April 2014, Part 1
Review: The Role of the PD-1 Pathway in Immunotherapy
For decades, chemotherapy, radiation therapy, and excisional surgery have served as the mainstays of cancer treatment. While often effective, these treatments affect healthy as well as neoplastic cells and therefore cause many unintended side effects, some of which may be life-threatening. Even after treatment, a substantial proportion of patients experience relapse of their cancer. Over the years, there has been an increasing recognition that the immune system can play a role in the induction of antitumor response. As the understanding of the interaction between the immune system and tumor biology has deepened, researchers have indeed found that immune-cell types can influence the growth of tumors.1
The immune system seeks to eliminate cells that are recognized as â€śforeign.â€ť This may include the rejection of human or animal tissues implanted as tissue and organ grafts or of cells that have been infected by bacteria and/or viruses. Likewise, newly transformed cancer cells can also be eliminated through an innate response by certain immune cells.2
The immune system mediates both immediate and longer-term responses to target cells. Cell types involved in the immediate, or innate, immune response include cytotoxic T lymphocytes (or CD8+), which directly contact infected cells and destroy them, while monocytes, macrophages, and dendritic cells secrete inflammatory cytokines and capture protein fragments from dead cells. These fragments, or epitopes, are then presented on antigen-presenting cells (APCs), chiefly dendritic cells, as part of the major histocompatibility complex and thereby help to initiate the adaptive immune response.1,3
In the adaptive immune response, some T cells are activated to respond to antigenic cells. Once activated, cytotoxic T cells migrate to the site of infection, where they work in conjunction with macrophages and other phagocytic lymphocytes to destroy microbes and tumor cells. Other activated T cells known as T-helper (or CD4+) cells remain in the lymphoid organ and play a role in regulating the adaptive immune response. T-helper cells also stimulate B lymphocytes to secrete immunoglobulins (Igs) that help to identify tumor cells. By this adaptive immune process, which typically takes place over a period of time, activated T cells can eradicate tumor cells from the body. The adaptive immune response is highly selective and works by clonal selection to make antibodies that are specific to the antigens that induced their production.1,3,4
The Immune Checkpoint Blockade
In their 2011 paper, â€śHallmarks of Cancer: The Next Generation,â€ť Douglas Hanahan and Robert Weinberg acknowledged the importance of the immune system in cancer development and identified immune evasion as essential to the transformation of normal cells into cancer cells. Researchers have begun to elucidate some of the complex biological mechanisms employed by cancer cells that enable them to avoid eradication by the immune system, and a new class of immunotherapeutic anticancer agents has emerged as a result.5
A key development for cancer immunotherapy has been the recognition of immune checkpoints, which consist of a large number of inhibitory pathways that regulate the duration and amplitude of physiological immune responses, minimize collateral tissue damage during infections, and maintain self-tolerance and prevent autoimmunity under normal conditions. However, it has become increasingly clear that certain tumors are able to â€śhijackâ€ť the normal immune response, downregulating inhibitory receptors on immune effector cells or their ligands on tumor cells. This process takes place when tumor cell ligands bind to host cell antigen receptors, thereby effectively disabling the protective functions of the immune systemâ€™s T cells and shielding the tumor against immune attack. It is thought that these negative regulatory pathways may be more potent than the normal regulatory pathways that stimulate T cells.6,7
Research is actively under way to identify therapeutic agents that have the ability to protect against the immunosuppressive effects of certain tumor cells. One such area of research involves the development of monoclonal antibodies to prevent tumor cell ligands from binding to host immune receptors. This approach, known as immune checkpoint blockade, is thought to have the potential to promote enhanced and sustained endogenous immunity against nonmutated as well as uniquely mutant antigens, resulting in effective and durable tumor control.6
The 2 checkpoint receptors that have been most actively studied in the context of clinical cancer immunotherapy are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed deathâ€“1 (PD-1).6
CTLA-4, the first immune checkpoint receptor to be clinically targeted, is a member of the Ig superfamily and is expressed on the surface of T-helper cells. The primary role of the CTLA-4 receptor is to downmodulate the early stages of T-cell activation. Antiâ€“CTLA-4 antibodies were developed to inhibit the negative regulatory effect of CTLA-4 in certain immunogenic tumors, thereby promoting T-cell activity. Antiâ€“CTLA-4 antibodies were the first immune checkpoint receptors to be commercialized.7
The PD-1 pathway has also emerged as a fertile area of cancer research, and recent evidence has confirmed the pivotal role of the PD-1 receptor and its ligands PD-L1 (also known as B7-H1) and PD-L2 (also known as B7-DC) in maintaining an immunosuppressive tumor microenvironment.6 Encouraging clinical findings from the PD-1 pathway blockade have validated its potential as a target for cancer immunotherapy.6,7
