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Feasibility of Telomerase-Specific Adoptive T-Cell Therapy for B-Cell Chronic Lymphocytic Leukemia and Solid Malignancies

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Feasibility of Telomerase-Specific Adoptive T-Cell Therapy for B-Cell Chronic Lymphocytic Leukemia and Solid Malignancies Cancer Microenvironment and Immunology Research Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies Sara Sandri1, Sara Bobisse2, Kelly Moxley3, Alessia Lamolinara4, Francesco De Sanctis1, Federico Boschi5, Andrea Sbarbati6, Giulio Fracasso1, Giovanna Ferrarini1, Rudi W. Hendriks7, Chiara Cavallini8, Maria Teresa Scupoli8,9, Silvia Sartoris1, Manuela Iezzi4, Michael I. Nishimura3, Vincenzo Bronte1, and Stefano Ugel1 Abstract Telomerase (TERT) is overexpressed in 80% to 90% of primary Using several relevant humanized mouse models, we demon- tumors and contributes to sustaining the transformed phenotype. strate that TCR-transduced T cells were able to control human B- The identification of several TERT epitopes in tumor cells has CLL progression in vivo and limited tumor growth in several elevated the status of TERT as a potential universal target for human, solid transplantable cancers. TERT-based adoptive selective and broad adoptive immunotherapy. TERT-specific cyto- immunotherapy selectively eliminated tumor cells, failed to trig- toxic T lymphocytes (CTL) have been detected in the peripheral ger a self–MHC-restricted fratricide of T cells, and was associated blood of B-cell chronic lymphocytic leukemia (B-CLL) patients, with toxicity against mature granulocytes, but not toward human but display low functional avidity, which limits their clinical hematopoietic progenitors in humanized immune reconstituted utility in adoptive cell transfer approaches. To overcome this mice. These data support the feasibility of TERT-based adoptive key obstacle hindering effective immunotherapy, we isolated an immunotherapy in clinical oncology, highlighting, for the first HLA-A2–restricted T-cell receptor (TCR) with high avidity for time, the possibility of utilizing a high-avidity TCR specific for à human TERT from vaccinated HLA-A 0201 transgenic mice. human TERT. Cancer Res; 76(9); 2540–51. Ó2016 AACR. Introduction tumor-infiltrating T cells (TIL), T-cell receptor (TCR) engineered T cells, or chimeric antigen receptor (CAR) transduced lymphocytes, The development of adoptive cell therapy (ACT) represents an all of them already tested in clinical settings (2). TIL-based ACT emerging and realistic approach to treat cancer patients. This is can result in a long-lasting and complete cancer regression in testified by the numerous phase II clinical trials, the approval of metastatic melanoma patients (3, 4). However, this approach specific T-cell therapies by the FDA, and the growing interest of remains a personalized treatment that displays several technical biotechnology and pharmaceutical industry to generate "off-the- constraints (5). The clinical response following adoptive TIL shelf" reagents to treat a large spectrum of tumors (1). At present, transfer was associated with T cells reactive toward mutated three types of ACT protocols can be defined based on isolated epitopes that were able to persist in patients for at least 1 month after lymphocyte infusion (6). These boundaries intrinsic to TIL- based ACT could be surmounted by gene therapy strategies based 1Department of Medicine, Section of Immunology, University of Ver- on genetically engineered lymphocytes where the desired TCR ona, Verona, Italy. 2Familial Cancer Clinic and Oncoendocrinology, € 3 sequence insertion, by a virus-mediated delivery into na ve T cells, Veneto Institute of Oncology, Padova, Italy. Department of Surgery, fi – Loyola University Medical Center, Maywood, California. 4CESI Aging can confer an antigen-oriented immune speci city (7 9). To Research Center, G. D'Annunzio University, Chieti Scalo, Chieti, Italy. develop rapidly and apply ACT to a wide range of human 5Department of Computer Science, University of Verona,Verona, Italy. 6 neoplastic diseases, the characterization of high-avidity TCRs that Department of Neurological and Movement Sciences, University of fi Verona, Verona, Italy. 7Department of Pulmonary Medicine, Erasmus ef ciently and broadly recognize cancer cells is thus a primary goal MC, Rotterdam, the Netherlands. 8University of Verona, Interdepart- (10). However, antitumor CTLs with a high-avidity TCR against mental Laboratory for Medical Research (LURM), Verona, Italy. non-mutated tumor-associated antigens (TAA) are normally 9 Department of Medicine, Section of Hematology, University of Ver- deleted during thymus education of self-reactive T cells (11), and ona, Verona, Italy. isolation of TCR recognizing individual mutations of patients' Note: Supplementary data for this article are available at Cancer Research cancers is feasible in theory (12) but currently not applicable to Online (http://cancerres.aacrjournals.org/). large scale, standardized therapy. Nowadays, high-avidity TCR Vincenzo Bronte and Stefano Ugel contributed equally to this article. sequences could be achieved by different approaches. T cells with