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Understanding Immune Checkpoint Inhibitors for Effective Patient Care

Krista M. Rubin
CJON 2015, 19(6), 709-717 DOI: 10.1188/15.CJON.709-717

Background: Immune checkpoint inhibitors represent a paradigm change in the treatment of melanoma and other advanced cancers. These agents manipulate key immune-regulating pathways to restore immune responses against tumors. The success of this approach is demonstrated by ipilimumab (Yervoy®) for the treatment of advanced melanoma, with improvement in three-year survival rates of about 20%. Newer checkpoint inhibitors targeting the programmed death-1 (PD-1) pathway have been approved and may have higher response rates and improved tolerability.

Objectives: This article aims to educate nurses and increase their comfort level with these new therapies.

Methods: The mechanism of action of immune checkpoint inhibitors is reviewed, and insight is provided on how nurses can use this knowledge to more effectively care for patients receiving these therapies.

Findings: The use of immuno-oncology agents is increasing. Oncology nurses must understand the basic immune mechanism of action responsible for the novel toxicity profile characterized by immune-related adverse events (irAEs) and clinical response patterns. Managing irAEs with immune checkpoint inhibitors is not necessarily more difficult than with conventional agents, but a difference does exist. Nurses and other healthcare providers must consider the underlying cause of toxicity with immune checkpoint inhibitors when making management decisions.

Metastatic melanoma has historically been considered an incurable cancer. However, the treatment landscape for metastatic or unresectable melanoma and other advanced malignancies is undergoing rapid change. New immunotherapies, termed immune checkpoint inhibitors, work by reactivating an immune response against tumors (Pardoll, 2012). Immune checkpoint inhibitors for treating melanoma include ipilimumab (Yervoy®), pembrolizumab (Keytruda®), and nivolumab (Opdivo®). The checkpoint inhibitor ipilimumab, which targets the cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathway, was approved for use in 2011 (Bristol-Myers Squibb, 2015b). Agents targeting the programmed death-1 (PD-1) pathway (i.e., pembrolizumab and nivolumab) are approved for the treatment of patients with unresectable or advanced melanoma that has progressed after ipilimumab (and, if positive for BRAF V600 mutation, a BRAF inhibitor). Nivolumab was recently approved for the treatment of non-small cell lung cancer (NSCLC) with progression after platinum-based chemotherapy on or after targeted therapy (Bristol-Myers Squibb, 2015a), and pembrolizumab was also recently approved for the same indication, but for those whose tumors express PD-L1 (a biomarker) (Merck & Co., 2015). In addition, the U.S. Food and Drug Administration approvals included the combination of nivolumab and ipilimumab as a first-line treatment for patients with metastatic melanoma and wild-type BRAF, as well as the approval of ipilimumab as an adjuvant therapy for stage III melanoma following surgery (Bristol-Myers Squibb, 2015b). Most oncology nurses will likely be caring for patients receiving these agents in the near future. To optimize patient care, nurses must have a basic understanding of these immuno-oncology agents and their associated toxicity profile.

Immune Checkpoint Pathways

The inhibitory cytotoxic CTLA-4 and PD-1 pathways dampen T-cell responses to minimize tissue damage (see Table 1). Figures 1 and 2 illustrate how the CTLA-4 and PD-1 checkpoint pathways operate in a successful antiviral immune response compared with an unsuccessful antitumor immune response. These two pathways have nonredundant roles in stopping T-cell functions.

T-cells are initially stimulated by antigens, including viral or tumor antigens, in lymph nodes. Up-regulation of CTLA-4 (a cell surface receptor) on T-cells is used to turn off T-cells that may inadvertently respond to self-antigens and, therefore, cause autoimmunity. PD-1 (also a T-cell surface receptor) has two key ligands, PD-L1 and PD-L2. During the course of the immune response, tissues and other infiltrating immune cells begin to express PD-L1 and/or PD-L2, and responding T-cells begin to express PD-1. When these T-cells encounter PD-L1 and/or PD-L2, they are turned off. This step is important for ending an ongoing immune response so as not to damage healthy tissues and to allow healing (Topalian, Drake, & Pardoll, 2012).

