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

Dendritic Cell Vaccines for Gliomas 99
The challenge with vaccination strategies is to break tolerance so that the
patient’s immune system recognizes cancer cells. Several aspects involving DC
vaccines need to be optimized to include the protocol of DC generation, DC
subtype, dose and timing interval of vaccination, route of administration,
approaches of antigen loading, and especially DC maturation (71). Recently, a
group of researchers has identified a small population of cancer stem cells in adult
and pediatric brain tumors (72). These cancer stem cells form neurospheres and
possess the capacity for self-renewal (72). They also express genes associated
with neural stem cells (NSCs) and differentiate into phenotypically diverse
populations including neuronal, astrocytic, and oligodendroglial cells (73–76).
Cancer stem cells are likely to share many of the properties of normal stem cells
that provide for a long life span, including relative quiescence, resistance to drugs
and toxins through the expression of several ABC transporters, an active DNArepair
capacity, and resistance to apoptosis. Clinically, it is observed that tumors
respond to chemotherapies only to recur with renewed resilience and aggression.
Although chemotherapy kills most of the cells in a tumor, cancer stem cells may
be left behind which allow recurrence of tumor. Recent studies suggest that
CD133 þ cancer stem cells are resistant to current chemotherapy (77,78) and
radiation therapy (79). However, cancer stem–like cells (CSCs) could be a novel
target for DC immunotherapy. More recently, Pellegatta and his colleagues have
reported that that neurospheres enriched in CSCs are highly effective in eliciting a
DC-mediated immune response against malignant GL261 glioma cells. These
findings suggest that DC targeting of CSCs provides a higher level of protection
against GL261 gliomas (80). Future vaccination therapies may be directly driven
toward CSC lysates or specific tumor antigens of CSCs to improve and ameliorate
the DC-vaccine efficacy (mostly evaluated as overall survival) (81).
Moreover, the effects of immunotherapy depend on the development of
antigen-specific memory CD8 þ T cells that can express cytokines and kill
antigen-bearing cells when they encounter the tumor. The induction of specific
CD8 þ -mediated antitumor immunity by DC vaccine involves the following
six steps: (i) antigen threshold, (ii) antigen presentation, (iii) T-cell response,
(iv) T-cell traffic, (v) target destruction, and (vi) generation of memory. Each of
these steps could be significantly impacted by chemotherapy (82). Cytotoxic
chemotherapy can be integrated with tumor vaccines using unique doses and
schedules to break down the barriers to cancer immunotherapy, releasing the full
potential of the antitumor immune response to eradicate disease. The development
of new protocols by combining chemotherapy with immunotherapy to
achieve therapeutic synergy will be applicable to many cancer types (83). Furthermore,
synergistic effects of DC immunotherapy followed by chemotherapy
have also been observed. Sensitization of malignant glioma to chemotherapy
through DC vaccination provides a novel strategy to overcome the immune
escape of cancer cells by immunoediting (66,71).
Finally, tumor cells can actively downregulate antitumor immunity and
even create a state of immunologic unresponsiveness or self-tolerance to tumor
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