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T-Cell Receptor Stimulation Enhances the Expansion and Function Of Published OnlineFirst September 26, 2019; DOI: 10.1158/1078-0432.CCR-18-3199 Clinical Trials: Immunotherapy Clinical Cancer Research T-Cell Receptor Stimulation Enhances the Expansion and Function of CD19 Chimeric Antigen Receptor–Expressing T Cells Natalia Lapteva1,2, Margaret Gilbert1, Iulia Diaconu1,LisaA.Rollins1, Mina Al-Sabbagh1, Swati Naik1,3,4,RobertA.Krance1,3,4, Tamara Tripic1, Manasa Hiregange1, Darshana Raghavan1,OlgaDakhova1, Rayne H. Rouce1,3,4,HaoLiu1,5, Bilal Omer1,3,4, Barbara Savoldo1,3, Gianpietro Dotti1,2,6, Conrad Russel Cruz1, Keli Sharpe1, Melissa Gates1, Aaron Orozco1, April Durett1, Elizabeth Pacheco1, Adrian P. Gee1,3,CarlosA.Ramos1,6,7, Helen E. Heslop1,3,4,6,7, Malcolm K. Brenner1,3,4,6,7, and Cliona M. Rooney1,2,3,4,8,9 Abstract Purpose: Current protocols for CD19 chimeric antigen cells (CD19.CAR-VST) without prior cytoreductive chemo- receptor–expressing T cells (CD19.CAR-T cells) require reci- therapy into 8 patients after allogeneic stem cell transplant. pients to tolerate preinfusion cytoreductive chemotherapy, Results: Absent virus reactivation, we saw no CD19. and the presence of sufficient target antigen on normal or CAR-VST expansion. In contrast, in patients with viral reacti- malignant B cells. vation, up to 30,000-fold expansion of CD19.CAR-VSTs was þ Patients and Methods: We investigated whether additional observed, with depletion of CD19 B cells. Five patients stimulation of CD19.CAR-T cells through their native recep- remain in remission at 42–60þ months. tors can substitute for cytoreductive chemotherapy, inducing Conclusion: Dual T-cell receptor and CAR stimulation can expansion and functional persistence of CD19.CAR-T even in thus potentiate effector cell expansion and CAR-target cell patients in remission of B-cell acute lymphocytic leukemia. We killing, even when infusing low numbers of effector cells infused a low dose of CD19.CAR-modified virus-specificT without cytoreduction. Introduction lymphodepleting chemotherapy. Optimal CAR-T–cell expansion and persistence currently requires administration of toxic cytor- Chimeric antigen receptor–expressing T cells directed to the eductive chemotherapy, which may be undesirable or impractical CD19 antigen (CD19.CAR-T) have proved remarkably effective for some patients (4). Even when cytoreductive therapy is an in treatment of pre-B acute lymphocytic leukemia (ALL) and acceptable option, engraftment of CAR-T cells may be insufficient other B-cell malignancies (1–3). In principle, signaling through for sustained antitumor activity if there are limiting numbers of CD19 and other CARs could be reinforced by concomitant or normal and malignant target cells expressing the CAR-target sequential signaling through the native T-cell receptor (TCR). antigen (5). We therefore examined whether combined TCR and Demonstration of such an effect would have two major benefits, CAR stimulation can obviate preinfusion cytoreduction, and by inducing CAR-T–cell expansion and reducing the toxicity of whether it can also expand functional CAR-T cells even when these cells are infused in small numbers and/or their cognate 1 Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Meth- antigen is present at insufficient levels for their desired expansion odist Hospital, Texas Children's Hospital, Houston, Texas. 2Division of Immu- nology, Department of Pathology, Baylor College of Medicine, Houston, Texas. and persistence. fi 3Division of Hematology and Oncology, Department of Pediatrics, Baylor To assess the putative bene ts of dual TCR/CAR stimulation, we College of Medicine, Houston, Texas. 4Texas Children's Hospital, Houston, Texas. chose patients who received allogeneic hematopoietic stem cell 5Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of transplantation (HSCT) as treatment for high risk pre-B-cell 6 Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, leukemia. These patients are at risk both for leukemic relapse 7 8 Houston, Texas. Houston Methodist Hospital, Houston, Texas. Program of and for severe viral infections, so that a T-cell product with both Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas. 9Department of Molecular Virology and Microbiology of Baylor antileukemic and antiviral activity could provide a safe means to fi College of Medicine, Houston, Texas. protect patients from both. Adoptively transferred virus-speci cT cells (VST) proliferate extensively after infusion into recipients of Note: Supplementary data for this article are available at Clinical Cancer – Research Online (http://clincancerres.aacrjournals.org/). T-cell depleted allogeneic HSCT with viral reactivation, and then return to