Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity
Highlights
► PD-1/B7-H1 are pivotal in maintaining an immunosuppressive tumor microenvironment. ► PD-1 and CTLA-4 play distinct roles in regulating immunity. ► B7-H1 upregulation on tumor cells likely reflects ‘adaptive resistance’. ► PD-1 blockade is active against NSCLC, thought to be a ‘non-immunogenic’ tumor. ► Monotherapies blocking PD-1 may be more effective in combinatorial regimens.
Introduction
Ever since it became clear that all cancer cells express tumor-specific and tumor-selective antigens derived from genetic alterations and epigenetic dysregulation, the immunology community has embraced the potential for immune-based therapies to induce targeted anti-tumor responses. However, skepticism about the clinical value of immunotherapies designed to specifically enhance T cell-mediated immunity against preselected commonly expressed tumor antigens, including cancer vaccines and adoptive T cell transfer strategies, has escalated [1]. A game changer for cancer immunotherapy has emerged in the form of monoclonal antibodies (mAbs) that block inhibitory receptors on immune effector cells or their ligands on tumor cells and antigen presenting cells (APCs) — so-called ‘immune checkpoints’. Immune checkpoint blockade has the potential to enhance and sustain endogenous immunity against non-mutated as well as uniquely mutant antigens, establishing durable tumor control. Recent evidence highlights the pivotal role of the Programmed Death-1 (PD-1) T cell co-receptor and its ligands B7-H1/PD-L1 and B7-DC/PD-L2 in maintaining an immunosuppressive tumor microenvironment. Encouraging early results from clinical blockade of this pathway have validated its potential as a target for cancer immunotherapy.
Section snippets
Receptor/ligand biology
The two checkpoint receptors that have been most actively studied in the context of clinical cancer immunotherapy, CTLA-4 and PD-1 [2, 3•, 4, 5, 6, 7, 8], play distinct roles in regulating immunity (Figure 1). CTLA-4, which regulates the amplitude of early activation of naïve and memory T cells, is transported to the T cell surface at levels that depend on the strength of the TCR signal. It acts physiologically as a signal dampener. Its importance in modulating T cell responses is demonstrated
Preclinical models
Preclinical evidence for PD-1's inhibitory role comes from several sources. Knockout mice develop late-onset, strain-specific autoimmunity; on a C57BL/6 background this manifests as sporadic glomerulonephritis [28], on a Balb/c background as an antibody-mediated cardiomyopathy [29]. These findings extend to models of organ-specific autoimmunity; on the non-obese diabetic (NOD) background, PD-1 KO mice develop accelerated insulitis as well as increased T cell production of effector cytokines [30
Clinical translation
An understanding of PD-1 pathway biology and the preclinical demonstration of its pivotal role in immunosuppression have fueled the clinical development of PD-1 pathway blockade for cancer therapy. There are currently four anti-PD-1 agents in the clinic: MDX-1106/BMS-936558/ONO-4538, CT-011, MK-3475, and AMP-224. The first three are reported to be PD-1 blocking mAbs, while the last is a B7-DC/IgG1 fusion protein (Table 1).
To date, most clinical experience with PD-1 blockade has been gained with
Conclusions
Despite early successes with monotherapies blocking PD-1 pathways, preclinical models indicate that combinatorial therapies will deliver maximum clinical impact. Several clinical trials are already planned or in progress, combining anti-PD-1 mAbs with cancer vaccines (melanoma, prostate cancer, renal cell carcinoma, AML), anti-tumor mAbs (lymphoma), or chemotherapies (pancreatic cancer, NSCLC). These synergistic treatment strategies will provide a foundation for the next generation of clinical
Disclosure statement
Consulting or advisory role: S.L.T., Bristol-Myers Squibb (uncompensated) and Amplimmune Inc. (spouse); C.G.D., Bristol-Myers Squibb and Amplimmune Inc.; D.M.P., Bristol-Myers Squibb (uncompensated) and Amplimmune Inc. Stock ownership: C.G.D., Amplimmune Inc. Research funding: S.L.T., Bristol-Myers Squibb.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Supported by NIH grants R01 CA142779 (S.L.T., D.M.P.), R01 CA127153 (C.G.D.), and 1P50CA58236-15 (C.G.D.); a grant from the Melanoma Research Alliance (S.L.T., C.G.D., D.M.P.); the Laverna Hahn Charitable Trust and the Barney Family Foundation (S.L.T.); the Patrick C. Walsh Fund, the OneInSix Foundation, and the Prostate Cancer Foundation (C.G.D.).
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