Page 1769 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 100 T-Cell Therapy of Hematologic Diseases 1573

TABLE Causes of Immunosuppression in Cancer Patients dimerizing agent (AP1903). In the presence of the drug, the iCasp9
100.2 promolecule dimerizes and activates the intrinsic apoptotic pathway
leading to cell death. The study infused donor-derived iCaspase9-T
Immunosuppression Induced by Tumors cells after haploidentical stem cell transplant and if patients developed
Release of chemokine by tumor cells that attract immunosuppressive T GVHD, administered a single dose of the dimerizing drug. There
lymphocytes was rapid destruction of >95% of the cells with prompt resolution
Antigen-specific CD4+/CD8+ T-cell tolerance of GVHD and faster immune reconstitution that allowed robust
5
protection against opportunistic infection. These promising results
Defective proximal TCR signaling (decreased expressions of CD3δ prompted the design of multicenter studies to reach the Food and
lck
fyn
chain, p56 , p59 tyrosine kinases)
Drug Administration approval and commercialization.
Impairment of antigen-processing machinery (TAP, LMP2, LMP7) or
downregulation of MHC molecules and costimulatory molecules
Activation of negative costimulatory signals (CTLA-4, PD-1, B7-H4, FUTURE APPLICATIONS AND IMPLEMENTATION OF
BTLA) CELL THERAPIES FOR CANCER
Tumor-derived immunosuppressive cytokines (TGF-β, IL-10, VEGF, With the approval of the first cell therapeutics for cancer (ProVenge;
PGE 2 )
Dendreon), and the publication of increasing numbers of reports of
Expression of immunomodulatory or proapoptotic molecules by tumor complete tumor responses after cellular immunotherapy, there is
(tryptophan-depleting enzyme IDO, galectin-1, FasL, TRAIL) increasing hope that this methodology will finally take its place in
Recruitment and expansion of immunosuppressive cell populations cancer therapeutics. T-cell therapies with engineered T cells for B-cell
(regulatory T cells, myeloid/plasmocytoid dendritic cells) lymphoid malignancies are currently a clinical reality, but much
Immunosuppression Induced by Therapy remains to be done to ensure the effectiveness and safety of these
Neutropenia, depletion and functional impairment of monocytes therapies. Equally important, and as illustrated by the fate of the
Hypogammaglobulinemia (decreased levels of IgA and IgM) Dendreon cancer vaccine, much remains to be learned about develop-
ment of a sustainable economic model for their affordable and broad
Defective T cell-mediated immune response clinical application. Nonetheless the integration of cellular therapies
BTLA, B- and T-lymphocyte attenuator; CTLA, cytotoxic T lymphocyte antigen; with other biologic agents and small molecules continues to offer the
FasL, Fas-Fas ligand; Ig, immunoglobulin; IL, interleukin; LMP7, latent prospect of truly transformative therapies for the treatment of hema-
membrane protein 7; MHC, major histocompatibility complex; PD-1, tologic and other malignancies.
programmed death-1; PGE2, prostaglandin E 2 ; TAP, transporter associated with
antigen processing; TCR, T-cell receptor; TGF-β, transforming growth factor-β;
TRAIL, tumor necrosis factor–related apoptosis-inducing ligand; VEGF, vascular
endothelial growth factor. REFERENCES

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