Download File - JOHN J. HADDAD, Ph.D.

88 Luptrawan et al.
NK cells can kill cancer cells without prior sensitization. They are
responsible for killing HLA class I–deficient tumor cells (38). In neoplastic
conditions, HLA class I expression is often altered, breaking NK cell tolerance
(5a). Ectopic HLA-G expression is a mechanism of tumor evasion of T and
NK cell lysis (39) and is believed to protect the fetus from allorejection by
maternal NK and T cells (5a). HLA-G is expressed on primary GBM and
by established glioma cell lines (39). HLA-G expression causes glioma cells to
be resistant to alloreactive CTL lysis and its inhibitory signals are strong enough
to counteract NK-activating signals.
NK and activated T cells regulate tumor growth via the Fas apoptosis
pathway; however, tumor cells may disrupt this pathway at many levels within
the signaling cascade (5a). Disruption of Fas-induced apoptosis or upregulation
of FasL may provide tumor-cell protection to T lymphocyte–induced cell injury
(5a). Decoy receptor 3 (DcR3) is expressed by brain tumors and inhibits Fasinduced
apoptosis (40,41). Decreased expression of Fas or secretion of FasL
decoy receptor, DcR3, by glioma cells inhibits death receptor–induced apoptosis.
Tumor cells can cause T-cell apoptosis when they counterattack T cells by
expressing FasL which engages Fas on the T-cell plasma membrane (5a).
DC–BASED IMMUNOTHERAPY: RESULTS OF
PHASE I AND II CLINICAL TRIALS
It is very difficult to therapeutically target every remaining individual tumor cell
due to the disseminated nature of GBM. It is extremely important to eliminate all
intracranial neoplastic foci left behind after surgical resection of the primary
tumor (4). The use of the immune system to target residual tumor cells is one
such strategy to enhance visibility of tumor cells to the immune system.
In a phase I study, Yu and colleagues describe the use of a DC vaccine in
patients with newly diagnosed high-grade glioma (42). After surgical resection
and external-beam radiotherapy, nine patients were given a series of three DC
vaccinations using DCs cultured from patients’ peripheral blood mononuclear
cells (PBMC) pulsed ex vivo with autologous tumor cell-surface peptide isolated
by means of acid elution. Each DC vaccination was given intradermally every
other week over a six-week period. Four of the nine patients who had radiological
evidence of disease progression underwent repeat surgery after receiving
the third vaccination. Two of the four patients who underwent re-resection had
robust infiltration of CD8 þ and CD45RO þ T cells which was not apparent in the
tumor specimen resected prior to DC trial entry (Fig. 1). Comparison of longterm
survival data between the study group and matched controls demonstrated
an increase in median survival of 455 days versus 257 days for the control group,
conferring some survival benefit after DC vaccination.
Given the promising results and absence of observed autoimmune toxicity
in the phase I study, Yu and colleagues expanded the study into a phase II
trial (43). Fourteen patients with recurrent (12 patients) and newly diagnosed