Immune checkpoints, such as programmed death ligand 1 (PD-L1) or its receptor, programmed death 1 (PD-1), appear to be Achilles’ heels for multiple tumor types. PD-L1 not only provides immune escape for tumor cells but also turns on the apoptosis switch on activated T cells. Therapies that block this interaction have demonstrated promising clinical activity in several tumor types. In this review, we will discuss the current status of several anti–PD-1 and anti–PD-L1 antibodies in clinical development and their direction for the future.
What Are PD-1 and PD-L1?
Programmed death 1 (PD-1) is an immune inhibitory receptor expressed on several immune cells, particularly cytotoxic T cells. It interacts with two ligands, programmed death ligand 1 (PD-L1) (B7-H1, CD274) and PD-L2 (B7-DC). While PD-L2 is expressed primarily on macrophages and dendritic cells, PD-L1 is expressed on tumor cells, as well as other immune cells. The interaction of these ligands with PD-1 inhibits T-cell activation and cytokine production. Their ligation with PD-1 during infection or inflammation in normal tissue is critically important in maintaining homeostasis of immune response to prevent autoimmunity. Their interaction in tumor microenvironments, however, provides an immune escape for tumor cells by turning off cytotoxic T cells. Thus, blocking these interactions may subject the tumor cells to attack from cytotoxic T cells.
How Is PD-L1 Expression Determined? What Is Its Significance?
PD-L1 expression is measured most commonly by immunohistochemistry (IHC). Tumoral PD-L1 expression status has been shown to be prognostic in multiple tumor types, including melanoma (MEL), renal cell carcinoma (RCC), and non–small-cell lung cancer (NSCLC). In addition, tumoral PD-L1 expression appears to correlate closely with response to anti–PD-1 antibodies. However, no test is uniformly accepted as the standard for quantitating PD-L1 expression. The IHC tests used in clinical trials are proprietary; data on similarities between and among the antibodies used and the assay conditions, staining pattern, threshold for signal detection, and assessment of positivity are not published. The protein expression patterns of PD-L1 on tumor cells, dendritic cells, and tumor-infiltrating immune cells differ, and exact cell type and degree of expression vary between assays. A different methodology for evaluating PD-L1 messenger RNA (mRNA) expression, using an antibody-independent in situ hybridization assay coupled with quantitative fluorescence, showed that increased PD-L1 mRNA transcript was associated with elevated tumor-infiltrating lymphocytes and better clinical outcomes in patients with breast cancer and NSCLC. The role of PD-L1 expression as a biomarker is discussed in this supplement to ONCOLOGY, in the review “Prognostic and Predictive Markers for the New Immunotherapies,” by Drs. Kathleen M. Mahoney and Michael B. Atkins.
Anti–PD-1 and Anti–PD-L1 Antibodies
Several PD-1 and PD-L1 antibodies are in clinical development (Table 1). Overall, they are very well tolerated; most did not reach dose-limiting toxicity in their phase I studies. As listed in Table 2, no clinically significant difference in adverse event profiles has been seen between anti–PD-1 and anti–PD-L1 antibodies. Slightly higher rates of infusion reactions (11%) were observed with BMS-936559 (anti–PD-L1) than with BMS-96558 (nivolumab). In an early stage of a nivolumab phase I study, there was concern about fatal pneumonitis. It has been hypothesized that PD-1 interaction with PD-L2 expressed on the normal parenchymal cells of lung and kidney provides unique negative signaling that prevents autoimmunity. Thus, anti–PD-1 antibody blockage of such an interaction may remove this inhibition, allowing autoimmune pneumonitis or nephritis. Anti–PD-L1 antibody, however, would theoretically leave PD-1–PD-L2 interaction intact, preventing the autoimmunity caused by PD-L2 blockade. With implementation of an algorithm to detect early signs of pneumonitis and other immune-related adverse events, many of these side effects have become manageable. However, it does require discerning clinical attention to detect potentially fatal side effects. In terms of antitumor activity, both anti–PD-1 and anti–PD-L1 antibodies have shown responses in overlapping multiple tumor types. Although limited to a fraction of patients, most responses, when observed, were rapid and durable.