Tumors can up-regulate PD-L1 and/or PD-L2 to inhibit activated antitumor T-cells (Zou & Chen, 2008). Checkpoint blockade works by reactivating T-cells that lead to enhanced antitumor response. CTLA-4 inhibitors (ipilimumab, tremelimumab) are designed to allow more T cells to become activated and to stay activated longer, thereby more effectively targeting tumor cells. One potential explanation for their anticancer effects is that CTLA-4 blockade supports the development of a larger number of activated antitumor T-cells (Tivol et al., 1995). PD-1 pathway inhibitors are designed to prevent activated antitumor T-cells from being turned off. In theory, they prolong and enhance ongoing antitumor immune responses (Pardoll, 2012). Anti–PD-1 agents (nivolumab, pembrolizumab, and pidilizumab) block PD-1 from binding both its ligands, PD-L1 and PD-L2. Anti–PD-L1 agents durvalumab (MEDI4736) and atezolizumab (MPDL3280A) block PD-1 and PD-L1 binding, whereas PD-1 and PD-L2 binding remains intact (Topalian, Drake, et al., 2012).

Immune Checkpoint Blockade in Practice

The power of immuno-oncology approaches was initially demonstrated by interleukin-2 (IL-2), a cytokine that promotes T-cell growth and proliferation. A proportion (7%) of patients who received high-dose IL-2 in early trials survived more than five years (Atkins, Kunkel, Sznol, & Rosenberg, 2000). IL-2 was approved for the treatment of metastatic melanoma in 1998; however, the significant toxicities associated with IL-2 treatment limited its widespread use (National Comprehensive Cancer Network [NCCN], 2015). Instead of the broad T-cell activation by IL-2, immune checkpoint inhibitors are designed to stimulate subsets of T-cells. Meaningful and durable responses occur in about 11% of ipilimumab-treated patients with advanced disease, in contrast to more transient responses, which occur in 12%–20% of patients receiving chemotherapy (Shah & Dronca, 2014). Of note, unlike chemotherapy, response rates with immune checkpoint inhibitors do not appear to decrease in patients who have had more lines of prior treatment. Targeted agents, such as BRAF and MEK inhibitors, have higher response rates (22%–50%) than ipilimumab; however, most tumors eventually develop resistance.

Phase I trials of PD-1 inhibitors in patients with previously treated melanoma have reported very promising response rates of 26%–38% (Hodi et al., 2014; Robert et al., 2014) and supported the fast-track approval of pembrolizumab in September 2014 and nivolumab in December 2014. A randomized phase III trial compared nivolumab versus dacarbazine in patients with treatment-naive metastatic melanoma; the overall response rate was 40% with nivolumab and 14% with dacarbazine (Robert, Long, et al., 2015). When two checkpoint inhibitors (ipilimumab and nivolumab) were used together in a phase I trial of patients with advanced melanoma, the response rate was 43%–53% at the maximum tolerated dose, higher than when either agent was used alone (Sznol et al., 2014). This combination also showed preliminary one- and two-year survival rates of 85% and 79%, respectively. Based on these results, healthcare providers can expect combination or sequential therapies in the future.

Long-term survival of greater than three years has been reported in about 20% of patients receiving ipilimumab, with reports of some patients from early trials surviving 10 years (Olszanski, 2014; Schadendorf et al., 2015). Initial reports of phase I melanoma trials of PD-1 reported one-year survival rates of 58%–69% (pembrolizumab and nivolumab) and two-year survival rates of 48% (nivolumab) (Hodi et al., 2014; Robert et al., 2014). Overall, one-year survival in the phase III trial in treatment-naive patients was significantly higher with nivolumab versus dacarbazine (73% versus 42%, p < 0.001) (Robert, Long, et al., 2015).

