 (2018).

Ruella, M. et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat. Med. 24, 1499–1503 (2018).

Monjezi, R. et al. Enhanced CAR T-cell engineering using non-viral Sleeping Beauty transposition from minicircle vectors. Leukemia 31, 186–194 (2017).