Page 208 - Read Online

Page 8 of 16 Landi et al. Neuroimmunol Neuroinflammation 2018;5:29 I http://dx.doi.org/10.20517/2347-8659.2018.35

Most often, pediatric brain tumors harbor fewer mutations compared to adult tumors, which have a lower
mutational load than most solid tumors [13,85] . In a large analyses from over 300 adult glioma samples, less
[86]
than 4% of tumors had a high tumor mutational load . Even rare tumors that were hypermutated did not
have significant T cell infiltration within the tumor. Taken together, these data explain at least in part why
checkpoint blockade as monotherapy is unlikely to be impactful for pediatric brain tumors.

CheckMate 143 was a phase III randomized trial to evaluate efficacy of nivolumab, an anti-PD-1 monoclonal
antibody compared to bevacizumab in adults with recurrent GBM. Nivolumab did not improve overall sur-
[77]
vival compared to bevacizumab . Two additional trials of combing nivolumab and radiation with or with-
[88]
[87]
out temozolomide in patients with newly-diagnosed, MGMT-unmethylated and MGMT-methylated
GBM are ongoing.
While there have been no completed studies evaluating efficacy of checkpoint inhibitors in pediatric brain
tumors, a number of trials are ongoing, including PD-1 antibodies as monotherapy or in combination with
a CTLA-4 antibodies, and another checkpoint inhibitor against indoleamine (2,3)-dioxygenase (IDO). How-
ever, based on the disappointing results in CheckMate 143 and more recently for an IDO inhibitor in large
[89]
phase III trial , these agents are likely to be more effective in combination with immunotherapies which
cause inflammation and promote T cell infiltration and activation first.

ACTIVE IMMUNIZATION
Active immunization therapies deliver an immune stimulus to trigger an endogenous anti-tumor response.
Typically, a vaccine is administered to stimulate and direct the host immune system to target antigens on the
tumor. Cancer vaccines are a promising area of immunotherapy and are typically well tolerated. Vaccines
containing tumor antigens, such as peptides, tumor lysate, or nucleic acids, and autologous dendritic cells
are the most common approaches used clinically for patients with brain tumors. The intent of any active im-
munization strategy is to trigger an anti-tumor T cell response. T cell activation optimally occurs when T
cells recognize antigen displayed on MHC molecules of antigen presenting cells in the setting of inflamma-
tion. Accordingly, active immunization approaches are designed to cause inflammation and antigen uptake
by antigen presenting cells in lymphoid tissues, most often in lymph nodes.

Dendritic cell vaccines
Dendritic cells (DC) are a critical link between the innate and adaptive immune systems. Upon encountering
foreign antigens, specifically pathogen-associated molecular patterns, DC release inflammatory cytokines
that activate the innate immune system. DC also process and present antigens to T cells and B cells, thereby
[90]
activating naïve, effector, and memory immune cells or maintaining tolerance against self-antigens .
Most commonly, DC for active immunization are generated by isolating monocytes from cancer patients
that are expanded and activated ex vivo. These DC are loaded with either tumor lysate, peptides, nucleic
acids, or viral epitopes that are expressed by the tumor. DC are usually matured with GM-CSF, then admin-
istered as a vaccine. Adjuvants such as tetanus toxoid are important to improve inflammation and immuno-
[90]
genicity in the host .
Clinical testing of DC vaccines has demonstrated modest yet encouraging results in patients with advanced
cancers [91,92] . There is general consensus that DC vaccines can induce tumor-specific T cell responses and
[92]
immunological memory, and this is a promising platform for pediatric brain tumors . To date, there have
[93]
been several trials using autologous DC vaccines loaded with tumor RNA or tumor lysate [94-96] for children
with brain tumors. At this juncture, DCs are reliably manufactured and extremely well-tolerated. However,
to improve efficacy, strategies to improve targeting, antigen loading, and migration in vivo are needed.