Adverse Events With Immune Checkpoint Inhibitors

Checkpoint inhibitors are associated with a novel toxicity profile that is inflammation-based and, therefore, are termed immune-related adverse events (irAEs). The key to toxicity management is to understand the concept of an immune-based etiology and subsequent treatment plan. Because T-cells are dispersed throughout the body, any organ can be affected. Patients can present with vast, sometimes nonspecific symptoms, which may be life threatening if not promptly recognized. When caring for patients receiving immunotherapy, nurses must be cognizant that these therapies and their associated toxicities differ from chemotherapy and targeted agents.

irAEs commonly include rash, pruritus, diarrhea/colitis, endocrinopathies, elevated liver enzymes, pneumonitis, nephritis, dermatitis, hepatitis, hypophysitis, thyroiditis, and uveitis. Differences in the side effect profiles of CTLA-4 and PD-1 checkpoint inhibitors are likely caused by differences in mechanism of action (MOA). PD-1 inhibitors such as nivolumab and pembrolizumab appear to have a more tolerable safety profile than ipilimumab (Larkin et al., 2015; Robert, Schachter, et al., 2015). The rate of grade 3–4 treatment-related AEs also was lower with nivolumab than with dacarbazine (DTIC-Dome®) in a phase III trial (12% versus 18%) (Robert, Long, et al., 2015).

Fatigue and mild rash are among the most commonly reported AEs with PD-1 inhibitors (Hamid et al., 2013; Larkin et al., 2015; Ribas et al., 2015; Robert, Long, et al., 2015; Topalian et al., 2014; Topalian, Hodi, et al., 2012). Ipilimumab is associated with gastrointestinal AEs. Any grade diarrhea occurred in 33% of patients in clinical trials, with grade 3–5 diarrhea or enterocolitis occurring in 6% of patients (Larkin et al., 2015). Diarrhea of any grade in clinical trials of PD-1 inhibitors was less common, occurring in 16%–18% of patients with melanoma, and grade 3 or higher diarrhea in less than 2% of patients (Larkin et al., 2015; Ribas et al., 2015; Robert et al., 2014; Robert, Long, et al., 2015; Topalian et al., 2014). In contrast, pneumonitis (any grade) may be more common with PD-1 inhibitors compared with ipilimumab, but is still rare—less than 4% of patients in clinical trials (Larkin et al., 2015; Ribas et al., 2015; Robert et al., 2014; Robert, Long, et al., 2015). Endocrinopathies resulting from PD-1 inhibitors include thyroiditis, hypophysitis, and hypopituitarism (Fecher, Agarwala, Hodi, & Weber, 2013; Hamid et al., 2013; Hodi et al., 2010; Topalian et al., 2014; Weber, Kähler, & Hauschild, 2012) (see Table 2).

PD-1 inhibitors are administered as an IV infusion every two or three weeks depending on the agent and continued until confirmed progression or unacceptable toxicity (Bristol-Myers Squibb, 2015a, 2015b; Merck & Co., 2015; Topalian et al., 2014). Ipilimumab is administered every three weeks for a total of four doses (Bristol-Myers Squibb, 2015b). Infusion-related hypersensitivity reactions are rare with both types of agents, and typically mild (Fecher et al., 2013; Hamid et al., 2013; Topalian et al., 2014; Weber et al., 2013).

Caring for patients receiving immune checkpoint inhibitors is best derived from the experiences of treating patients with ipilimumab (Fecher et al., 2013; Rubin, 2012; Weber et al., 2012). Clinical trials of PD-1 inhibitors, therefore, adopted irAE management strategies that were developed for ipilimumab. irAEs typically occur within the first few months of therapy, and prolonged exposure does not appear to increase their incidence (Fecher et al., 2013; Topalian et al., 2014). Onset of irAEs can be rapid and typically observed during the induction period of ipilimumab treatment (Tarhini, 2013); however, irAEs can occur at any time during therapy or even after completion or discontinuation; therefore, ongoing monitoring is necessary. In general, treatment of moderate or severe irAEs requires interruption of the checkpoint inhibitor and the use of corticosteroid immunosuppression.

