The Emerging Role of In Vitro-Transcribed mRNA in Adoptive T Cell Immunotherapy
2019; Elsevier BV; Volume: 27; Issue: 4 Linguagem: Inglês
10.1016/j.ymthe.2019.01.018
ISSN1525-0024
AutoresJessica Foster, David M. Barrett, Katalin Karikó,
Tópico(s)RNA Interference and Gene Delivery
ResumoAdoptive T cell therapy is a form of cellular therapy that utilizes human immune cells, often empowered by the expression of recombinant proteins, to attack selected targets present on tumor or infected cells. T cell-based immunotherapy has been progressing over the past several decades, and reached a milestone with the recent US Food and Drug Administration (FDA) approval of chimeric antigen receptor T cell therapy for relapsed and refractory leukemia and lymphoma. Although most studies have used viral vectors, a growing number of researchers have come to appreciate in vitro-transcribed (IVT) mRNA for the development, testing, and application of T cell-based immunotherapeutics. IVT mRNA offers inherent safety features, highly efficient recombinant protein translation, and the ability to control pharmacokinetic properties of the therapy. In this review, we discuss the history of IVT mRNA in adoptive T cell therapy, from tumor-infiltrating lymphocytes and T cell receptor-based therapies to chimeric antigen receptor therapy and gene-editing techniques, as well as prior and ongoing clinical trials. Adoptive T cell therapy is a form of cellular therapy that utilizes human immune cells, often empowered by the expression of recombinant proteins, to attack selected targets present on tumor or infected cells. T cell-based immunotherapy has been progressing over the past several decades, and reached a milestone with the recent US Food and Drug Administration (FDA) approval of chimeric antigen receptor T cell therapy for relapsed and refractory leukemia and lymphoma. Although most studies have used viral vectors, a growing number of researchers have come to appreciate in vitro-transcribed (IVT) mRNA for the development, testing, and application of T cell-based immunotherapeutics. IVT mRNA offers inherent safety features, highly efficient recombinant protein translation, and the ability to control pharmacokinetic properties of the therapy. In this review, we discuss the history of IVT mRNA in adoptive T cell therapy, from tumor-infiltrating lymphocytes and T cell receptor-based therapies to chimeric antigen receptor therapy and gene-editing techniques, as well as prior and ongoing clinical trials. The existence of mRNA, a labile molecule that carries information of the encoded protein from the chromosome to the site of translation, was discovered in the early 1960s. However, technologies to generate in vitro-transcribed (IVT) mRNA only became available in 1984, and ever since, IVT mRNA has been utilized for its therapeutic potential.1Sahin U. Karikó K. Türeci Ö. mRNA-based therapeutics—developing a new class of drugs.Nat. Rev. Drug Discov. 2014; 13: 759-780Google Scholar Within cells, mRNA is the blueprint for protein production. IVT mRNA can be translated into any protein when introduced into cells, thus providing an opportunity to manipulate and augment cells in any imaginable way. In addition, IVT mRNA has become an attractive tool because of its rapid and facile production, as well as its safety profile. Unlike DNA, IVT mRNA has no risk of causing insertional mutagenesis and no long-term concern for side effects because of its labile nature. The affordability and ease-of-use allow for iterative trials in the development of novel therapies. Immunotherapy is the use of the immune system to attack specific targets, such as malignant cells or viruses. Immunotherapy encompasses many different types of therapy that utilize different components of the immune