Gliomas and meningiomas include more than two thirds of all brain tumors. We will only focus on gliomas as they represent the major clinical challenge and the tumors mostly investigated by different types of immunotherapies.
In the context of EGFR amplification, deletions can take place. The most frequent is EGFRvIII which displays a truncated extracellular domain with ligand-independent constitutive activity and, notably in this context, creates a novel, targetable epitope that is exclusively present in cancer.
A randomized, double blind, placebo-controlled phase II study was subsequently developed with 124 patients randomized to receive the vaccine (ICT-107) or unpulsed DC in association with the standard treatment, showing some gain in terms of progression free survival but not yet overall survival, as presented at the ASCO meeting in 2014; DC have also been loaded with autologous tumor lysate (ATL). A study comparing this with glioma associated peptides (GAA) as a pulsing strategy for DC suggested that ATL-DC vaccination is associated with wider patient eligibility compared with GAA-DC vaccination; GBM (Glioblastoma) may express cytomegalovirus (CMV) proteins, whose potential role as immune target appears clinically appealing. In particular, cytomegalovirus phosphoprotein 65 (pp65) is expressed in about 90% of GBM but not in normal brain, making it an attractive target for immunotherapy. Recent data indicate that pre-conditioning the vaccine site with the recall antigen tetanus/diphtheria (Td) toxoid can significantly improve lymph node homing of DC and consequently, the efficacy of tumor-antigen-specific DC. The chemokine CCL3 played a critical role in increasing the homing capability of DC. If these observations are to be confirmed in a larger number of patients and with other pulsing strategies they will turn out to be of major relevance in clinical use.
A randomized phase 3 open label study of nivolumab, a anti-PD-1 antibody, versus bevacizumab in adult subjects with recurrent GBM is ongoing and will hopefully provide great hopes that this and/or other checkpoint inhibitors may provide survival gain and evidence of immune re-activation also in patients affected by GBM or other brain cancers.
TIL in GBM have been studied in relation to prognosis and GBM subtype, as defined by TCGA analysis, but so far have never been expanded or investigated in ACT clinical trials; Recently, CAR T cells transduced with humanized scFv directed to EGFRvIII have been obtained; these CARs will be used in phase I study on patients with GBM positive for such deletion. Comparison with results obtained by direct immunization with the EGFRvIII plus adjuvant (rindopepimut in ACT III and IV studies) will be of great interest to determine the most effective strategy to be offered to the fraction of patients with GBM carrying the EGFRvIII deletion.
We believe that the number of studies we have summarized here start to demonstrate that the time for "realizing the promise" of cancer immunotherapy for brain cancer is now.
Finocchiaro G et al. Novel Mechanisms and Approaches in Immunotherapy for Brain Tumors[J]. Discovery medicine, 2015, 20(108): 7-15.
Fecci PE et al. Immunotherapy for primary brain tumors: no longer a matter of privilege. Clin Cancer Res 20(22):5620-5629, 2014.