In the author’s clinic, the staff found the majority of irAEs associated with checkpoint inhibitors to be recognizable and manageable. When patients present with toxicity, nurses should evaluate for and rule out noninflammatory causes. As an example, when a patient presents with diarrhea, investigate for possible infectious etiologies, such as Clostridium difficile. Presuming other causes have been ruled out, treatment courses can be pursued (see Figure 3). Of note, steroid use does not appear to diminish the clinical efficacy of ipilimumab in patients who have demonstrated a clinical response (Fecher et al., 2013; Harmankaya et al., 2011). Whether or not the use of steroids adversely affects the efficacy of PD-1 inhibitors is unknown.

Dose reductions of immune checkpoint inhibitors are not used to manage irAEs, unlike traditional cancer treatments. Some irAEs are more difficult to diagnose, such as hepatitis or early thyroiditis, both of which can be asymptomatic. For this reason, thyroid and liver enzyme levels should be monitored prior to commencing treatment (Bristol-Myers Squibb, 2015a, 2015b; Fecher et al., 2013; Weber et al., 2012), with ongoing periodic monitoring during and after treatment (Bristol-Myers Squibb, 2015a, 2015b; Merck & Co., 2015). In many patients, treatment can resume following the near or complete resolution of mild or moderate irAEs.

Treatment Responses With Immune Checkpoint Inhibitors

Traditional chemotherapeutic agents work nonselectively on dividing cells to promote cell death, and both healthy and tumor cells can be affected (see Table 3). These agents are effective at killing tumor cells rapidly, and toxicity results from the untoward effects on the healthy cells causing anemia, leukopenia, diarrhea, rash, and other side effects (Chapman et al., 2011; Flaherty, Robert, et al., 2012; Florea & Büsselberg, 2011; Marchesi et al., 2007; Sosman et al., 2012). Targeted agents are designed to inactivate specific mutations that are overexpressed in tumor cells, or restrict blood flow to the tumor. Some mutated proteins confer growth advantages to the tumor, and inactivating them inhibits tumor cell growth (Olszanski, 2014). Responses to targeted agents often are rapid (days to weeks) and have a more favorable safety profile than chemotherapy. However responses with targeted agents often are short-lived, and most patients develop resistance within five to seven months (Luke & Hodi, 2013; Olszanski, 2014).

Restarting effective immune responses using checkpoint inhibitors can take time and is dependent on the individual patient’s immune system. Therefore, it may be weeks to months after treatment initiation before a clinical or radiologic response is seen, and tumor progression often occurs prior to response (Kannan, Madden, & Andrews, 2014; Wolchok et al., 2009). In clinical trials of PD-1 inhibitors in patients with melanoma, the majority of responding patients showed responses by 12–16 weeks; however, responses as early as five weeks and as late as 30 weeks after treatment initiation have been reported (Hodi et al., 2014; Robert et al., 2014; Robert, Long, et al., 2015; Weber et al., 2013). Importantly, ongoing durable responses with checkpoint inhibitors can last much longer compared with those seen with conventional agents and provide a more meaningful remission.

The most mature data with PD-1 inhibitors are from a trial of nivolumab in patients with melanoma. The median duration of response was 99 weeks, and 56% of responses were ongoing at the time of analysis; however, the data are preliminary (Hodi et al., 2014). The long-lived responses support the theory that the immune system is keeping the tumor contained and, in some patients, complete responses have been reported (Ribas et al., 2015; Robert et al., 2014; Robert, Long, et al., 2015; Topalian et al., 2014). Survival curves for ipilimumab suggest that death from disease progression tends to decrease once patients have survived two to three years. After reaching this milestone, some patients may have long-term survival (Olszanski, 2014; Prieto et al., 2012; Schadendorf et al., 2015). Therefore, checkpoint inhibitors offer the promise of long-term survival for some patients.

