Discussion

• This patient’s case illustrates a difficult case of recurrent glioblastoma in an otherwise healthy man.
• He underwent maximal safe resection after his initial diagnosis, then began standard chemoRT in a reasonable window of time.
• Despite being unmethylated for O6-methylguanine-DNA methyltransferase (MGMT), his initial post-chemoRT MRI showed possible pseudoprogression. The patient looked well clinically. We decided to pursue adjuvant temozolomide with close observation.
• He was stable until October 2016 (completed seven cycles of temozolomide).
• Repeat resection confirmed recurrence, and only 10% to 15% of tissue was necrotic. It was unclear if this necrosis was due to tumor or treatment effect.
• There was value in repeating molecular testing as PD-1 and PD-L1 status changed.
• Amplification of epidermal growth factor receptor (EGFR) was noted in both the 2015 and 2016 tumor samples. This occurs in approximately 40% of patients with glioblastoma.
• The EGFR variant III (EGFRvIII) was detected. It occurs in nearly half of the tumors that have EGFR amplification. It is associated with increased proliferation of glioma cells.
• In a prospective study by Montano and colleagues, patients with EGFRvIII- mutated tumors exhibited longer OS. In paired samples from primary and recurrent glioblastoma, EGFRvIII expression was approximately two-fold lower than in primary glioblastoma.
• This patient’s tumor tested positive for PD-1 via immunohistochemical screening in 2015, but not in 2016.
• There are limited trials for immunotherapy for recurrent glioblastoma, so we elected to propose using a checkpoint inhibitor via an off-label, compassionate-use program.
• Because the patient’s tumor was positive for PD-1, we elected to try nivolumab. The medication was given in a similar fashion to the now-closed CheckMate-143 trial (NCT02017717), dosed every 2 weeks.
• The central nervous system (CNS) has been described as an “immune privileged” organ because of the intact blood–brain barrier (BBB), lack of same lymphatic system as the rest of the body, and lower levels of T cells.
• This theory has been studied at length and challenged by researchers who feel that the CNS works in tandem with the immune system. In 2015, a CNS lymphatic system was discovered. Additional work demonstrated that T cells can migrate through cerebrospinal fluid-filled channels.
• The idea of an intact BBB is also known to be false in glioblastoma. There is increased permeability of BBB by tumor, surgical intervention, medications such as dexamethasone and inflammation. This further allows the immune system to influence CNS behavior.
• After a complex cascade of antigen presentation, activated T cells travel to the CNS to interact with tumor cells. This is regulated by PD-1 and PD-L1 inhibition.
• PD-1 is induced and is presented on activated T cells. PD-1 inhibitors such as nivolumab inhibit this process, allowing for more glioblastoma tumor cell destruction.
• Preclinical models supported the theory, and some therapies promoted long-term survival in animal models of glioma. This led to several clinical trials studying PD-1 inhibition in recurrent and newly diagnosed glioblastoma.
• One caveat of therapy with checkpoint inhibition is that they do not have the same pattern of response as seen with conventional chemotherapeutic or targeted agents. Response may begin as the appearance of initial increase in disease and/or T2 changes on MRI.
• These changes may represent a treatment response that will evolve into a true response. This led to iRANO, modified Respone Assessment in Neuro-Oncology (RANO) criteria for patients receiving immunotherapy.
• Meanwhile, while awaiting a response, patients may become more symptomatic. Recognizing that the skull is a confined place, intracranial edema must be managed. Typically, medicines such as dexamethasone and/ or bevacizumab are used when this happens.
• CheckMate-143 (NCT02017717) was the first randomized clinical trial in glioblastoma with a PD-1 checkpoint inhibitor.
• Preliminary results from this trial show that nivolumab for initial recurrence of glioblastoma did not meet its primary endpoint of improved OS over bevacizumab monotherapy.
• There are two first-line glioblastoma clinical trials, CheckMate-498 (NCT02617589) and CheckMate-548 (NCT02667587), evaluating the combination of nivolumab with radiation therapy with or without temozolomide in (MGMT) unmethylated and methylated patients.

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