Blocking the programmed cell death 1 (PD-1) pathway with monoclonal antibodies has shown promising antitumor responses in clinical trials, with less toxicity than has been seen with prior immune therapies such as interleukin 2 and ipilimumab. Pembrolizumab, an anti–PD-1 antibody, recently gained US Food and Drug Administration (FDA) accelerated approval for the treatment of patients with ipilimumab-refractory melanoma, while nivolumab, another anti–PD-1 antibody, and MPDL3280A, an anti–programmed cell death 1 ligand (PD-L1) antibody, have been granted FDA “breakthrough designation” for treatment of subsets of patients with refractory Hodgkin lymphoma and metastatic bladder cancer, respectively. Encouraging antitumor activity has also been seen with these agents in patients with other malignancies, including non–small-cell lung cancer and head and neck cancer, tumors not previously thought to be immune-responsive. PD-L1 expression has emerged as a potential predictive biomarker for PD-1–directed therapy. Multiple, distinct, companion assays for PD-L1 positivity have been developed, but there is as yet no comparison, standardization, or prospective validation of these assays. PD-L1 expression on tumor cells and/or the tumor-immune infiltrate is likely only part of the predictive model necessary for selecting patients predisposed to respond to monotherapy. Additional predictive biomarkers are necessary to identify patients most likely to benefit from PD-1–based combination therapy, since tumor cell PD-L1 expression appears to have limited predictive value in this setting.
Historically, active immune therapies such as interleukin 2 (IL-2) produced durable responses in only a small minority of patients while being associated with significant, nearly universal toxicity. This has limited their applicability to selected patients, usually with either melanoma or renal cell cancer (RCC) treated at experienced centers. The immune checkpoint inhibitor ipilimumab, while being better tolerated than high-dose (HD) IL-2, also exposes patients to a risk of significant toxicity. Therefore, there has been considerable effort over the past decade to identify patients most likely to benefit from these agents in order to enhance their therapeutic index. The discovery and availability of alternative treatment options for patients with advanced melanoma (BRAF inhibitor therapy) and RCC (vascular endothelial growth factor [VEGF]-targeted therapy) in the last decade have intensified the need to identify those patients who will not benefit from immunotherapy, so as not to delay the use of these more generally accessible alternative therapies, particularly in symptomatic patients. Programmed cell death 1 (PD-1) pathway–blocking antibodies appear to exhibit an improved therapeutic index, relative to HD IL-2 and ipilimumab, and efficacy against an expanded array of tumor types (eg, non–small-cell lung cancer (NSCLC), bladder cancer, head and neck cancer), each of which has a distinct array of standard treatments. This has further highlighted the need for clinically useful biomarkers that can help determine how best to incorporate these new agents into treatment algorithms for patients with specific diseases. Finally, identifying factors that predict the subpopulations of patients and tumor types that respond to immunotherapy is critical to both understanding the mechanism of action of immunotherapy and the efficient development of novel immunotherapy combinations.
Definition of Biomarkers
A biomarker is a biologic molecule, such as a protein or gene, that is measureable in tissue, blood, or other body fluids, and is an indicator of some clinically significant condition. Biomarkers can be diagnostic, surrogate, prognostic, or predictive. While the gold standard of diagnosis in oncology is a pathologic tissue review, a highly elevated prostate-specific antigen (PSA) level in the right clinical setting can be diagnostic of prostate cancer. Although the value of PSA level as a diagnostic biomarker is limited by its sensitivity and specificity, it can be an excellent surrogate biomarker for monitoring prostate cancer response to treatment. Prognostic biomarkers refer to markers that correlate with the natural progression or aggressiveness of a disease. Prognostic biomarkers are useful for informing patients about the risk of recurrence or median survival for their particular type of malignancy and for minimizing confounding factors when analyzing clinical trial cohorts or when prospectively stratifying patients in randomized clinical trials. Predictive biomarkers are defined by their role in predicting a response to a given treatment. Therefore, these are most useful if they can be assessed before the initiation of treatment. This review will focus on predictive biomarkers, as these are most relevant to decision making regarding immunotherapy selection; we will only mention prognostic or surrogate markers to the extent that such discussion sheds potential light on the mechanisms underlying the value of a predictive biomarker.
Biology of the Immune Response
The immune system is controlled by a delicate balance of immune-stimulatory and immune-inhibitory forces that enable the rapid destruction of cells expressing foreign antigens while preventing uncontrolled destruction of normal tissues. The inhibitory forces include regulatory T cells (Tregs), immunosuppressive cytokines, and immune checkpoints, such as the cytotoxic T-lymphocyte antigen 4 (CTLA-4)/B7 and the PD-1/programmed cell death 1 ligand (PD-L1) pathways. For example, IL-2 not only activates CD8+ effector T cells and subsets of natural killer cells, but also CD4+CD25+ and CD4+Foxp3+ Tregs, which constitutively express the IL-2 receptor alpha chain. Studies in viral models of acute and chronic infections shed light on this phenomenon. PD-1 expression is induced by activation of T lymphocytes, and after a successful immune response has eliminated the foreign antigen, PD-1 expression decreases.[2,3] If the immune response is unsuccessful in eliminating the antigen-expressing cells, as in cancer or chronic infections, prolonged antigen stimulation leads to elevated PD-1 expression and induction of the expression of immune-inhibitory ligands, such as PD-L1 or PD-L2, on tumor cells and infiltrating immune cells. The binding of PD-1–expressing T cells to PD-L1 or PD-L2 leads to T-cell dysfunction and “exhaustion,” and results in eventual escape from immune elimination. In addition to this model of adaptive immune inhibition or resistance, as illustrated in melanoma, other tumors may evade immune surveillance by overexpression of PD-L1 secondary to genetic amplification or as a result of aberrant signaling.
Some tumors have an inflamed phenotype, while others have only a sparse immune infiltrate. While the extent of the immune infiltrate can be a good prognostic indicator in some cancers,[7,8] the antitumor response is clearly insufficient to prevent disease progression. In inflamed tumors, negative immune-regulatory factors tend to dominate due to the chronic nature of the immune infiltrate, as illustrated in Gajewski et al (Figure 1A). Therefore, it is hypothesized that patients with tumors containing T-cell infiltrates might be induced to respond to immunotherapy if the immune cells within the tumor microenviroment can be reactivated.
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