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Gururangan et al. Neuroimmunol Neuroinflammation 2018;5:45 I http://dx.doi.org/10.20517/2347-8659.2018.44 Page 11 of 15

NCT03396575) using the ttRNA DC vaccine + x-ALT platform with some modifications from the reMATCH
trials. While the general strategy in both clinical trials is similar to reMATCH, dose-intensive temozolomide
TM
(temodar , Merck, Kenilworth, NJ) (TMZ) is used in these two studies as both adjuvant chemotherapy
post standard chemo-radiotherapy (concurrent TMZ) and as a lymphodepletive agent prior to HSC and
ttRNA DC + -x-ALT and during maintenance monthly ttRNA DCs. We have introduced a few changes in
these two trials including (1) obtain autologous lymphocytes after 3 bi-weekly ttRNA DCs following chemo-
radiotherapy; (2) ex-vivo expansion using REP; and (3) administer up to a total of 10 ttRNA DCs.

CONCLUSION
The field of adoptive T-cell therapy using x-ALT + tt-RNA DCs in children with brain tumors is evolving
and appears, in our preliminary experience, to have provided sustained benefit in a handful of patients
with recurrent medulloblastoma without undue toxicity. It is obvious that success in a larger proportion
of treated children is unlikely to equal what has been observed in adults with metastatic melanomas. This
might be related to the differences in the degree of immunogenicity and mutational load seen in tumors
like melanomas that is hard to match in pediatric brain tumors that appear to have an immunosuppressive
microenvironment. It is intriguing to speculate whether the rare population of children with germline p53
[30]
mutations with medulloblastoma [105] or MMR deficiency malignant gliomas might be a more suitable
population to evaluate this therapeutic approach given the exceptionally high mutational load in these
tumors compared to wild type counterparts. For most pediatric CNS tumors with an immunosuppressed
landscape as previously discussed due to decreased MHC class I expression, decreased or absent TILs,
high programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) expression, or increased
MDSC infiltration, significant refinements need to be made to improve immune responses and outcome. It
is also entirely possible that utilizing this strategy in the upfront setting in treatment-naïve patients might
provide better outcomes due to lack of prior treatment related immune suppression and minimal tumor
burden. Radiotherapy, typically given at diagnosis, will further reduce tumor bulk and augment immune
[106]
responses through multiple mechanisms . The role of the microbiome in affecting outcome following
immune checkpoint inhibitor therapy has been confirmed recently in pre-clinical studies of mice bearing
melanoma and non-small lung cancer tumors [107,108] . Whether such optimization of fecal microbiome in
patients receiving ALT will prove beneficial remains be evaluated. Using NGS methodology and HLA-typing
to improve prediction of MHC-I class and MHC-II class binding epitopes to create a robust neoantigen
[47]
[109]
predominant transcriptome for electroporation into DCs , nanoparticle vaccines , and/or the use of
immune checkpoint inhibitors [30,110] are other potential strategies to enhance efficacy in an adjuvant setting
or relapse following x-ALT + ttRNA DCs. With these refinements and more this form of ACT promises to be
an important therapeutic approach in the management of pediatric brain tumors.

DECLARATIONS
Authors’ contributions
Conceived and wrote the manuscript: Gururangan S
Helped with critical review and revisions: Sayour E, Mitchell DA

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.