Die Bedeutung der neoadjuvanten Checkpointinhibition in der Behandlung des Rezidiv-Glioblastoms

Glioblastoma has a dismal prognosis. After recurrence treatment options are limited. Anti-PD-1 antibody Pembrolizumab demonstrated benefit as adjuvant monotherapy in multiple types of cancer- except glioblastoma. It is stipulated that neo-adjuvant immune checkpoint inhibition together with reresection and adjuvant alkylating chemotherapy might lead to sustained anti-tumor immune responses and clinical benefit in patients with recurrent glioblastoma.

Patients aged ≥18 years with recurrent IDH wild-type glioblastoma (CNS WHO grade 4) scheduled for surgical debulking were included. Eligibility criteria included Eastern Conference Cooperative Oncology Group (ECOG) Score ≤2, first line therapy with at least radiotherapy, unequivocal evidence of tumor progression. Patients received pembrolizumab 200 mg intravenous infusions 14±5 days prior to- and every three weeks after re-surgery additionally to CCNU (up to six-week cycles). To examine CPI response, transcriptome sequencing (RNAseq), T-cell receptor sequencing in tumor samples and detection of inflammatory cytokines (Il-1a, Il-1b, Il-6, Il-8, TNF-a, IFN-y, MCAF, GM-CSF) in blood using ELISA and qPCR, was performed.

A total of ten patients received neoadjuvant pembrolizumab prior to re-resection. Mean age was 54.7 years (33-68), female:male ratio was 8:2. Complete resection was achieved in 70.0%, gross total resection in 10.0%, partial resection in 10.0% and biopsy in 10.0%. A total of 10 neoadjuvant and 24 adjuvant cycles of CPI were given. Fever associated with CPI occurred in 2 patients. No severe adverse occurred. Overall PFS was 12.9±3.6 months and OS 28.2±6.5 months. After re-surgery, mean PFS was 5.0±1.1 months, mean OS was 15.3±4.9 months. 6 out of 10 patients are still alive.

Lower levels of INF-y and Interleukine-6 and -8 after neoadjuvant CPI were associated with a longer OS (p=0.05) but not PFS (p=0.69). RNAseq revealed distinct longitudinal transcriptome changes in response to neoadjuvant CPI. Similar longitudinal changes were detected regarding the immune contexture, TCR diversity and clonality.

Neoadjuvant checkpoint inhibition is well tolerated and associated with distinct changes to tumor transcriptome and immune milieu. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances the local and systemic anti-tumor immune response and may represent a more efficient approach to the salvage treatment of this uniformly lethal tumor.