Page 875 - Hematology_ Basic Principles and Practice ( PDFDrive )

758 Part VI Non-Malignant Leukocytes

EBV-specific T cells demonstrated their safety, but infused T cells had numerous benign macrophages that have ingested apoptotic tumor
limited antitumor activity against HD and NHL in comparison to cells (Fig. 54.7A–C). Although almost all endemic BLs in equatorial
EBV-LPD. This lack of efficacy could be due in part to immunosup- Africa are associated with EBV, the virus has been implicated less
pressive factors secreted by lymphoma cells or may simply be quan- often in sporadic cases, and in the United States only 20% of BL are
titative in that the method used for EBV-specific T-cell generation EBV positive. In developing countries, an intermediate type of BL
produces T-cell lines that are dominated by clones reactive to viral has been described, both in its clinical presentation and association
proteins not expressed in latency type II lymphoma. To improve with EBV, which varies from 25% to 80%. As with NPC and HD,
T-cell efficacy methods to expand T-cell specific for the EBV proteins there is strong circumstantial evidence linking EBV to BL. The EBV
LMP1 and LMP2 expressed in latency type II lymphoma and to genome is clonal as in other EBV-associated malignancies. The
genetically modify the expanded T cells to render them resistant majority of BLs carry a translocation between the long arm of chro-
against inhibitory cytokines have been developed. We conducted two mosome 8, the site of the MYCC oncogene (8q24), and the Ig heavy
clinical studies with LMP1/2 (LMP)-specific T cells in patients with chain region on chromosome 14, t(8;14). Although the t(8;14)
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EBV-positive HD and NHL. The initial trial targeted LMP2 alone translocation is seen in endemic as well as sporadic BLs, the exact
and the subsequent LMP1 and LMP2. On both trials combined, 50 location of the chromosomal breakpoints on chromosome 8 and 14
patients received LMP-specific T cells. Of 29 patients who received differ. Other chromosomal translocations seen in BLs are between
these cells as adjuvant therapy, 28 remained in remission for a median MYCC and the κ-light chain locus on chromosome 2, t(2;8), or the
of 3.1 years. Thirteen out of 21 patients infused with active disease λ-light chain locus on chromosome 22, t(8;22).
had objective clinical responses with 11 patients being complete. Current treatment strategies rely on intensive chemotherapy, and
While LMP-specific T cells had clinical activity, generation required overall survival depends on extent of disease at presentation, being
not only LCLs but also recombinant adenovirus vectors encoding 90% to 100% for local and 60% to 70% for advanced disease. The
LMP1 and LMP2. After having developed an LMP-specific T-cell prospect for the development of an EBV-specific immunotherapy
production process that is devoid of LCLs and recombinant adeno- for BLs is problematic because lymphoma cells evade the immune
virus vectors, these cells are currently being tested in clinical studies. system by downregulating the expression of EBV latency antigens,
To evaluate if rendering LMP-specific T cells resistant to the immu- cell adhesion molecules, and MHC class I molecules. EBNA1, the
nosuppressive lymphoma environment enhances their antitumor only EBV protein expressed in BL, autoregulates its own transla-
activity, we focused on targeting TGF-β, which promotes tumor tion and inhibits HLA class I presentation because of an internal
growth, limits T-cell effector function, and actives inhibitory, regula- glycine-alanine repeat region. However, the characterization of
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tory T cells. These detrimental effects of TGF-β can be overcome by EBNA1-specific CD4 T cells, as well as rare CD8 T cells that can
modifying T cells to express a dominant negative TGF-β receptor recognize BL through EBNA1, has provided impetus to explore the
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(DNR), which lacks its intracellular signaling domain. DNR expres- role of CD4 T cells in the control and therapy of BL. In addition,
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sion blocks TGF-β signaling and restores T-cell effector function in EBNA1-specific CD4 T cells had potent antitumor activity in a
the presence of TGF-β. Initial testing in humans indicate that DNR- murine model of BL. As discussed in the EBV-LPD section, induction
modified LMP-specific T cells benefit patients who failed therapy of the lytic EBV cycle is another attractive EBV-targeted approach
with unmodified cells. For a detailed discussion on cell therapy with for BL.
