Page 62 - Read Online

the mutated region showed great promise for the treatment has been approved for the treatment of recurrent GBM
of (R132H)-mutated tumors. In an intracranial and has been also used in combination with cytotoxic
[22]
glioma model, the R132H mutation could be effectively agents such as irinotecan with favorable results. [33]
targeted by the immune system: the results of this study
demonstrated a significant increase in survival of treated Overexpression and/or amplification can be found in
mice compared to controls and 25% of the mice were up to 40% of primary GBM. Several EGFR mutations
+
cured. After evaluating the CD8 T cell response in spleen have been reported, the most frequent being EGFRvIII
[34]
there was a significant difference for the immunized that occurs in 25-64% of cases. Cetuximab is a
mice compared to controls. [23] chimeric monoclonal antibody against EGFRvIII with
high affinity. In a phase II study, involving patients
Heat shock proteins (HSP) are evolutionary conserved with recurrent GBM, cetuximab combined with
family of proteins that serve as molecular chaperones bevacizumab and irinotecan was safe, except from
[24]
and inhibit non specific protein aggregation. HSP skin toxicity and displayed encouraging response
can be recognized and activate APC cells which rates. Nevertheless, the combination treatment does
in turn present them on major histocompatibility not seem to be more effective in comparison to
complexes I (MHC I) and II (MHC II). Various bevacizumab and irinotecan alone. Recently, an
[25]
[35]
HSP have been utilized for this purpose. Peptides antibody drug conjugate, named AMG 595 was tested.
bound to HSP-96 proved safe in a phase I trial and AMG 595 is composed of maytansinoid DM1, which
resulted in a 47 weeks median survival after surgical are potent microtubule-targeted compounds blocking
excision in the 11/12 patients that responded to the the proliferation of cells at mitosis. After conjugation
vaccination. In a phase II study of 41 patients, that to an anti-EGFRvIII antibody, it was observed that
[26]
received complete excision of recurrrent GBM and the drug inhibited the proliferation of U251 cells and
vaccination, the median overall survival reached 42.6 induced tumor mitotic arrest in xenografts expressing
weeks. The HSP47 was also utilized as a glioma EGFRvIII. [36]
[27]
associated antigen. In 26.9% of GBM patients there
was a positive cytotoxic T lymphocyte response that Cancer stem cells display a high tumorigenic
resulted in a significant better progression-free and potential and treatment resistance, given their low
[28]
overall survival than negative responders. Recently, proliferation rate, eventually resulting in GBM
a vaccine composed of the recombinant mycobacterial recurrence. Targeting GBM stem cells is an attractive
HSP65 with mouse glioma 261 (GL261) tissue lysate treatment strategy and various approaches have
increased the survival of mice bearing GL261 gliomas been tested. The AC133 epitope expressed on the
by enhancing the ratios of brain-infiltrating Th17 CD133 glycoprotein has been used as a marker to
cells subset and inflammatory cells. Of note, identify stem cells. Recently, a recombinant specific
[29]
although efficient for studies based on anti-glioma antibody that binds both to AC133 and to T cells (via
therapeutic modalities, GL261 cells exhibit moderate the CD3 receptor) has been developed. This agent
immunogenicity. [30] suppressed the outgrowth of AC133 subcutaneous
+
GBM xenografts. Nevertheless, it is important to
[37]
TUMOR SPECIFIC TARGETS note that CD133 as well as other markers such as
CD15, do not discriminate between tumorigenic and
Monoclonal antibodies constitute an attractive non-tumorigenic cells, thus questioning their use in
type of biological therapy. The selection of tumor glioma to identify CSCs. [38,39]
antigens suitable for antibody targeting and therapy
requires firstly, the target antigen to be confined The highly immunosuppressive tumor
in the tumor and secondly, to be absent or to have microenvironment is considered to be a significant
a very low expression on normal tissue. Antigens barrier to successful immunotherapy. The fibrinogen-
involved in angiogenesis are a suitable target of like protein 2 (FGL2) that can be found in malignant
monoclonal antibodies, in fact GBM is a highly cells has been reported to act as an immune-suppressor
vascular tumor that expresses high levels of the in GBM, permitting the tumor to grow by suppressing
pro-angiogenic vascular endothelial growth factor tumor-targeted immune responses. Mice treated with
(VEGF) and VEGF receptors. Hypoxic conditions an anti-FGL2 antibody had a median survival of 27
[31]
that are present in this tumor further increase VEGF days compared with 17 days as the median survival
production. Bevacizumab is a humanized monoclonal of mice injected with an isotype control antibody. [40]
immunoglobulin G1 antibody that neutralizes the
biological activity of human VEGF-A and inhibits its T CELL ENGINEERING
binding to vascular growth factor receptor 1 (VGFR-1)
and VGFR-2 on tumor endothelial cells. Such agent Chimeric Antigen Receptor (CAR) cells are cytotoxic
[32]

Neuroimmunol Neuroinflammation | Volume 3 | March 14, 2016 53