The Role of PD-1 as an Immune Checkpoint Receptor
PD-1, a member of the extended CD28 superfamily of T-cell regulators, is a cell surface protein molecule that serves as an immune checkpoint receptor in the inhibition of T-cell responses.8 PD-1 is expressed innately during thymic development in immature lymphocytes known as thymocytes. In addition, PD-1 is inducibly expressed on peripheral CD4+ (T-helper) and CD8+ (cytotoxic T) lymphocytes as well as on B cells, natural killer T cells, monocytes, and some dendritic cells when they are activated.9 The major role of PD-1 is to inhibit cytokine production, cytolytic function, and T-cell proliferation in the periphery, thereby limiting inflammation and preventing autoimmunity.6,7,10
The PD-1 pathway refers to the interaction between the PD-1 receptor and its ligands PD-L1 and PD-L2. PD-L1 is expressed on a broad variety of hematopoietic (T cells, B cells, dendritic cells, macrophages, mast cells) and nonhematopoietic cell types (parenchymal cells, some endothelial cells), whereas PD-L2 expression is limited to APCs, including macrophages, dendritic cells, certain B-cell subtypes, and mast cells.9-11
The 2 PD-1 ligands are upregulated in response to proinflammatory cytokines. Interferons and tumor necrosis factorâ€“alpha induce PD-L1 expression in T cells and B cells, while interleukin (IL)-2, IL-7, and IL-15 have been shown to induce PD-L1 expression in human T cells.6,9,12 Conversely, PD-L2 expression has been shown to take place when stimulated by interferons, IL-4, and, on dendritic cells, by granulocyte-macrophage colony-stimulating factor.6,9 It should be noted that many of these inflammatory signals have not yet been defined completely.7
Along the PD-1 pathway, naive T cells become activated in response to stimulatory signals, after which they upregulate PD-1 expression. These activated T cells then begin to migrate to peripheral tissues. Inflammatory signals in the tissues induce PD-L1 and/or PD-L2 expression, which downregulates the activity of T cells and limits collateral tissue damage by immune cells in infected tissues. Excessive induction of PD-1 on T cells during chronic antigen exposure, such as a viral infection, can cause T cells to become â€śexhausted,â€ť or anergic, leading to sustained immunosuppression.7
Clinical Activity of Investigational PD-1 Blockers
As the understanding of PD-1 pathway biology and its critical role in immunosuppression has evolved, there has been a groundswell fueling the clinical development of PD-1 pathway blockers. Tumor cell expression of PD-L1 has emerged as a potential biomarker of response, consistent with pathway biology.6
Prior animal studies suggested that PD-1 blockade may result in less toxicity than other similar immunotherapeutic mechanisms, such as CTLA-4, for example. Thus far, this has been borne out by the data, and investigational PD-1 blockers appear to have a favorable toxicity profile compared with that of an approved CTLA-4 blocker.7,13 The reduced toxicity is consistent with the milder autoimmune phenotype seen in PD-1 knockout mice compared with analogous CTLA-4 mice.13
Antibodies to PD-1 have also demonstrated clinical activity in a variety of cancer types, including melanoma, renal cell carcinoma (RCC), colorectal cancer, nonâ€“small cell lung cancer (NSCLC), and a number of hematologic malignancies.7 Interestingly, one of the investigational antiâ€“PD-1 agents has shown clinical activity against NSCLC, long thought to be a â€śnonimmunogenicâ€ť tumor, suggesting the potential for PD-1 blockade to reactivate endogenous antitumor immunity in a wide spectrum of malignancies.6 Also of note, many of the findings for different investigational agents have been complementary, further validating the PD-1 pathway as a logical target for immunotherapy.6
In a multicenter, phase 1 clinical trial with a fully human IgG4 antiâ€“PD-1, PD-L1â€“specific antibody, researchers reported significant antitumor activity in patients with advanced melanoma, metastatic NSCLC, RCC, and ovarian cancer despite the fact that many participating subjects had progressed through multiple rounds of prior treatment with conventional and experimental chemotherapeutic agents. These findings validate the PD-1/PD-L1 axis as a therapeutic target. Most tumor responses were durable beyond 1 year, resulting in prolonged disease stabilization. Toxic effects were generally of low grade, which is consistent with expectations based on animal studies.14
Data suggest that PD-L1 expression may be a logical marker to identify candidates for immunotherapy. In one study, treatment with an investigational agent led to an objective response rate of 36% (n=25) in patients with PD-L1+ tumors, compared with 0% (n=17) in patients with PD-L1â€“ tumors. In the future, these findings may have important clinical ramifications in targeting appropriate patients for therapy.15
In another clinical study of 135 patients treated with an investigational humanized monoclonal IgG4-kappa isotype antibody against PD-1, 38% of patients demonstrated a confirmed response when evaluated by central radiologic review. Again, this agent demonstrated durable response with relatively mild toxicities. Furthermore, the response rates were similar for CTLA-4â€“naive and CTLA-4â€“experienced patients, suggesting that prior CTLA-4 therapy did not impact the PD-1 blockade.16
Strategies for Combination Immunotherapy