Corresponding Author: Vincenzo Bronte, University Hospital and Department higher functional avidity could be generated in vitro by stimula- of Medicine, Immunology Section, Verona, P.le L.A. Scuro, 10, Verona, VR 37134, tion with autologous dendritic cells (DC) transfected with RNA Italy. Phone: 39-045-8124007; Fax: 39-045-8126455; E-mail: encoding an allogeneic major histocompatibility complex [email protected] (MHC) and the desired TAA (13). Alternatively, TCR can be doi: 10.1158/0008-5472.CAN-15-2318 isolated from mouse CTLs primed in vivo by vaccination of Ó2016 American Association for Cancer Research. transgenic mice bearing human HLA-A2 molecules (14, 15), an 2540 Cancer Res; 76(9) May 1, 2016 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2016 American Association for Cancer Research. Anti-Telomerase Adoptive T-cell Therapy approach that was recently improved by the immunization of Generation of hTERT865–873– and hHCV1406–1415–specific, TCR- human antigen–negative mice engineered to bear the whole transduced T cells human TCR-a and b gene loci together with the HLA-A2 allele OKT-3–activated PBMCs were infected with the viral superna- (16). We previously reported the feasibility to isolate and enrich a tant of the hTERT865–873/PG13 cell line in the presence of hIL15 polyclonal T-cell population specific for human telomerase (100 mg/mL) and rIL2 (300 IU/mL; ref. 34). PBMCs were then (hTERT)865–873 epitope through in vitro stimulation of mouse T immunomagnetically enriched for CD34 (Miltenyi) and expand- lymphocytes isolated from HLA-A2.1 transgenic mice (17). These ed. Control HCV1406–1415 (KLVALGINAV)–specific, TCR-trans- CTLs recognized different hTERT-expressing human cancer cell duced T cells were generated following the same protocol. The þ þ lines, as well as colon cancer stem cells (17). Telomerase is percentage of CD4 and CD8 T cells (usually 20% and 80%, reactivated in the majority of human tumors independently of respectively) was always tested before in vitro or in vivo studies. In their histology (18), and several hTERT epitopes, which are general, the amount of T cells used for in vivo treatments were þ naturally processed and presented in association with MHC adjusted in order to inject 2.5  106 CD8 cells. molecules on tumor cell surface, have been already documented (19–22). It is thus not surprising that TERT was ranked among the Generation and expansion of telomerase-specific T cells from most prioritized TAAs (23), and several active immunotherapeu- B-CLL and HD PBMCs tic approaches based on TERT antigen have been exploited to B-CLL patients and HD were selected for HLA-A2 status, as target, both in vivo and in vitro, either autologous or allogeneic assessed by FACS. T cells were immunomagnetically isolated from antigen-presenting cells (APC), including antigenic peptides PBMCs. Human DCs were generated from CD14-selected mono- (24–27), RNA-based vaccines (28), as well as plasmid or viral cytes (Miltenyi Biotec) and, after 100 mg/mL LPS maturation, vectors encoding hTERT (29). Unfortunately, clinical responses in pulsed with 10 mg/mL of the specific peptide. DCs were then used these trials were limited, suggesting the need for more powerful, to stimulate T cells at an E/T ratio of 10:1 in complete RPMI- immune-based strategies. In the current study, we show the 1640 in presence of IL7 (10 ng/mL), IL15 (2 ng/mL), and IL2 feasibility to transduce human T cells with a high-avidity mouse (10 IU/mL; all from Miltenyi Biotec). At days 7 and 15 of culture, þ TCR able to recognize hTERT865–873 peptide in association with T cells were restimulated with peptide-pulsed DCs. CD8 T cells HLA-A2 molecules to control human solid tumors and hemato- were screened for hTERT865–873 dextramer positivity and logic malignancies, such as chronic lymphocytic leukemia (B- hTERT865–873–specific reactivity in IFNg ELISA. CLL). The high levels of hTERT in leukemic B cells correlated with poor clinic outcome (30, 31). We show here that hTERT-based Systemic treatment of mouse leukemic chimeras þ ACT can selectively eliminate leukemic B cells, causing a minor Chimeras were generated combining 106 CD45.2 IgH.TEm þ À À À À toxicity against normal myeloid cells, making this approach and 4  106 CD45.1 syngeneic WT BM cells in Rag2 / gc / suitable to clinical translation. mice, after preconditioning with Busulfan (25 mg/kg). When þ CD45.2 cells raised to 15% of total B cells, 5  106 Materials and Methods mTERT198–205– or OVA257–264–specific CTLs were intravenously Mice injected twice in mice after g-irradiation, followed by recombi- C57BL/6 (C57BL/6NCrl) mice were purchased from Charles nant IL2 administration (17). River Laboratories Inc.; OT-1 (C57Bl/6-Tg(TcraTcrb)1100Mjb/ þ J) and CD45.1 mice (B6.SJL-PtrcaPepcb/BoyJ) from The Jack- Systemic treatment of human leukemic chimeras son Laboratory; NOG (NOD.Cg-Prkdcscid Il2rgtm1Sug/JicTac) NOG mice were g-irradiated (1.20 Gy) and subsequently À/À À/À tm1Fwa tm1Wjl À þ and Rag2 /gc mice (B10;B6-Rag2 II2rg )from engrafted with 105 human HLA-A2 CD34 cells via tail-vein Taconic. The transgenic mice IgH.TEm have been described injection, as previously reported (35).
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