Abstract
Targeting the Immune Checkpoint molecules (ICs; CTLA-4, PD-1, PD-L1/2, and others) which provide inhibitory signals to T cells, dramatically improves survival in hard-to-treat tumors. The establishment of an immunosuppressive environment prevents endogenous immune response in glioblastoma; therefore, manipulating the host immune system seems a reasonable strategy also for this tumor. In glioma patients the accumulation of CD4+/CD8+ T cells and Treg expressing high levels of CTLA-4 and PD-1, or the high expression of PD-L1 in glioma cells correlates with WHO high grade and short survival. Few clinical studies with IC inhibitors (ICis) were completed so far. Notably, the first large-scale randomized trial (NCT 02017717) that compared PD-1 blockade and anti-VEGF, did not show an OS increase in the patients treated with anti-PD-1. Several factors could have contributed to the failure of this trial and must be considered to design further clinical studies. In particular the possibility of targeting at the same time different ICs was pre-clinically tested in an animal model were inhibitors against IDO, CTLA-4 and PD-L1 were combined and showed persistent and significant antitumor effects in glioma-bearing mice. It is reasonable to hypothesize that the immunological characterization of the tumor in terms of type and level of expressed IC molecules on the tumor and TIL may be useful to design the optimal ICi combination for a given subset of tumor to overcome the immunosuppressive milieu of glioblastoma and to efficiently target a tumor with such high cellular complexity.
Highlights
Since the discovery in 2005 of the clinical utility of Temozolomide in glioblastoma (GBM) patients [1], no other cytotoxic drug was added in the standard treatment protocols
From conventional cytotoxic or from targeted therapies that are aimed at the cancer cells, the therapies that involve the modulation of Immune Checkpoint molecules (ICs) attempt to redirect the function of the immune system to elicit cancer cell death
Antibodies against the “classic” IC molecules (CTLA-4, PD-1, PD-L1, and PD-L2) are considered the “first generation” IC inhibitors (ICis) that interfere with the immune escape of tumor cells, followed by second and third generations ICis targeting other immunoregulatory molecules and pathways [9, 10]
Summary
Since the discovery in 2005 of the clinical utility of Temozolomide in glioblastoma (GBM) patients [1], no other cytotoxic drug was added in the standard treatment protocols. Disabling the entire IC network (CTLA-4/PD-L1/IDO) [57] or the dual IC blockade (TIM-3/PD-1) coupled with radiosurgery [59], both resulted in the survival of 100% of the treated mice In all these treatments it was possible to demonstrate the activation of the immune system within the tumor (cytokines production, TIL activation, etc.) and sustained anti-tumor immune response since regrowth of the tumor was not observed after tumor cell re-challenge. The second completed study was NCT02550249, a phase II study that enrolled 29 patients and had as primary outcome the evaluation of the expression of PD-L1 in tumor cells and lymphocytes upon treatment with Nivolumab In this case the results are not available. INT230-6 (cytotoxic carrier, intratumor) + Nivolumab Bevacizumab + Lomustine + Nivolumab + TMZ + Radiotherapy Dendridic cell vaccine + Nivolumab Nivolumab + Anti-LAG-3 Oncolytic Adenovirus (intratumor) + Nivolumab
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