Next steps in immuno-oncology: enhancing antitumor effects through appropriate patient selection and rationally designed combination strategies

Abstract

Background: Cancers escape immune surveillance via distinct mechanisms that involve central (negative selection within the thymus) or peripheral (lack of costimulation, receipt of death/anergic signals by tumor, immunoregulatory cell populations) immune tolerance. During the 1990s, moderate clinical benefit was seen using several cytokine therapies for a limited number of cancers. Over the past 20 years, extensive research has been performed to understand the role of various components of peripheral immune tolerance, with the co-inhibitory immune checkpoint molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand (PD-L1) being the most well-characterized at preclinical and clinical levels.

Patients and methods: We used PubMed and Google Scholar searches to identify key articles published reporting preclinical and clinical studies investigating CTLA-4 and PD-1/PD-L1, frequently cited review articles, and clinical studies of CTLA-4 and PD-1/PD-L1 pathway inhibitors, including combination therapy strategies. We also searched recent oncology congress presentations and clinicaltrials.gov to cover the most up-to-date clinical trial data and ongoing clinical trials of immune checkpoint inhibitor (ICI) combinations.

Results: Inhibiting CTLA-4 and PD-1 using monoclonal antibody therapies administered as single agents has been associated with clinical benefit in distinct patient subgroups across several malignancies. Concurrent blockade of CTLA-4 and components of the PD-1/PD-L1 system using various schedules has shown synergy and even higher incidence of durable antitumor responses at the expense of increased rates of immune-mediated adverse events, which can be life-threatening, but are rarely fatal and are reversible in most cases using established treatment guidelines.

Conclusions: Dual immune checkpoint blockade has demonstrated promising clinical benefit in numerous solid tumor types. This example of concurrent modulation of multiple components of the immune system is currently being investigated in other cancers using various immunomodulatory strategies.

Figure 1.

Mechanisms of immune tolerance. Immune tolerance involves a range of overlapping mechanisms that involve not only the periphery (e.g. tumor site), but also central lymphoid organs, especially thymus. They include intrathymic negative regulation (central), decreased costimulation, anergic signals from tumor cells, and immunoregulation (e.g. from Treg and MDSC [peripheral]). Arg1, arginase 1; HLA, human leukocyte antigen; ICP, immune checkpoint protein; IDO, indoleamine 2,3-dioxygenase; IGF-1, insulin-like growth factor; IL-10, interleukin 10; KGF, keratinocyte growth factor; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; NF-κB, nuclear factor kappa-B; PD-L1, programmed death ligand 1; STAT, signal transducer and activator of transcription; RANKL, receptor activator of nuclear factor kappa-B ligand; TGF, transforming growth factor; Treg, regulatory T cells; VEGF, vascular endothelial growth factor.

Figure 2.

Implications of CTLA-4 and PD-1 dual pathway blockade. Interruption of CTLA-4:B7 binding by T cells in lymph nodes via anti-CTLA-4 increases T-cell proliferation, activation, and survival, potentially leading to an increased number of activated T-cell clones that can respond to tumor antigens. Blockade of PD-1:PD-L1 binding at the tumor site via anti-PD-1 restores the activity of antitumor T cells that have become inactivated. CTLA-4 and PD-1 blockade may also reduce the suppressive effects of Tregs at the tumor site. Please note that T cells may express other (i.e. non-CTLA-4, non-PD-1, PD-L1) co-stimulatory (+?) as well as co-inhibitory immune checkpoint proteins (-?), whereas tumor cells upregulate almost exclusively co-inhibitory ICPs via genetic (gene amplification) [17] or epigenetic mechanisms (upregulation of PI3K) [87]. BTLA, B- and T-lymphocyte attenuator; CTLA-4, cytotoxic T-lymphocyte antigen 4; GITR, glucocorticoid-induced TNFR-related protein; ICOS, inducible costimulator; LAG-3, lymphocyte activation gene-3; LGALS9, lectin, galactoside-binding, soluble-9; KIR, killer-cell immunoglobulin-like receptor; PD-1, programmed death-1; PD-L1, programmed death ligand 1; TCR, T-cell receptor; TNFSRF, tumor necrosis factor receptor superfamily-14; Treg, regulatory T cells.