the long-term memory population, where they retain the Corresponding Author: Cliona M. Rooney, Baylor College of Medicine, One ability to reexpand in response to virus reactivation (6). We Baylor Plaza, Houston, TX 77030. Phone: 832-824-4693; Fax: 832-825-4732; fi E-mail: [email protected] reasoned that if donor VSTs were modi ed with leukemia- specific CD19.CAR, they also should expand in the presence of Clin Cancer Res 2019;XX:XX–XX viral infection or reactivation and protect patients from both viral doi: 10.1158/1078-0432.CCR-18-3199 infections and leukemic relapse, thereby achieving dual ends Ó2019 American Association for Cancer Research. through a single means. www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst September 26, 2019; DOI: 10.1158/1078-0432.CCR-18-3199 Lapteva et al. cell manufacture at median of 11 days prior to transplant (range Translational Relevance 1–31 days prior to HSCT). It is widely accepted that cytotoxic lymphodepletion prior to adoptive T-cell immunotherapy is essential for the expan- Adenoviral and retroviral vectors sion and antitumor efficacy of adoptively transferred chimeric Both vectors were produced by the Vector Production Facility of antigen receptor–modified T cells (CAR-T cell). However, not the Center for Cell and Gene Therapy, Baylor College of Medicine. all patients, in particular hematopoietic stem cell transplant The CD19.CAR scFv domain, FMC-63, targeting the CD19 antigen (HSCT) recipients, can tolerate this treatment. Here we show was provided by Heddy Zola (Child Health Research Institute, that viruses can induce exponential expansion of CD19 Women's and Children's Hospital, Adelaide, South Australia, chimeric antigen receptor expressing virus-specific T cells Australia; ref. 7). The CAR.CD19-28z vector was generated as without cytokine release syndrome or neurotoxicity in HSCT described previously (8–10). Briefly, a spacer region derived from recipients at high risk for relapse of B-cell acute lymphoblastic the human IgG1-CH2CH3 domain was cloned in-frame between leukemia. This work provides proof of the concept that CAR-T the scFv and the signaling domains and cloned into the SFG cells can be expanded via their T-cell receptor (TCR) without retroviral backbone. Clinical grade packaging cell lines were lymphodepletion and supports investigation of viral vaccines generated with the use of PG13 cells (gibbon ape leukemia virus or oncolytic viruses to expand T cells bispecific for cognate viral pseudotyping packaging cell line; CRL-10686, ATCC). antigens via their TCR and for tumor antigens via their CAR. To generate antigen-presenting cells (APC) for VST generation, we used a previously described adenoviral vector, Ad5f35-pp65 containing the immunodominant pp65 protein of CMV (11, 12), to transduce EBV-transformed B lymphoblastoid cell lines (LCL). Ad5f35-pp65–transduced LCLs presented de novo–expressed We therefore tested the efficacy of CD19.CAR-VSTs in pp65, the hexon and penton proteins from the Ad vector and þ eight HSCT recipients in remission from high-risk, CD19 B-cell endogenous EBV proteins (13). ALL (B-ALL). Patients received donor T cells specific for cytomeg- alovirus (CMV), Epstein–Barr virus (EBV), and adenovirus Generation of EBV-transformed B LCLs (multivirus-specific T cells) modified with a second generation LCLs were generated in our Good Manufacturing Practices CD19.CAR. CD19.CAR-VSTs could be detected by PCR for a (GMP) facility by infection of peripheral blood mononuclear median of 182 weeks (range 8 weeks to 5 years), but only in the cells (PBMC) from each stem cell donor, with a clinical grade EBV presence of viral reactivation was there a substantive expansion produced by a clinical grade B95-8 producer cell line, in the of CD19.CAR-VSTs and associated B-cell aplasia, despite the presence of cyclosporin A (1 mg/mL; Sandoz) as described pre- presence of significant numbers of normal B cells in all patients viously (14). Autologous LCLs were irradiated and used as APCs at the time of infusion. Hence, concomitant signaling through the after transduction with Ad5f35-pp65. TCR and CAR can enhance the proliferation and the function of CAR-VSTs. Generation of multivirus-specific T cells VSTs specific for CMV, EBV, and adenovirus were expanded from 40–60 mL of peripheral blood from the stem cell donor. Patients and Methods PBMCs were purified using Lymphoprep (Axel-Shield PoC As). To Patients generate APCs for the first stimulation of VSTs, donor LCLs were The study was conducted in accordance with the U.S. Common transduced with Ad5f35-pp65 at 10,000 virus particles per cell, Rule following approval by an Institutional Review Board of irradiated, and cocultured with autologous PBMCs
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