Recurrent glioma clinical trial, CheckMate-143: the game is not over yet

Abstract

Glioblastoma (GBM) is the most common, and aggressive, primary brain tumor in adults. With a median patient survival of less than two years, GBM represents one of the biggest therapeutic challenges of the modern era. Even with the best available treatment, recurrence rates are nearly 100% and therapeutic options at the time of relapse are extremely limited. Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody, has provided significant clinical benefits in the treatment of various advanced cancers and represented a promising therapy for primary and recurrent GBM. CheckMate 143 (NCT 02017717) was the first large randomized clinical trial of PD pathway inhibition in the setting of GBM, including a comparison of nivolumab and the anti-VEGF antibody, bevacizumab, in the treatment of recurrent disease. However, preliminary results, recently announced in a WFNOS 2017 abstract, demonstrated a failure of nivolumab to prolong overall survival of patients with recurrent GBM, and this arm of the trial was prematurely closed. In this review, we discuss the basic concepts underlying the rational to target PD pathway in GBM, address implications of using immune checkpoint inhibitors in central nervous system malignancies, provide a rationale for possible reasons contributing to the failure of nivolumab to prolong survival in patients with recurrent disease, and analyze the future role of immune checkpoint inhibitors in the treatment of GBM.

Keywords: PD-1/PD-L1; checkpoint inhibitor; gliolastoma; immunotherapy; malignant glioma.

Figure 1. Commonly employed immunotherapeutic strategies enhance antitumor immunity by addressing different components of the immune response

1) Antitumor immunity can be directly bolstered with the adoptive transfer of specialized and functional T cells. 2) Therapeutic vaccines that enhance dendritic cell function and presentation of tumor antigens promote more efficient activation of antigen specific CD8+ T cell responses. 3) Oncolytic viruses can selectively infect and lyse tumor cells, releasing tumor associated antigens into the glioma microenvironment which can be taken up by the resident DCs. 4) Monoclonal antibodies targeting immune cell (ex. CTLA-4, PD-1) and tumor-expressed (PD-L1, VEGF) molecules can be used to inhibit signaling through pathways that promote tumor cell growth or inhibit immune cell responses.

Figure 2. PD-1 is constitutively expressed on activated T cells, B cells, and other myeloid cells

Release of IFN-γ by activated T lymphocytes during inflammatory responses directly induces local PD-L1 expression on surrounding cells. Binding of PD-L1 to lymphocyte-expressed PD-1 transmits an inhibitory feedback signal that suppresses T cell proliferation and cytokine release and induces T cell anergy, apoptosis, and the development of regulatory T cells, thereby attenuating inflammatory responses.

Figure 3. In the setting of cancer, PD-L1 is upregulated on tumor cells in response to IFN-γ released by infiltrating immune cells during antitumor immune responses, as well as through tumor-specific IFN-γ-independent mechanisms

PD-L1 serves as a receptor on cancer cells that, through interactions with PD-1expressing TIL, induces an intrinsic resistance to CTL killing and suppresses antitumor immune responses.

Figure 4. In recurrent disease, efficacy of nivolumab is limited by its inability to cross the blood brain barrier and a paucity of functional circulating T-cells with which to interact and form a protective barrier against subsequent possible PD-1/PD-L1 interactions

Exposed to numerous immunosuppressive influences within the glioma microenvironment, including uninhibited PD-1/PD-L1 interactions, T-cells already sequestered within the TME are expected to be heavily dysfunctional and unable to be rescued solely with immune checkpoint inhibition.