conventional or genetically modified T cells targeting non-viral
antigens for hematologic malignancies see Chapters 98 and 100. In
addition to genetically modifying T cells to enhance their antitumor Nasopharyngeal Carcinoma
activity, combining the adoptive transfer of T cells with monoclonal
antibodies that block immune checkpoints, such as PD-1/PD-L1, NPC arises from the epithelial cells of the nasopharynx. The WHO
hold the promise to enhance their antitumor activity. This approach classifies NPC into keratinizing squamous cell carcinoma (type 1),
has not been tested in humans; however, clinical studies are currently nonkeratinizing carcinoma (type 2), and undifferentiated carcinoma
being planned. (type 3, most common). Type 2 and 3 carcinomas are associated with
EBV (Fig. 54.7D, E); however, environmental and genetic factors
Epstein-Barr Virus-Associated Non-Hodgkin Lymphoma play an important role in oncogenesis, because the incidence of NPC
varies 50- to 100-fold from Southern China to Western countries.
in HIV Patients EBV was initially linked to NPC by the observation that patients had
elevated levels of VCA-IgG, VCA-IgA, and EA-IgG antibodies.
Patients infected with HIV are at high risk to develop NHL. The Further studies showed that EBV-DNA is present in every tumor cell
incidence increases with age, and the male-to-female ratio is approxi- of type 2 and 3 carcinomas with remarkable consistency. As in HD,
mately 2 : 1. Depending on certain histologic features, the EBV associa- the EBV episome in an individual tumor is clonal.
tion ranges from 30% in systemic HIV-related BL (HIV-BL) to 70% EBV antibody responses have been used to follow tumor burden
to 80% in HIV-related immunoblastic lymphoma (HIV-IBL), and in patients with NPC; in addition, VCA-IgA antibodies and antibod-
virtually all cases of primary central nervous system lymphoma ies against EBV DNase are predictive for NPC in high-risk popula-
(PCNSL) are EBV-positive. In biopsies of EBV-associated HIV-NHL, tions. More recently, detection of EBV-DNA in serum by different
there is considerable variation in the number of EBV-positive cells, and PCR methods has shown to be useful for the diagnosis, prognosis,
the pattern of EBV latent gene expression varies among tumor types and monitoring of patients with NPC. Most patients with NPC are
as in immunocompetent individuals (Fig. 54.6, E, F). In HIV-infected treated with radiation. Other modalities such as surgery, chemo-
patients, the development of EBV-associated HIV-NHL is preceded by therapy, and combined approaches may be appropriate in selected
a loss of functional EBV-specific T cells, suggesting that strategies to circumstances, but a detailed discussion is beyond the scope of this
boost the endogenous EBV-specific T-cell response might prevent chapter. In NPC, as for EBV-positive lymphomas, only a limited
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lymphomas. Restoring CD4 T-cell counts in patients with HIV with number of EBV latent antigens are expressed. Three therapeutic
highly active antiretroviral therapy (HAART) has decreased the inci- vaccine studies targeting LMP2, LMP1 and LMP2, or EBNA1 and
dence of PCNSL and HIV-NHL. The clinical experience with T-cell LMP2 have been conducted, and the results of these trials were dis-
therapy for EBV-associated HIV-NHL is limited. cussed in the earlier section EBV Vaccine Development.
The adoptive transfer of autologous EBV-specific T cells is being
actively explored. Several groups have reported that the infusion of
Burkitt Lymphoma T cells is safe and has resulted in clinical responses, especially in
patients with locoregional disease. In addition, EBV-specific T cells,
BL is a high-grade malignant small noncleaved B-cell lymphoma. given as adjuvant after chemotherapy, resulted in a significant increase
Histology usually reveals a “starry-sky” pattern resulting from in 3-year overall survival in comparison to historical controls, who