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Page 2 of 15 Gururangan et al. Neuroimmunol Neuroinflammation 2018;5:45 I http://dx.doi.org/10.20517/2347-8659.2018.44

surgery, chemotherapy, and/or irradiation leading to cures around 70% overall but with a high cost in terms
[2]
of permanent neuro-cognitive and hormonal deficits . The prognosis for those with recurrent disease
remains dismal and novel approaches are urgently needed for refractory tumors. With the recent spurt in
enthusiasm in the field of cancer immunotherapy, there is an increasing interest to utilizing this approach
to treat children with recurrent central nervous system (CNS) tumors. The focus of this review is our
experience in using adoptive lymphocyte transfer (ALT) with total tumor derived mRNA loaded dendritic
cells (DCs) following myeloablative (MA) conditioning chemotherapy in pediatric brain tumors. This work
is a form of adoptive cellular therapy (ACT) pioneered in large part by Dr. Rosenberg at the National Cancer
[3]
Institute that resulted in durable remissions in patients with metastatic melanoma and heralded a new
approach in the field of adoptive cellular immunotherapy that could be extended to other cancers.

The CNS is not an immune privileged site
[4,5]
The CNS and by extension brain tumors have been thought to be protected from the immune system .
Several lines of evidence lent credence to this theory including an intact blood brain barrier (BBB), lack of
prototypical lymphatic structures, a general lack of antigen presenting cells (APCs) within the brain tissue,
low to absent expression of major histocompatibility (MHC) class I molecules, constitutive expression of
immunosuppressive cytokines including transforming growth factor-β and IL-10, and the slow rejection
[5]
allogenic tissue implanted in the brain as compared to other sites . However, there is also ample evidence
to the contrary including the occurrence of paraneoplastic syndromes in which a spontaneous immune
[6]
response to tumors causes immune damage to the central and peripheral nervous system structures ,
objective immune responses in brain metastases in patients with recurrent metastatic melanomas treated
[3]
with adoptive T-cell therapy , and immune infiltrates seen in primary CNS tumors including malignant
[5]
gliomas that are a few examples of how the CNS cannot be considered an immune privileged site . While
the BBB is relatively impermeable in the normal state, tumors generally disrupt the BBB, and tumor release
[5]
of inflammatory cytokines can further induce migration of immune cells into the brain . Released tumor
antigens can either be engulfed by APCs and migrate through the cerebrospinal fluid and exit from the
cribriform plate to the nasal mucosa or be transported via the interstitial fluid and drain along the capillary
walls of blood vessels to reach cervical nodes to sensitize the immune system. Microglia (the CNS resident
[5]
macrophages) can also play a role through innate or adaptive immunity mechanisms .

IMMUNE SYSTEM AND CANCER
The immune system and the responses thereof have been traditionally divided into innate and adaptive
[7]
immunity with a considerable interaction and cross talk between the two systems . Innate immunity is
mediated by phagocytes (DCs, macrophages, neutrophils), natural killer (NK) cells, mast cells, eosinophils,
[8]
and basophils . Innate immunity is mediated through receptors that are pre-determined in the germline
by approximately 100 genes and are called pattern recognition receptors targeting a specific set of ligands
[8]
grouped as pathogen or damage associated molecular patterns . Innate responses are rapid and occur
within a matter of hours following a pathogenic threat.

The key players in the acquired form of immunity include the APCs, T-helper (CD4), T-suppressor cells, and
[9]
cytotoxic CD8+ cells) . Acquired immune responses depend on T and B cell receptor diversity generated
somatically during lymphocyte development that are not genetically pre-determined towards a specific
antigen and arise on exposure to a pathogen or foreign antigen by random site specific recombination in
the immunoglobulin (B-cells) or T-cell receptor (TCR) genes and clonal expansion of such lymphocytes
[7,9]
on further antigen exposure . Degeneracy (in contrast to specificity) is a typical characteristic of antigen
recognition in adaptive immunity, which refers to the cellular response from a single receptor that interacts
[7]
with several ligands (antigens in this case) that are structurally different . Acquired immune responses on
an average takes 7-10 days to initiate and peak following antigen encounter.