Neuroimaging of Peptide-based Vaccine Therapy in Pediatric Brain Tumors: Initial Experience

Abstract

The potential benefits of peptide-based immunotherapy for pediatric brain tumors are under investigation. Treatment-related heterogeneity has resulted in radiographic challenges, including pseudoprogression. Conventional MR imaging has limitations in assessment of different forms of treatment-related heterogeneity, particularly regarding distinguishing true tumor progression from efficacious treatment responses. Advanced neuroimaging techniques, including diffusion magnetic resonance (MR), perfusion MR, and MR spectroscopy, may add value in the assessment of treatment-related heterogeneity. Observations suggest that recent delineation of specific response criteria for immunotherapy of adult brain tumors is likely relevant to the pediatric population and further validation in multicenter pediatric brain tumor peptide-based vaccine studies is warranted.

Keywords: MR spectroscopy; Pediatric brain tumors; Pseudoprogression; Vaccine therapy.

Figure 1. Example of Timing of MRI scans for New Diagnosis of High-Grade Pediatric Glioma treated with Radiation and Serial Peptide Based Vaccine Therapy

The time of conventional MRI during the course of peptide-vaccine therapy for this particular strata (A) of the vaccine study was approximately every 6 weeks after initiation of therapy. Strata A of included new diagnosis of high-grade gliomas based on imaging (DIPG) or biopsy and included initial radiotherapy followed by peptide-based vaccine. Note, additional time points of imaging were obtained during clinical pseudoprogression. The timing of serial MRI was different for different strata. Diffusion imaging was integrated with all conventional MRI scans. MRS spectroscopy and perfusion MR were performed in conjunction with only certain conventional MRI scan for logistical reasons.

Figure 2

A (top) Tumor pseudoprogression. Left: MR baseline before and after radiation immediately before vaccine therapy. Tumor is unchanged from diagnosis. Middle: after 15 weeks post first vaccine dose, the patient had tumor enlargement (non-enhancing FLAIR hyperintensity) and worsened neurological symptoms. Right: Steroids were started and the MR findings and symptoms improved. B. (bottom) Development of additional lesions: Same patient as Figure 2A, but after first pseudoprogression later in the course of the peptide vaccine therapy. Note the development of small lesions (left side of figure) (hyperintense FLAIR signal abnormality in the middle cerebellar peduncle (first in the right middle cerebellar peduncle, and then left middle cerebellar peduncle), that undergo subsequent cystic necrosis and shrinkage on follow up scans (right side of figure).

Figure 3. Biopsy proven pseudoprogression of a cervical medullary anaplastic astrocytoma

4.5-year-old with a biopsy-proven cervicomedullary anaplastic glioma (top row baseline) who developed worsening neck pain after his 4^th vaccine, which became increasingly severe immediately after his fifth vaccine, 6.5 months after diagnosis, 4 months after completion of irradiation and 3 months after beginning vaccination. He exhibited neurological worsening and MRI showed formation of a necrotic cyst superior to the tumor in the medullary region (second row). Vaccines were withheld, and the cyst continued to increase in size; his neck pain became debilitating and he underwent laminectomy and cyst decompression 2.5 months later (third row). He had rapid clinical improvement and resolution of the cyst on subsequent MRI scan. Biopsies showed no mitotically active tumor, and he resumed vaccine therapy. Six weeks later, he developed clinical and radiographic worsening with recurrence of neck pain. An MRI showed re-accumulation of the cyst and increased enhancement and size of the solid component, which prompted discontinuation of the vaccine regimen (fourth row). He was started on palliative oral chemotherapy and has shown a dramatic clinical improvement over the next 3 months, is back at school and almost completely off steroids. Five years later the patient is still alive with small stable residual lesion (fifth row)

Figure 4. Focal changes in pediatric DIBG during immunotherapy

Areas of non cystic changes without enhancement (A), areas of non cystic changes with enhancement (B), areas of cystic changes without enhancement (C), and areas of cystic changes with peripheral enhancement (D).

Figure 5. Comparison of Pseudoprogression case (from Figure 2) with Averaged Spectra of Long Term Survival Group and Short Term Survival Group

The top row (Short Term Survival) shows that there is increase in the choline to creatine ratio between the first two time points. The middle row shows that in the Long Term Survival Group there is relative stability in the choline to creatine ratio over time. The bottom row shows the MRS for the Pseudoprogression case from Fig. 2 in which there is preservation of choline to creatine ratio across time points. Metabolite levels, including myo-inositol and lipids/lactate remain stable across all three time points in the patient with pseudoprogression (last row).

Figure 6. sfDM to evaluate the spatial- temporal changes in ADC measurements in pediatric DIPG treated with peptide-based vaccination

sfDM demonstrates decrease in ADC signal after radiation (blue voxels, left bottom row). During immunotherapy, focal increase in ADC signal (red voxels, right bottom row) preceded the appearance of necrosis. The stability of the ADC signal (green voxels, right bottom row) is consistent with treatment related necrosis rather than tumor progression.

Figure 7. ²³Na-MR of a necrotic lesion in pediatric subject

[A] shows a ring enhancing necrotic lesion (red arrowheads); This lesion was a new recurrent lesion, separate from a lesion in the frontal lobe (not shown) that has initially responded to peptide-based vaccine therapy [B] short echo and [C] longer echo ²³Na-MR showing total/extracellular sodium and increased foci in the periphery of lesion (red arrow); [D] co-registered targeted subtracted overlap image show that the periphery of the necrosis (red arrowheads) had increased intracellular sodium (ICS) (red and yellow voxels) and decreased central ICS (bluish and voxels) representing tumor related cavitation/necrosis confirmed to be a recurrent tumor by follow up.