Central Nervous System Neuroblastoma Metastases Pseudoprogression Following IntraVentricular anti-B7H3 Radioimmunotherapy

While immunotherapy has revolutionized solid tumor treatment, pseudoprogression, radiographically defined as the initial increase in tumor volume followed by tumor shrinkage, is less clearly defined. This is particularly noteworthy for patients with central nervous system metastases, commonly seen in patients with advanced melanoma or non-small cell lung cancer treated with PD-1 or CTLA-4 inhibitors.

B7-H3 (CD276) is a transmembrane protein belonging to the B7 family of costimulatory molecules.[1] Several solid tumors overexpress B7-H3, embryonal tumors in particular are intimately and uniformly linked to B7H3 expression; expression is associated with immune escape, tumor cell invasion and metastases.[2, 3] We present the first report of pseudoprogression following anti-B7H3 radioimmunotherapy.

A 4-year old female was diagnosed with neuroblastoma involving a retroperitoneal mass with osseous and bone marrow metastases. The tumor was diploid and lacked amplification of the MYCN oncogene. She underwent therapy with multiagent chemotherapy, tandem autologous bone marrow transplants, focal radiation therapy to the primary mass, and intravenous anti-GD2 (disialo-ganglioside) antibody therapy as described.; the patient was then declared to be in remission. Two years after initial diagnosis, the patient suffered a new generalized seizure. MRI revealed 2 new left parietal lobe lesions, the largest 1.4 cm with edema, enhancement and restricted diffusion (Fig 1A). Neurosurgical resection revealed pathology confirming metastatic neuroblastoma. Given the known predilection for neuroblastoma to develop leptomeningeal seeding following brain parenchymal metastases, sraniospinal radiation therapy with irinotecan and Temodar as described, induced a second remission with expected MRI appearance in the operative cavity (Fig 1B). She was then registered to clinicaltrials.gov (NCT00089245) with intraventricular 131-I-Omburtomab targeting B7-H3 micrometastases administered through an indwelling intraventricular catheter in the CSF space . The patient received an imaging dose (2mCi ¹³¹I-Omburtamab) for dosimetry demonstrating tracer activity throughout the thecal space, followed by 50 mCi ¹³¹I-Omburtamab therapy. She remained clinically well over several weeks In week 5, a follow up brain MRI revealed increased nodular enhancement around both operative cavities with adjacent leptomeningeal enhancement, concerning for progressive neuroblastoma (Fig 1C). A spine MRI, CSF and metaiodobenzylguanidine (MIBG) scan were negative for disease. The patient remained asymptomatic. A repeat brain MR performed 2 weeks later showed interval resolution of both the operative cavity and leptomeningeal enhancement and edema. The patient was treated with intravenous anti-GD2 monoclonal antibody for 5 cycles and remained clinically well. Repeat brain and spine MR performed 6 months later shows continued remission with complete resolution of all enhancement and edema (Fig 1D).

Figure 1.

MRI of left parietal lobe lesions in patient with neuroblastoma metastatic to the CNS: (Panel A) axial T1 weighted post contrast image demonstrates enhancing nodularity along the superficial lateral aspect of the left frontal lobe in a pial location. (Panel B) corresponding axial flair imaging for the exact location of the abnormal enhancement along the superficial lateral aspect of the left parietal lobe demonstrating little associated edema, supporting the pial location of the mass. (Panel C) Axial T1 Weighted images demonstrating increased nodular enhancement at the site of treated metastatic disease (Panel D) corresponding Axial FLAIR imaging (Panel E) Axial T1 post contrast showing decreased enhancement and resolution of all enhancement (Panel F).

It is clear that inflammatory cell infiltrates caused by commonly used immunotherapeutic agents pose a diagnostic dilemma for radiologists and clinicians. Pertinent to CNS metastases, even small amounts of ensuing edema can cause neurologic compromise. Further treatment may also need to be appropriately withheld pending pseudoprogression resolution. Immune-related response criteria have been devised to assist clinicians, but the full spectrum and incidence of pseudoprogression, especially as it relates to CNS metastases, is poorly understood.

Over 100 patients with CNS NB have been treated with anti-B7H3, and it is possible that some early radiographic interpretations of progressive disease removing a patient from the trial, were in fact, pseudopression. This was the first case to demonstratethat anti- B7-H3 immune therapy may be associated with CNS pseudoprogression. Targeting the B7 family of checkpoint regulators is at the forefront of cancer research, although the immune-regulatory role of B7-H3 remains elusive. B7-H3 expression is associated with poor outcome in several cancers and is uniquely overexpressed in cancers compared to normal human tissues. Here we present radiographic imagings speculated to be aninflammatory reaction after anti- B7-H3 therapy, with spontaneous radiographic resolution two weeks later, all in the absence of steroid administration. The patient remains alive with no evidence of progression, now > 18 months since initial CNS event, well beyond the median reported survival for patients with CNS neuroblastoma. Though the precise frequency and timeline is unclear, B7-H3 directed therapy may be added to the list of immunotherapeutic agents recognized to cause pseudoprogression. Key efforts are being made to correlate the appearance of CNS neuroblastoma pseudoprogression with overall survival.