Page 1765 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 100 T-Cell Therapy of Hematologic Diseases 1569

complication of DLI usually increases in frequency and severity if significant reduction of the time necessary for the generation of clini-
donor and recipient are unrelated or human leukocyte antigen (HLA) cal grade VSTs (<10 days), without compromising their specificity or
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haploidentical. Strategies aimed at retaining the benefits of GVL increasing the risk of GVHD. Another important change has been
whilst preventing GVHD have included the depletion of alloreactive the creation of banks in which VSTs from donors with common HLA
T cells in the donor lymphocyte product and the incorporation of polymorphisms can be manufactured in advance and stored for
suicide genes into the infused donor T cells so that they may be killed immediate administration to partially HLA matched transplant
4,5
if the GVHD activity exceeds the benefits from GVL. Recently, the recipients with active virus infections. Crawford and colleagues previ-
manipulation of the stem cell graft to deplete only the αβ T-cell ously demonstrated that such a “third party” bank of polyclonal
receptor (TCR)+ T lymphocytes whilst retaining the γδTCR+ T-cell EBV-VSTs could be safely infused based on the best available HLA
compartment may reduce GVHD without compromising stem cell match and had a high success rate in patients who developed EBV-
engraftment and retain some protection against opportunistic infec- lymphoproliferation after solid organ transplantation (SOT). In a
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tions. Ultimately, investigators may wish to identify tumor-restricted phase-II multicenter trial, 33 patients with EBV-LPD had an overall
target antigens on the malignant cells and infuse antigen specific T response rate of 64% at 5 weeks and 52% at 6 months. These
cells directed to them. It has proved feasible to prepare donor-derived impressive results in SOT recipients led us to develop a similar
T lymphocytes specific for mHags and to show both the feasibility multicenter study to evaluate whether “best matched” VSTs may have
and potential efficacy of the approach, although scalability remains similar activity against EBV, CMV, and adenovirus after allogeneic
challenging. 7 HSCT. We observed a circa 75% response rate to all three viruses,
comparable to the reported response rates obtained by infusing VSTs
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generated from the stem cell donor. This approach may be suited
Infusion of Activated T Lymphocytes for further scale up and broader application. An alternative approach
is to eliminate ex vivo expansion of VSTs by selecting such cells
When T cells are polyclonally stimulated, for example by simultane- directly from leukapheresis products. This can be accomplished by
ously cross-linking their CD3 and CD28 receptors by CD3/CD28 using HLA-multimers to bind the relevant cells, or by overnight
monoclonal antibodies on beads, then the cells proliferate. They also exposure to viral peptides to stimulate γ-IFN production followed by
secrete tumoricidal cytokines such as TNFα and can mediate MHC- bead selection of γ-IFN+ cells. These selected VSTs are then infused
unrestricted cytotoxicity towards a range of tumor target cells. Efforts into the recipients without any ex vivo expansion, and their use is
have been made to harness these effects by producing large numbers being explored for the prevention and treatment of CMV and other
of CD3/CD28-activated T cells for cancer patients and infusing viral infections after HSCT.
them. Although infusion of CD3/CD28-ATL after autologous stem
cell transplant may improve patients T-cell reconstitution, as yet there
8
is no evidence to suggest improved antitumor activity. ATL that are Adoptive Immunotherapy of
additionally primed with interferon gamma (IFN-γ) and interleukin Virus-Associated Malignancies
(IL)-2 (so called cytokine-induced killer cells or CIK) may have
superior clinical potential for hematologic malignancies and early The encouraging results of adoptive immunotherapy with EBV-VSTs
phase clinical trials may be showing clinical benefits. 9 in the immunocompromised host led us to extend this strategy to
other EBV-associated tumors (lymphoma and nasopharyngeal cancer)
Adoptive Immunotherapy With Virus-Specific Cytotoxic that develop in the immunocompetent patient. Unlike EBV-LPD,
which expresses the highly immunogenic viral latency antigens
T Lymphocytes EBNA1, EBNA2, and EBNA3, these other EBV tumors express a
limited number of poorly processed (EBNA1) or weakly stimulatory
Viral infections are one of the most common causes of morbidity and (latent membrane protein [LMP]1 and LMP2) EBV-derived antigens.
mortality after allogeneic HSCT, and are more prevalent as the degree We have therefore used VSTs specific for these EBV antigens, begin-
of antigen mismatching between donor and recipient is increased. ning with the cells directed to LMP2. Initially, the VSTs were gener-
Cord blood transplantation in particular, is associated with often- ated from patients with Hodgkin lymphoma or non-Hodgkin
intractable virus infections that are becoming recognized as a major lymphoma by using dendritic cells that are engineered to overexpress
limitation of the approach. The most common problematic viral LMP2. The infusion of polyclonal LMP2-specific T cells containing
+
+
infections after allogeneic HSCT are reactivated herpes viruses, both CD4 and CD8 T cells increased LMP2-specific T-cell
including cytomegalovirus (CMV) which typically causes pneumo- responses, and lead to sustained complete tumor regression in 56%
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nitis and hepatitis and the gamma herpes virus Epstein-Barr Virus of patients with relapsed/resistant EBV+ lymphoma. Complete
(EBV), which may cause a rapidly fatal lymphoproliferative disease responses have also been obtained in EBV-associated nasopharyngeal
(LPD). In children and recipients of cord blood transplants, adeno- carcinoma (NPC), a tumor which originates from the epithelial cells
viral disease is also common. Adoptive transfer of virus-specific T cells of the nasopharynx, and a promising increase in overall survival has
(VSTs) appears to effectively prevent and treat these infections after been obtained in phase II studies. Like EBV-associated lymphomas,
6
transplant. Infusion of even small numbers of specific cells (10 or NPC express the same restricted set of weakly immunogenic viral
less) may be sufficient for benefit, since the lymphodepletion of the antigens including EBNA1, LMP1, and LMP2. As for the VSTs
immediate posttransplant period is associated with the release of infused after allogeneic HSCT, simplification of manufacture has
homeostatic cytokines such as IL-7 and IL-15 which augment the been accomplished by using peptide libraries as a source of viral
expansion of virus specific T cells when they encounter their antigen. antigens. VSTs so generated retain their specificity and may have
The feasibility of adoptive transfer of VSTs after HSCT has greatly increased longevity in vivo based on their less differentiated pheno-
increased over the past decade because of the simplification of the type. The development of this simplified therapeutic strategy has
procedures required to isolate or expand these cells ex vivo. The allowed the implementation of larger scale commercialization.
pioneering approach developed at Fred Hutchinson Cancer Research Infection with human papilloma virus (HPV; particularly sero-
Center and St. Jude Children’s Research Hospital aimed at generating types 16 and 18) has been associated with orogenital epithelial
ex vivo CMV-specific CD8+ T-cell clones and polyclonal EBV-VSTs cancers. T lymphocytes directed to the persisting viral antigens (such
were effective in controlling CMV and EBV-reactivation after allo- as E5 and E6) may be effective treatment for these tumors, and a
geneic HSCT, respectively. However, the broad application of these recent study using T cells genetically manipulated to express an
therapeutic approaches was significantly limited by the laborious anti-HPV E6 TCR induced sustained tumor regression in two
process required to generate VSTs with sufficient specificity and in patients with advanced metastatic cervical cancer (Hinrichs et al,
sufficient number for adoptive transfer. The recent introduction of unpublished data). A number of groups are now exploring the value
long-peptide libraries (pepmixes) as a source of viral antigens, allowed of the approach.