MEL is among the first types of solid tumors in which nivolumab has shown promising antitumor activity. In a phase I study across all dose levels, nivolumab resulted in an objective response rate (ORR) of 28% (95% confidence interval [CI], 19–38) in patients with advanced MEL who had no prior ipilimumab treatment. Responses were adjudicated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, with modification. A recently updated analysis in 107 MEL patients confirmed these responses and suggested potential survival benefit.[9,10] The ORR was 32% (95% CI, not reported [NR]). The median duration of response was 99.4 weeks (range, 17.0+ to 117.0+). More than half (11/21) of responding patients who discontinued therapy for reasons other than progressive disease responded for more than 24 weeks. The 1-, 2-, and 3-year overall survival (OS) rates were 63% (95% CI, 53–71), 48% (95% CI, 38–57), and 41% (95% CI, 31–51), respectively. Median OS was 17.3 months (95% CI, 12.5–36.7). Survival analysis by type of response suggested that patients who had immune-related responses, such as reduction in the target lesion in the presence of new lesions or following initial progression, had similar OS to patients with RECIST responses.[9,10]
Nivolumab in patients who were pretreated with ipilimumab was tested as part of a “sequential cohort” of an ongoing phase I trial. Nivolumab was given at two dose levels (1 mg/kg and 3 mg/kg every 2 weeks). Of 33 patients, ORR by RECIST criteria was 31% (95% CI, NR). The 1-year survival rate was 70% (95% CI, NR). The residual plasma concentration of prior ipilimumab at the start of nivolumab appears to have an influence on response to nivolumab. An ipilimumab concentration ≥ 7.255 μg/mL (the median) was associated with greater ORR to nivolumab (57.1% vs 14.3%).
Pembrolizumab (MK-3475, lambrolizumab) is a humanized immunoglobulin G (IgG)-4 kappa antibody against PD-1. In KEYNOTE-001, the safety and antitumor activities of pembrolizumab were tested in the largest-ever phase I study of patients with metastatic MEL (N = 411). This study began with ipilimumab-naive (IPI-N) and ipilimumab-treated (IPI-T) patients, and later implemented a randomized dosing comparison of 2 mg/kg vs 10 mg/kg in ipilimumab-refractory (IPI-R) and IPI-N patients. Among patients evaluable by RECIST 1.1, overall ORR was 34% (95% CI, 29–39). The ORRs were 40% (95% CI, 32–48) in IPI-N patients and 28% (95% CI, 22–35) in IPI-T patients. The 1-year OS rate was 69%; median OS has not yet been reached. A subgroup analysis suggested that a tumor size smaller than the median of 90 mm was an independent predictor of response.
In the randomized comparison of 2 mg/kg vs 10 mg/kg of pembrolizumab in IPI-R and IPI-N patients, there was no statistically significant difference between the ORRs for the two cohorts by either RECIST 1.1 (independent central review) or immune-related response criteria (investigator review). In the IPI-N cohort, the ORRs by RECIST 1.1 were 33% (95% CI, 20–49) vs 40% (95% CI, 26–56) in the 2-mg/kg and 10-mg/kg arms, respectively (P = .4835). In the IPI-R cohort, the ORRs were 26% in both arms (95% CI, 17–37 in the 2-mg/kg arm and 95% CI, 17–36 in the 10-mg/kg arm). According to Kaplan-Meier estimates of OS in IPI-N patients, 1-year OS rates were 72% (95% CI, 15–NR) and 64% (95% CI, 10–NR), and in IPI-R patients, they were 58% (95% CI, 11–NR) and 63% (95% CI, NR)—in the 2-mg/kg and 10-mg/kg arms, respectively. Given favorable benefit-risk profiles at both doses, 2 mg/kg every 3 weeks was recommended for future investigation. The most common immune-mediated adverse event of any grade was hypothyroidism (~8%). There was a < 1% incidence of grade 3 or 4 pneumonitis, hepatitis, colitis, or hypophysitis reported.
