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Sustained complete response of recurrent glioblastoma to combined checkpoint inhibition in a young patient with constitutional mismatch repair deficiency

To the Editor: Glioblastoma multiforme (GBM) is one of the most aggressive childhood brain tumors associated with poor prognosis and less than 10% survival at 5 years.1 Importantly, at recurrence the median time to death is approximately 3 months and virtually all patients succumb to their disease. Multiple chemotherapeutic regimens have failed to induce significant improvements in survival. Novel therapies are thus urgently needed to improve the dismal survival in these patients. Immune checkpoint inhibition (ICI) is a highly promising concept in cancer therapeutics. Indeed, specific blockade of PD-1, CTLA4, PD-L1, and other immune checkpoints can be effective in arresting tumor growth and promoting tumor regression in several cancers, and induce in some cases prolonged survival in highly malignant tumors such as melanomas or lung cancer.2,3 However, only 10–30% of those patients will have sustained response to ICI, suggesting that combinational therapies with other checkpoint inhibitors, chemotherapy or other targeted agents may be needed to increase response rates. Perhaps the most important genetic factor predicting response to ICI is the tumor mutational burden. Indeed, it has been shown that tumors with a high mutational load (hypermutant) will have significantly higher response to ICI, in keepingwith positive results observed in melanomas, lung, or mismatch repair deficient colorectal cancers, which harbor the highest mutational load.4 We have shown that pediatric GBM, which arise in the context of constitutional mismatch repair deficiency (CMMRD), has the highest mutational load of all human cancers.5,6 Subsequently, we reported in Journal of Clinical Oncology7 the first response at recurrence for PD-1 blockade observed in relapsed childhood GBM. We described two siblings with CMMRD having hypermutant GBM whom at recurrence revealed objective response to the PD-1 inhibitor nivolumab.7 The index case had metastatic GBM that showed sustained response for 11 months before disease progression. Her brother was diagnosed at 3.5 years of age with a right frontoparietal GBM. The tumor was initially treated with subtotal resection followed by radiation and temozolomide. Ten months following initial diagnosis, his magnetic resonance imaging (MRI) demonstrated a multinodular regional GBM recurrence (Figure 1A) associated with left hemiparesis. He received nivolumab monotherapy infusion every 2 week obtained on a compassionate basis. After an initial symptomatic tumoral pseudoprogression at the MRI after the first dose, he showed significant clinical improvement and radiological response. Six months after immunotherapy initiation, tumor progression occurred with a new nodule in the surgical area (Figure 1B). This was accompanied by a worsening of his left hemiparesis. Based on positive results seen in patients with melanoma,8 we chose to add another CTLA-4 inhibitor (ipilimumab). Following institutional approval, the child received the combination of ipilimumab with nivolumab every 3 week for a total of four doses. The addition of ipilimumab had been well tolerated. Strikingly, MRI 3 months after initiation of the combinational therapy revealed significant improvement in his tumor status (Figure 1C) andMRI done 1-year postinitiation of ICI revealed no evidence of disease. The patient is still receivingmaintenance phase nivolumab every 2weeks and his imaging confirms sustained complete response, 30months after his first recurrence (Figure 1D). Clinically, he is going to school, has a normal life, and a normal performance for a 7-year-old male without any side effects from the ongoing checkpoint inhibition. We described a young child with CMMRD having a prolonged remission with a well-tolerated immunotherapy for a relapse GBM. This approach, reported in melanoma and other hypermutant cancers, would be beneficial for other mismatch repair deficient and pediatric hypermutant cancers for which no treatment exists. Combinational ICI was beneficial for the nodular relapse seen during therapy in our patient. Furthermore, the synergistic effect achieved by the addition of CTLA-4 inhibition upon failure of PD-1 blockade is intriguing and has not been observed in other adult hypermutant cancers when single agent fails. It is plausible that CMMRDcancers respond to different ICI due to continuous accumulation ofmutations and the unique clonal evolution of these tumors. These data strongly justify prospective trials specific to this unique population to test ICI combinations in replication repair hypermutant cancers.