Page 434 - Williams Hematology ( PDFDrive )

409

CHAPTER 26 ADOPTIVE CELLULAR THERAPY

OF VIRAL DISEASES
IMMUNE CELL THERAPY Two broad subsets of antigen-specific T cells cooperate to terminate

acute viral infections and control reactivation of latent viruses. CD8+
Carolina Berger and Stanley R. Riddell cytotoxic T lymphocytes (CTLs) recognize viral peptides presented by
major histocompatibility complex (MHC) class I molecules and lyse
infected cells, and produce inflammatory cytokines. CD4+ T-helper
(Th) cells recognize viral peptides presented by class II MHC molecules
SUMMARY and produce cytokines that amplify T-cell responses and promote B-cell
proliferation and antibody production. A deficiency of CD8+ and CD4+
T cells represent an important component of the host response to patho- Th cells occurs after allogeneic hematopoietic stem cell transplantation
gens and tumors. Adoptive T-cell therapy, in which T cells are isolated or (HSCT) as a consequence of the administration of intensive chemora-
engineered to be specific for molecules expressed on diseased cells and diotherapy, anti–T-cell monoclonal antibodies (mAbs), and/or immu-
administered to patients, has shown efficacy in infections and malignancy. nosuppressive drugs, and these patients are at risk for life-threatening
Clinical applications of T-cell therapy have been facilitated by identification viral infections. Clinical trials have shown that adoptive T-cell ther-
1–5
of target antigens expressed by viruses and tumors, improvement in strate- apy has antiviral activity against cytomegalovirus (CMV), Epstein-Barr
gies for the isolation and genetic engineering of antigen-specific T cells with virus (EBV), and adenovirus infection in immunocompromised alloge-
intrinsic qualities that enable their persistence in vivo, and recognition that neic HSCT recipients. 6,7
transferring T cells into a lymphopenic environment improves the efficiency
of cell transfer and treatment efficacy. Insights into the obstacles to routinely T-CELL THERAPY OF CYTOMEGALOVIRUS
achieving an effective antitumor response either by T-cell therapy or vacci- INFECTION
nation have been derived from careful analysis of clinical trials, and further The first application of adoptive T-cell therapy with antigen-specific T
development of immune cell therapy combined with interventions that cells in humans was to treat CMV infection after allogeneic HSCT. CMV
target specific regulatory or inhibitory pathways that are present in tumor is a DNA virus that infects hematopoietic progenitors, monocytes, and
8
microenvironments and impede effective immunity represent promising endothelial cells. To evade complete elimination by host immunity,
areas for future applications. CMV encodes proteins that interfere with antigen presentation in cells
that contain replicating virus, and establishes latency. Normal CMV+
9
individuals maintain high levels of CD8+ and CD4+ T cells that are
specific for CMV antigens, and these responses are essential to control
infection. 10–12 CMV frequently reactivates in individuals with a T-cell
immunodeficiency, such as after allogeneic HSCT and solid-organ
transplantation, and contributes to morbidity and mortality. Lympho-
cytopenia and a deficiency of functional CMV-specific T cells persist for
Acronyms and Abbreviations: ALL, acute lymphatic leukemia; BCMA, B-cell several months in many HSCT recipients, including cord blood trans-
maturation antigen; CAR, chimeric antigen receptor; cDNA, complemen- plant recipients, and CMV reactivation is frequent. 13–15 Antiviral drugs
16–18
tary DNA; CDR3, complementarity determining region 3; CEA, carcinoem- are used to suppress CMV, but often provide only temporary control
of reactivation, and restoration of immune function is essential to con-
bryonic antigen; CLL, chronic lymphatic leukemia; CMV, cytomegalovirus; tain CMV infection. 13,19–21
CRS, cytokine release syndrome; CTL, cytotoxic T lymphocyte; DLI, donor
lymphocyte infusion; E, early viral protein; EBV, Epstein-Barr virus; EGFR, Target Antigens for Cytomegalovirus-Specific T Cells
epidermal growth factor receptor; ERBB2IP, erbb2 interacting protein; Studies of the specificity of CMV-specific T cells isolated from immu-
GD2, disialoganglioside; GVHD, graft-versus-host disease; GVL, graft- nocompetent CMV seropositive individuals identified antigens to tar-
versus-leukemia; HHV-6, human herpes virus-6; HLA, human leukocyte get in T-cell therapy. 15,21 A majority of CD8+ CTLs elicited by in vitro
antigen; HSCT, hematopoietic stem cell transplantation; HSV, herpes sim- stimulation with autologous CMV-infected cells recognize virion pro-
plex virus; HSV-TK, herpes simplex virus thymidine kinase; iCasp9, inducible teins, including the pp65 and pp150 matrix proteins that are introduced
caspase-9; IE, immediate early viral protein; IFN-γ, interferon-γ; IL, interleu- into the cytoplasm of cells immediately following viral entry and pro-
kin; L1CAM, L1-cell adhesion molecule; LCL, lymphoblastoid cell line; LPD, cessed and presented for T-cell recognition. Although virion proteins
lymphoproliferative disease; mAbs, monoclonal antibodies; mHAgs, minor are important targets for CD8+ T cells, stimulation of peripheral blood
mononuclear cells (PBMCs) from normal CMV+ donors with panels of
histocompatibility antigens; MHC, major histocompatibility complex; PBMC, CMV peptides, or with cells infected with a CMV strain in which the
peripheral blood mononuclear cell; PD-1 receptor, programmed death-1 immune evasion genes had been deleted, identified significant CD8+
receptor; PML-RARα, promyelocytic leukemia–retinoic acid receptor α pro- T-cell responses to intermediate-early (IE) or early (E) viral proteins. 10,11
tein; scFV, single-chain variable fragment; SNP, single nucleotide polymor- IE and E are not efficiently presented to T cells in vitro by cells rep-
phism; T , central memory T cell; TCR, T-cell receptor; T , effector T cell; T , licating wild-type CMV, but evidence from animal models suggests
EM
E
CM
effector memory T cell; Th, T helper; TIL, tumor-infiltrating lymphocyte; T , that IE-specific T cells recognize cells that are reactivating CMV from
REG
22
regulatory T cell; T , T memory stem cell; WT-1, Wilms tumor antigen-1. latency. Thus, reconstitution of responses both to virion and IE or E
SCM
antigens may be necessary to restore control of both the latent and rep-
licating pools of virus in immune-deficient hosts. 23

Kaushansky_chapter 26_p0409-0420.indd 409 9/17/15 6:00 PM