system. Adoptive T cell therapy is one form of immunotherapy that focuses on ex vivo expansion of T cells and manipulation of cells for targeted cytotoxicity, prior to returning the T cells into the patient (Figure 1). In this review, we discuss the recent use of IVT mRNA in adoptive T cell therapy, ranging from tumor-directed immunotherapy to infectious disease applications. We highlight the strengths and weaknesses of using IVT mRNA for this approach, as well as the recent clinical trials applying this technology. Non-viral gene transfer into primary T lymphocytes has long been problematic because of the poor efficiency of delivery. However, initial preclinical and clinical studies confirmed that dendritic cells (DCs) electroporated ex vivo with antigen-encoding IVT mRNA generate potent immune responses.2Van Tendeloo V.F.I. Ponsaerts P. Lardon F. Nijs G. Lenjou M. Van Broeckhoven C. Van Bockstaele D.R. Berneman Z.N. Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells.Blood. 2001; 98: 49-56Google Scholar, 3Zhao Y. Boczkowski D. 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Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells.Blood. 2001; 98: 49-56Google Scholar Similar results were also observed in macrophages5Van De Parre T.J. Martinet W. Schrijvers D.M. Herman A.G. De Meyer G.R. mRNA but not plasmid DNA is efficiently transfected in murine J774A.1 macrophages.Biochem. Biophys. Res. Commun. 2005; 327: 356-360Google Scholar and CD40-activated B cells electroporated with IVT mRNA.6Van den Bosch G.A. Ponsaerts P. Nijs G. Lenjou M. Vanham G. Van Bockstaele D.R. Berneman Z.N. Van Tendeloo V.F. Ex vivo induction of viral antigen-specific CD8 T cell responses using mRNA-electroporated CD40-activated B cells.Clin. Exp. Immunol. 2005; 139: 458-467Google Scholar, 7Van den Bosch G.A. Van Gulck E. Ponsaerts P. Nijs G. Lenjou M. Apers L. Kint I. Heyndrickx L. Vanham G. 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After investigating a variety of electroporation conditions, they could achieve >90% efficiency and >80% viability.9Zhao Y. Zheng Z. Cohen C.J. Gattinoni L. Palmer D.C. Restifo N.P. Rosenberg S.A. Morgan R.A. High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation.Mol. Ther. 2006; 13: 151-159Google Scholar They also electroporated T cells with IVT mRNA encoding the α and β chains of T cell receptor (TCR) directed against NY-ESO-1, MART-1, and p53. These T cells transduced with TCR mRNA produced interferon (IFN) gamma when exposed to T2 cells pulsed with the corresponding peptides or specific melanoma cell lines expressing NY-ESO-1.9Zhao Y. Zheng Z. Cohen C.J. Gattinoni L. Palmer D.C. Restifo N.P. Rosenberg S.A. Morgan R.A. High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation.Mol. Ther. 2006; 13: 151-159Google Scholar That same year, Schaft et al.10Schaft N. Dörrie J. Müller I. Beck V. Baumann S. Schunder T. Kämpgen E. Schuler G. A new way to generate cytolytic tumor-specific T cells: electroporation of RNA coding for a T cell receptor into T lymphocytes.Cancer Immunol. Immunother. 2006; 55: 1132-1141Google Scholar also reported successful introduction of glycoprotein 100 (gp100)-specific TCR into primary T cells using IVT mRNA, again with excellent cytotoxicity in peptide-loaded T2 cells and melanoma cell lines. In 2006, Rabinovich et al.11Rabinovich P.M. Komarovskaya M.E. Ye Z.J. Imai C. Campana D. Bahceci E. Weissman S.M. Synthetic messenger RNA as a tool for gene therapy.Hum. Gene Ther. 2006; 17: 1027-1035Google Scholar were the first to transduce T cells with IVT mRNA encoding chimeric antigen receptors (CARs) directed against CD19 and demonstrated functionality of those T cells in vitro. By 2009, several studies reported using IVT mRNA to create hematopoietic cells with CARs. Birkholz et al.12Birkholz K. Hombach A. Krug C. Reuter S. Kershaw M. Kämpgen E. Schuler G. Abken H. Schaft N. Dörrie J. Transfer of mRNA encoding recombinant immunoreceptors reprograms CD4+ and CD8+ T cells for use in the adoptive immunotherapy of cancer.Gene Ther. 2009; 16: 596-604Google Scholar reported the efficacy of ErbB2 and carcinoembryonic antigen (CEA)-directed CAR T cells created with IVT mRNA, with modest cytotoxicity against a variety of cancer cell lines in vitro. Yoon et al.13Yoon S.H. Lee J.M. Cho H.I. Kim E.K. Kim H.S. Park M.Y. Kim T.G. Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model.Cancer Gene Ther. 2009; 16: 489-497Google Scholar applied the electroporation method described by Zhao et al.9Zhao Y. Zheng Z. Cohen C.J. Gattinoni L. Palmer D.C. Restifo N.P. Rosenberg S.A. Morgan R.A. High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation.Mol. Ther. 2006; 13: 151-159Google Scholar on stimulated peripheral blood lymphocytes as the effector cells. Using T cells transduced with IVT mRNA encoding Her2/neu-directed CAR and containing signaling domains of CD28 and CD3 zeta, antitumor activity could be demonstrated in both in vitro and in vivo ovarian tumor models.13Yoon S.H. Lee J.M. Cho H.I. Kim E.K. Kim H.S. Park M.Y. Kim T.G. Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model.Cancer Gene Ther. 2009; 16: 489-497Google Scholar As a follow-up, they investigated cytokine-induced killer cells electroporated with IVT mRNA encoding the same Her2/neu CAR.14Yoon S.H. Lee J.M. Woo S.J. Park M.J. Park J.S. Kim H.S. Park M.Y. Sohn H.J. Kim T.G. Transfer of Her-2/neu specificity into cytokine-induced killer (CIK) cells with RNA encoding chimeric immune receptor (CIR).J. Clin. Immunol. 2009; 29: 806-814Google Scholar Again, they showed significant antitumor effects against in vitro and in vivo tumor models. While in both studies lymphocytes transduced with CAR mRNA inhibited tumor growth better than Herceptin, a monoclonal antibody (mAb) specific for Her2/neu, in both studies tumor growth was slowed only without any tumor regression.13Yoon S.H. Lee J.M. Cho H.I. Kim E.K. Kim H.S. Park M.Y. Kim T.G. Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model.Cancer Gene Ther. 2009; 16: 489-497Google Scholar, 14Yoon S.H. Lee J.M. Woo S.J. Park M.J. Park J.S. Kim H.S. Park M.Y. Sohn H.J. Kim T.G. Transfer of Her-2/neu specificity into cytokine-induced killer (CIK) cells with RNA encoding chimeric immune receptor (CIR).J. Clin. Immunol. 2009; 29: 806-814Google Scholar In 2009, Rabinovich et al.15Rabinovich P.M. Komarovskaya M.E. Wrzesinski S.H. Alderman J.L. Budak-Alpdogan T. Karpikov A. Guo H. Flavell R.A. Cheung N.K. Weissman S.M. Bahceci E. Chimeric receptor mRNA transfection as a tool to generate antineoplastic lymphocytes.Hum. Gene Ther. 2009; 20: 51-61Google Scholar separated T cells and natural killer (NK) cells from PBMCs for transfection with CAR mRNA. The IVT CAR mRNA was introduced into CD3+/CD4+ T cells and CD3+/CD8+ T cells, as well as NK cells. Electroporation of all these cell populations resulted in high levels of surface expression of CAR.15Rabinovich P.M. Komarovskaya M.E. Wrzesinski S.H. Alderman J.L. Budak-Alpdogan T. Karpikov A. Guo H. Flavell R.A. Cheung N.K. Weissman S.M. Bahceci E. Chimeric receptor mRNA transfection as a tool to generate antineoplastic lymphocytes.Hum. 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Plesa G. et al.Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells.Sci. Transl. Med. 2013; 5: 197ra103Google Scholar These unfortunate events highlighted the importance of safety issues when using permanently altered T cells and increased the interest in safe alternatives such as IVT mRNA. As discussed above, Zhao e
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