Biomedical Engineering Reference
In-Depth Information
after two intradermal injections with OVA adsorbed aquasomes resulted in a
mixed Th1/Th2-type immune response. OVA-sensitized mice model, treatment
with OVA adsorbed aquasomes elicited lower levels of IgE (
p
< 0.05), serum
histamine and higher survival rate in comparison with alum adsorbed OVA.
Symptoms of anaphylactic shock in OVA aquasome-treated mice were weaker
than the one induced in the alum adsorbed OVA group. Results from their stud-
ies demonstrated the valuable use of aquasomes in allergen immunotherapy.
111
7.4.3 NMs for Tumor Immunotherapy
Tumors induce local immune suppression as a mechanism to avoid detection
and elimination by the host immune system and also elicit immune responses
against tumor-associated self-antigens.
115,162,163
Strategies to combat such
immunosuppression using non-cell-based therapies such as cytokines, immune
receptor-targeting monoclonal antibodies, or Toll-like Receptor (TLR) ago-
nists to break tumor-associated tolerance, by blocking tumor-induced suppres-
sive factors or directly providing the co-stimulatory signals have been studied
prime an anti-tumor immune response.
164-168
However, the side effects of these
immune-agonists dampen their clinical value to achieve therapeutic efficacy
while avoiding excessive systemic exposure.
169-171
Two immunostimulatory agents that exhibit the two edged action of immu-
notherapy are anti-CD40 antibodies and CpG oligonucleotides.
115
The CD40
signaling triggered through the anti-CD40 ligation leads to strong activating
signals to APCs providing them the capacity to prime strong anti-tumor cyto-
toxic T-cell responses.
172,173
The efficacy of anti-CD40 therapy against a wide
variety of tumor models, either as a monotherapy
174,175
and combined with
chemotherapy,
176
or combined with other immunostimulants such as interleu-
kin (IL)-2
177
have been documented in pre-clinical studies. The application
of anti-CD40 therapy in phase I clinical trials for human patients have also
been reported for non-Hodgkins lymphoma, multiple myeloma, and other solid
malignancies.
178-180
These achieved moderate levels of therapeutic efficacy but
the maximum tolerated dose for human therapy has been limited by inflam-
mation in non-target organs.
178,180,181
Intravenous administration of anti-CD40
leads to systemic exposure to the immuno-agonist that causes various symp-
toms of cytokine release syndrome (such as fever, headaches, nausea, chills),
ocular inflammation, elevated hepatic enzymes (indicative of liver damage),
and hematologic toxicities including T-cell depletion.
115
Inflammatory effects
in the liver, lungs, and gut have been documented in mice including evidence of
systemic cytokine release.
182-184
Most of the reported side effects were transient
but long-term immunosuppression following anti-CD40 therapy that was pos-
sibly related to the activation-induced apoptosis of CD4
+
or CD8
+
T-cells has
been reported in mice.
185
The CpG oligonucleotides, ligands for Toll-like receptor (TLR) 9 expressed
by APCs belong to another class of potent immunostimulatory factors that has