Implications for Nursing

Oncology nurses, the healthcare team, patients, and caregivers should have general knowledge that checkpoint inhibitors are designed to solicit immune responses. Antitumor immune responses will vary from patient to patient, and responses can be delayed. However, for some, significant patient benefit may result. The novel toxicity profile of these agents is based on mechanism of action and must be understood by oncology nurses. Managing irAEs requires different interventions (e.g., decreasing the inflammation) than managing irAEs with conventional agents. By following developed algorithms, most grade 3–4 irAEs can be managed with treatment interruption and/or steroids, and, in some cases, a multidisciplinary approach may be needed (e.g., endocrinologist, gastroenterologist, pulmonologist). Often, treatment with checkpoint inhibitors can be resumed after irAE resolution or improvement to baseline. Prompt recognition and early intervention of irAEs is the most effective management strategy.

In addition, patient and caregiver education about immunotherapy and irAEs is important (Davies, 2014; Ledezma & Heng, 2013; Rubin 2012). In many centers, patients receiving ipilimumab, nivolumab, or pembrolizumab will be provided with a drug-specific wallet card detailing symptoms to watch for and when to notify their healthcare provider. The wallet card also provides information useful to other healthcare providers (e.g., emergency department staff) by describing the common and novel immune effects. Symptom checklists also are integrated into the patient visit, either formally (by completion of the checklist by the nurse or possibly even the patient) or informally (with a directed review of systems). Patients are counseled regarding the expected time to response and importance of open and ongoing communication regarding the development of new or worsening symptoms. Patients must understand that, even in the case of apparent initial radiologic tumor progression, improvements in patient symptoms and/or performance status or other clinical parameters may indicate treatment efficacy. It also may be helpful to remind patients that a delayed response is “worth the wait” because many responses last longer than those seen with conventional agents.

Conclusion

The approvals of PD-1 inhibitors for advanced melanoma and NSCLC provide important new treatment options for patients with these malignancies. In addition, in the United States, the approval of nivolumab in combination with ipilimumab for patients with wild-type BRAF provides an additional treatment option to improve clinical outcomes in advanced melanoma. Although these treatment approaches are different than conventional agents, patient management is not more difficult. Nurses with an awareness and understanding of the immune mechanism of action of immuno-oncology agents will be well positioned to manage the toxicities associated with these therapies.

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Sznol, M., Kluger, H., Callahan, M.K., Postow, M.A., Gordon, R.A., Segal, N.H., . . . Wolchok, J.D. (2014). Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL) [Abstract LBA9003]. Journal of Clinical Oncology. Retrieved from http://meetinglibrary.asco.org/content/126008-144

Tarhini, A. (2013). Immune-mediated adverse events associated with ipilimumab CTLA-4 blockade therapy: The underlying mechanisms and clinical management. Scientifica (Cairo), 2013, 857519. doi:10.1155/2013/857519

Tivol, E.A., Borriello, F., Schweitzer, A.N., Lynch, W.P., Bluestone, J.A., & Sharpe, A.H. (1995). Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity, 3, 541–547.

Topalian, S.L., Drake, C.G., & Pardoll, D.M. (2012). Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Current Opinion in Immunology, 24, 207–212.

Topalian, S.L., Hodi, F.S., Brahmer, J.R., Gettinger, S.N., Smith, D.C., McDermott, D.F., . . . Sznol, M. (2012). Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New England Journal of Medicine, 366, 2443–2454.

Topalian, S.L., Sznol, M., McDermott, D.F., Kluger, H.M., Carvajal, R.D., Sharfman, W.H., . . . Hodi, F.S. (2014). Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. Journal of Clinical Oncology, 32, 1020–1030. doi:10.1200/JCO.2013.53.0105

Weber, J.S., Kähler, K.C., & Hauschild, A. (2012). Management of immune-related adverse events and kinetics of response with ipilimumab. Journal of Clinical Oncology, 30, 2691–2697. doi:10.1200/JCO.2012.41.6750

Weber, J.S., Kudchadkar, R.R., Yu, B., Gallenstein, D., Horak, C.E., Inzunza, H.D., . . . Chen, Y.A. (2013). Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. Journal of Clinical Oncology, 31, 4311–4318. doi:10.1200/JCO.2013.51.480

Wherry, E.J. (2011). T cell exhaustion. Nature Immunology, 12, 492–499.