As research proceeds, the prospect of combining immunotherapeutic agents should be considered. Despite early successes with monotherapeutic approaches to PD-1 blockade, preclinical models indicate that combination therapies may deliver incrementally greater clinical impact.6
A rational combination strategy must account for the different steps of the immune response that need to be addressed to generate anticancer immunity, consider the effects of different agents at these steps, and assess the potential for overlapping or synergistic effectiveness in inhibiting or preventing tumor growth. The combination of antiâ€“CTLA-4 and antiâ€“PD-1 is intuitive from a biological perspective, as the 2 agents remove the brakes from T-cell activation at 2 distinct stages: proÂliferation (CTLA-4) and effector function (PD-1). Despite the opportunity for synergistic effectiveness, it will be vital to pay close attention to adverse events and carefully define the potential for serious toxicity in combination regimens.13
The strategic vision for combination treatment can also be viewed in the context of adaptive resistance. Antiâ€“PD-1 blockers rely on a strong endogenous antiÂtumor immune response to induce PD-L1 expression in tumors. Conversely, when there is a weak endogenous response, little or no PD-L2 upregulation takes place, and antiâ€“PD-1 antibodies are far less likely to elicit the desired response. However, if PD-1 pathway blockade were combined with a therapy that could induce a stronger endogenous response, such as a vaccine, PD-1 expression could be induced, and PD-1â€“blocking antibodies might then be effective in patients who may not have responded to either treatment alone.17
The PD-1 checkpoint pathway plays an important role in modulating the immune system.7,18 Under normal conditions, the immune system recognizes microbes and other antigens, including tumor cells, and can mount an active response.4,5 However, researchers have found that tumors can evade normal immune attack by exploiting the PD-1 immune checkpoint pathway via the PD-1 receptor.7,18 By exploiting the PD-1 checkpoint pathway, cancer cells are able to evade the immune response and continue to thrive and proliferate in the tumor microenvironment.7,13,18
The oncology research community has long sought therapeutic agents that can activate the immune system to fight cancer, and the PD-1 checkpoint pathway is a promising avenue in the research of treatments for advanced cancers. Evidence indicates that specific monoclonal antibodies have the ability to counteract T-cell inhibition induced by tumor cells via the PD-L1 and PD-L2 ligands.7,13,16,18,19 Furthermore, expression of PD-L1 on tumors is correlated with reduced survival in esophageal, pancreatic, and other types of cancers, highlighting this pathway as a target for immunotherapy.20
Several immunotherapeutic compounds are currently being studied, and the clinical findings are highly anticipated. However, many questions remain unanswered. Although preliminary findings have been favorable,16,19 the longer-term durability of PD-1 blockade agents remains to be seen. Likewise, although PD-1+ status appears to be a predictor for tumor-mediated immune evasion,18 researchers have not yet identified a biomarker that can serve as a useful prognostic indicator. Some have suggested that combinatory regimens may hold more therapeutic promise than monotherapy, and in theory, it is intuitive to expect a synergistic effect from different, but complementary, mechanisms.13,17 HowÂever, clinical research for combination therapies is still in its infancy, and much remains unknown.
In cancer research, immune checkpoint blockade is a promising emerging approach to immunotherapy, and clinical findings thus far indicate that the PD-1 checkpoint pathway represents a significant opportunity to enhance antitumor immunity with the potential to produce durable responses.
- Borghaei H, Smith MR, Campbell KS. Immunotherapy of cancer. Eur J Pharmacol. 2009;625:41-54.
- Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology. 2007;121:1-14.
- Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th ed. New York: Garland Science; 2002.
- Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23(suppl 8):viii6â€“viii9.
- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646-674.
- Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24(2):207-212.
- Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209.
- Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515-548.
- Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219-242.
- Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-125.
- Riella LV, Watanabe T, Sage PT, et al. Essential role of PDL1 expression on nonhematopoietic donor cells in acquired tolerance to vascularized cardiac allografts. Am J Transplant. 2011;11:832-840.
- Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127ra37.
- Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-489.
- Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-2465.
- Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.
- Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambroÂlizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134-144.
- Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-264.
- Azuma T, Yao S, Zhu G, et al. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008;111:3635-3643.
- Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167-3175.
- Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 2005;11:2947-2953.
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