International Regensburg Center for Interventional Immunology (RCI)
Total Page：16
File Type：pdf, Size：1020Kb
Cancer Immunology, Immunotherapy (2020) 69:677–682 https://doi.org/10.1007/s00262-019-02467-w MEETING REPORT International Regensburg Center for Interventional Immunology (RCI) symposium on “Synthetic immunology and environment‑adapted redirection of T cells”, 17–18 July, 2019, Regensburg, Germany Philipp Beckhove1 · Matthias Edinger2 · Markus Feuerer3 · Luca Gattinoni4 · Hinrich Abken5 Received: 21 August 2019 / Accepted: 28 December 2019 / Published online: 2 March 2020 © The Author(s) 2020 Keywords Synthetic immunology · Cell therapy · CAR · TCR · Treg cells · Regensburg center for interventional immunology (RCI) Abbreviations FoxP3 Forkhead box protein-P3 AKT Protein kinase B GMP Good manufacturing practice AML Acute myeloid leukemia GvHD Graft versus host disease APC Antigen presenting cell iCAS9 Inducible caspase-9 ATTAC Assay for transposase accessible chromatin IRF4 Interferon regulatory factor-4 BiTE Bispecifc T cell engager MAGE-C2 Melanoma associated antigen-C2 BTK Bruton tyrosine kinase MDS Myelodysplastic syndrome CAR Chimeric antigen receptor miRNA MicroRNA CCR4 C–C motif chemokine receptor-4 miSFITs MicroRNA silencing-mediated fne-tuners CDK Cyclin dependent kinase mTOR Mechanistic target for rapamycin CRISPR Clustered regularly interspaced short palin- NSG Non-obese diabetic severe combined immu- dromic repeats nodefciency gamma DC Dendritic cell PD-1 Programmed cell death-1 EWS Ewing sarcoma pDC Plasmacytoid dendritic cell FLI1 Friend leukemia integration-1 PHF19 PHD fnger protein-19 FoxO1 Forkhead box protein-O1 PRAME Preferentially expressed antigen in melanoma PRAS40 Proline-rich AKT substrate of 40 kD PRC2 Polycomb repressive complex-2 * Hinrich Abken PTPN2 Protein tyrosine phosphatase non-receptor [email protected] type-2 RCI Regensburg Center for Interventional 1 Regensburg Center for Interventional Immunology (RCI) and Chair for Interventional Immunology, University Immunology Regensburg, Regensburg, Germany RHEB RAs homolog enriched in brain 2 Regensburg Center for Interventional Immunology (RCI), scFv Single chain fragment of variable region José Carreras Center and Clinic III Internal Medicine, sgRNA Single guide RNA University Hospital Regensburg, Regensburg, Germany SHIP-1 Src homology phosphoinositide 3 Regensburg Center for Interventional Immunology (RCI) phosphatase-1 and Chair for Immunology, University Regensburg, SOCS1 Suppressor of cytokine signaling-1 Regensburg, Germany STAT5 Signal transducer and activator of 4 Regensburg Center for Interventional Immunology (RCI) transcription-5 and Chair for Functional Immune Cell Modulation, TAG-72 Tumor-associated glycoprotein-72 University Regensburg, Regensburg, Germany Tbet T cell specifc T-box transcription factor 5 Regensburg Center for Interventional Immunology TCR T cell receptor (RCI) and Chair for Genetic Immunotherapy, University Regensburg, Franz-Josef-Strauss-Allee 11, TET-2 Ten-eleven-translocation-2 93053 Regensburg, Germany TGF-β Transforming growth factor-β Vol.:(0123456789)1 3 678 Cancer Immunology, Immunotherapy (2020) 69:677–682 Th T helper for Cellular Immunotherapies, University of Pennsylvania, TRUCK T cell redirected for unrestricted cytokine- Philadelphia, USA) reviewed in a keynote lecture the history mediated killing of CAR T cells and highlighted the immune response of WT-1 Wilms tumor-1 patients with metastatic colorectal cancer treated with frst- generation CD3-chain CAR T cells targeting the tumor- associated glycoprotein-72 (TAG-72), one of the frst human Introduction CAR T cell trials in the treatment of solid tumors performed in the 1990s. Targeting TAG-72 by CAR T cells seemed to Immunotherapeutic strategies are well established for be safe; in some patients there was a precipitous decline of the treatment of autoimmune diseases and in transplanta- TAG-72 serum levels indicating some anti-tumor response. tion medicine since many years; only recently signifcant However, CAR T cells showed limited persistence demand- improvements in cancer therapy were achieved with the ing the incorporation of a co-stimulatory domain and the introduction of therapeutic antibodies along with conven- use of a fully human CAR construct to mitigate anti-CAR tional chemotherapy. A paradigm shift for the immuno- immunogenicity. Long-term persistence is still a major therapeutic treatment of cancer began with the introduction issue for CAR T cell therapy; in lymphoma/leukemia trials of checkpoint inhibitors illustrating the potency of immu- CD27+ PD1− CD8+ CAR T cells seem to be prognostic for notherapeutic strategies by releasing a broad productive long-term CAR T cell persistence and efcacy. Dr June also anti-tumor and eventually autoimmune response. The most reported on