Wolchok, J.D., Hoos, A., O’Day, S., Weber, J.S., Hamid, O., Lebbe, C., . . . Hodi, F.S. (2009). Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria. Clinical Cancer Research, 15, 7412–7420. doi:10.1158/1078 -0432.CCR-09-1624

Wolchok, J.D., Kluger, H., Callahan, M.K., Postow, M.A., Rizvi, N.A., Lesokhin, A.M., . . . Sznol, M. (2013). Nivolumab plus ipilimumab in advanced melanoma. New England Journal of Medicine, 369, 122–133. doi:10.1056/NEJMoa1302369

Zou, W., & Chen, L. (2008). Inhibitory B7-family molecules in the tumour microenvironment. Nature Reviews. Immunology, 8, 467–477. doi:10.1038/nri2326

About the Author(s)

Krista M. Rubin, RN, MS, FNP-BC, is a nurse practitioner in the Center for Melanoma in the Division of Hematology-Oncology and Department of Dermatology at the Massachusetts General Hospital Cancer Center in Boston. The author takes full responsibility for the content of the article. Writing and editorial support were provided by Britt Anderson, PhD, and Karin McGlynn at StemScientific, an Ashfield Company, and were funded by Bristol-Myers Squibb. Rubin received support from Amgen, Inc., Bristol-Myers Squibb, and Merck Oncology. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers or editorial staff. Mention of specific products and opinions related to those products do not indicate or imply endorsement by the Clinical Journal of Oncology Nursing or the Oncology Nursing Society. Rubin can be reached at kmrubin@mgh.harvard.edu, with copy to editor at CJONEditor@ons.org. (Submitted December 2014. Revision submitted February 2015. Accepted for publication February 13, 2015.)

 

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Sosman, J.A., Kim, K.B., Schuchter, L., Gonzalez, R., Pavlick, A.C., Weber, J.S., . . . Ribas, A. (2012). Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. New England Journal of Medicine, 366, 707–714. doi:10.1056/NEJM oa1112302

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Topalian, S.L., Hodi, F.S., Brahmer, J.R., Gettinger, S.N., Smith, D.C., McDermott, D.F., . . . Sznol, M. (2012). Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New England Journal of Medicine, 366, 2443–2454.

Topalian, S.L., Sznol, M., McDermott, D.F., Kluger, H.M., Carvajal, R.D., Sharfman, W.H., . . . Hodi, F.S. (2014). Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. Journal of Clinical Oncology, 32, 1020–1030. doi:10.1200/JCO.2013.53.0105

Weber, J.S., Kähler, K.C., & Hauschild, A. (2012). Management of immune-related adverse events and kinetics of response with ipilimumab. Journal of Clinical Oncology, 30, 2691–2697. doi:10.1200/JCO.2012.41.6750

Weber, J.S., Kudchadkar, R.R., Yu, B., Gallenstein, D., Horak, C.E., Inzunza, H.D., . . . Chen, Y.A. (2013). Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. Journal of Clinical Oncology, 31, 4311–4318. doi:10.1200/JCO.2013.51.480

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Wolchok, J.D., Hoos, A., O’Day, S., Weber, J.S., Hamid, O., Lebbe, C., . . . Hodi, F.S. (2009). Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria. Clinical Cancer Research, 15, 7412–7420. doi:10.1158/1078 -0432.CCR-09-1624

Wolchok, J.D., Kluger, H., Callahan, M.K., Postow, M.A., Rizvi, N.A., Lesokhin, A.M., . . . Sznol, M. (2013). Nivolumab plus ipilimumab in advanced melanoma. New England Journal of Medicine, 369, 122–133. doi:10.1056/NEJMoa1302369

Zou, W., & Chen, L. (2008). Inhibitory B7-family molecules in the tumour microenvironment. Nature Reviews. Immunology, 8, 467–477. doi:10.1038/nri2326