an alternative way how to improve CAR T cell promising, albeit also the most sophisticated and challeng- persistence. By in-depth analysis of a persistent CAR T cell ing approach of interventional immunology, is the targeted clone in a patient his team identifed that the CAR encoding redirection of immune cells by genetic engineering as indi- sequence disrupted the TET-2 (Ten-Eleven-Translocation-2) vidually tailored “living drugs”, as illustrated by the success gene that mediates DNA demethylation and is a master regu- of chimeric antigen receptor (CAR)-modifed T cells for the lator in myelopoiesis and a tumor suppressor gene. Such treatment of leukemia and lymphoma. Emerging synthetic CAR T cells exhibited a central memory phenotype and an immunology approaches provide a broad set of novel tools epigenetic profle consistent with altered T cell diferentia- for immune cell (re-)programming to equip efector cells tion. Experimental knock-down of the TET-2 gene improves with defned, specifc and enhanced anti-tumor capacities, CAR T cell function and persistence paving the way for a probably also for solid tumors. Being dedicated to this fas- rational design of long-term persistent CAR T cells. cinating feld of research the Regensburg Center for Inter- The level of targeted CD19 determines the efcacy of ventional Immunology (RCI) hosted the “Synthetic Immu- anti-CD19 CAR T cell therapy of B cell malignancies as nology and Environment-adapted Redirection of T cells” pointed out by Michael C. Jensen (Seattle Children’s Ben symposium in the Thon-Dittmer-Palais Regensburg on Towne Center for Childhood Cancer Research, Seattle 17–18 July, 2019. The aim of the symposium was to discuss Children’s Research Institute, Seattle, WA, USA). The in- convergent mechanisms of immune regulation and T cell depth analysis of a phase I trial with a defned composition reprogramming in cancer and autoimmunity, to identify and of CD19 CAR T cells revealed that the durability of remis- dissect programs in immune cells that determine their tissue sion correlated with engineered cell products containing function and to defne which capacities immune cells need increased frequencies of TNF-α secreting CD8+ CAR T to cure diseased tissues. With this goal about 150 scientists cells. The therapeutic efcacy was moreover dependent on discussed over two days the recent developments in synthetic high CD19 levels at the time of infusion to trigger CAR T biology approaches and genetic engineering of immune cells cell proliferation. T cells artifcially expressing truncated ranging from sensor systems towards efector functions for CD19 stimulated anti-CD19 CAR T cells and improved the development of environment-smart immune cell thera- their persistence and functionality in vivo. Dr Jensen sug- pies to treat cancer and autoimmune disorders. gested that re-stimulation by healthy B cells through a co-expressed CD19 CAR may enhance the efcacy of a CAR T cell attack against solid tumors. Beyond CD19 Improving CAR and TCR redirected T cell other targets are currently explored for the treatment of therapy of leukemia/lymphoma lymphoma/leukemia by CAR T cells. With this respect, Marcela V. Maus (Massachusetts General Hospital and Until now, more than 1000 patients were treated with anti- Harvard Medical School, Boston, MA, USA) reported CD19 CAR T cells in the US alone; more than 270 trials are recent data on CAR T cells targeting CD37 that were actively exploring CAR T cells in the treatment of hema- active against lymphoma/leukemia of both B and T cell tologic and solid cancer around the world. Appreciating origin without evidence of signifcant T cell fratricide; a the success of CAR T cell therapy, Carl H. June (Center phase I trial is going to be initiated. 1 3 Cancer Immunology, Immunotherapy (2020) 69:677–682 679 CAR T cell efcacy can also be enhanced by combina- CAR T cells on the road to target solid tions with other immuno-oncological approaches. Carl H. tumors June reported co-treatment with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib along with anti-CD19 CAR T Targeting solid tumor lesions by CAR or TCR redirected T cells improves responses against mantle cell lymphoma cells is still a major issue; various hurdles were identifed and and B cell chronic lymphocytic leukemia. In line with strategies developed during the last years. Apart from active these data Marcela V. Maus demonstrated that ibrutinib immune repression, lack or low levels of targetable antigen is increases the in vivo persistence and anti-tumor activity of a common mechanism of cancer cells to become invisible to CAR T cells in model systems. The strategy thereby com- redirected T cells. To provide targetable antigen, Michael C. bines therapies paving the way to a two-pronged assault Jensen developed a technology to decorate