Pidilizumab is a humanized anti–PD1 IgG1 kappa with binding affinity at 20 nM. A phase II study in MEL patients showed ORR (by investigator review) of 7% in IPI-N patients and 5% in IPI-T patients. The rate of immune-related stable disease was 37%. The 12-month survival rate was 64% (95% CI, 55.6–72.0). Pidilizumab is being investigated in hematologic malignancies.
MPDL3280A is an IgG1-engineered, anti–PD-L1 antibody. A phase I study in 38 patients with metastatic MEL reported a 39% ORR (95% CI, NR), with 43% achieving a 24-week progression-free survival (PFS). Both patients with cutaneous (33%) and mucosal (25%) MEL responded. Patients with PD-L1–positive status by IHC had a 27% ORR (95% CI, NR). Similarly, patients with a negative status had a 20% ORR (95% CI, NR). An additional 60% of patients with PD-L1–positive tumors had stable disease, suggesting that PD-L1–positive patients are more likely to derive clinical benefit. No grade 3 or 4 pneumonitis or treatment-related deaths occurred. Based on these findings and a potential synergy with vemurafenib, a phase Ib study is currently testing the safety and tolerability of this combination in patients with BRAF V600E mutations (National Cancer Institute ClinicalTrials.gov ID NCT01656642).
BMS-936559 is a fully human, anti–PD-L1, IgG4 monoclonal antibody. In a study of 1-, 3-, and 10-mg/kg doses in metastatic MEL patients, 9 of 52 (17%; 95% CI, 8–30) achieved objective responses. Three patients achieved a complete response (CR). Five of 9 responding patients had an objective response lasting beyond 1 year. In addition, 14 of 52 patients (27%; 95% CI, 16–41) had stable disease lasting at least 24 weeks.
MEDI4736 is an engineered IgG1 kappa monoclonal antibody with triple mutations in the Fc domain to remove antibody-dependent, cell-mediated cytotoxic activity. It has shown high affinity and selectivity for PD-L1 and, reportedly, no binding to PD-L2. In its dose escalation study of doses ranging from 0.1 mg/kg every 2 weeks to 15 mg/kg every 3 weeks, no dose-limiting toxicity or drug-related deaths were seen. Tumor regression was seen in multiple tumor types, including MEL, NSCLC, RCC, and colorectal cancer (CRC). Segal et al reported the results of a multiarm expansion study using a dose of 10 mg/kg every 2 weeks in 44 patients with MEL (uveal and cutaneous). Although an analysis of antitumor activity in MEL patients has not been reported, preliminary data suggest that several patients with both cutaneous and uveal MEL remained in the study beyond 12 weeks, and no serious adverse events have been reported.
In light of their promising activity as single agents, several combinations of anti–PD-1 and anti–PD-L1 antibodies have been studied. A preclinical study has shown that dual immune checkpoint blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and PD-1 resulted in more pronounced antitumor activity than either single blockade alone. Wolchok et al reported the clinical activity of concurrent administration of nivolumab and ipilimumab in 53 patients with advanced MEL; the resulting ORR was 40% (95% CI, 27–55) (by modified World Health Organization [WHO] criteria), and responses were “rapid and deep.” In an updated survival analysis, Sznol et al reported 1- and 2-year OS rates of 85% and 79% (95% CI, NR), respectively; median OS was 40 months, and median PFS was 27 weeks. This study added another cohort of 40 patients who received nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab 1 mg/kg every 3 weeks for 4 more cycles, then 3 mg/kg every 2 weeks for up to 48 cycles. Results confirmed clinical activity, with an ORR of 43% (95% CI, NR). Responses were seen regardless of PD-L1 tumor expression status or BRAF mutation status.
Nivolumab in combination with multiple peptide vaccines in IPI-R or IPI-N MEL patients was well tolerated. This study also found that increased peripheral blood regulatory T cells and decreased antigen-specific T cells were associated with progression.The clinical benefit of adding a vaccine remains to be seen.
A phase I/II study of MEDI4736 in combination with a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) or with trametinib alone is ongoing (NCT02027961). Other immune modulatory agents, such as interferon (IFN) alfa-2b, are combined with various anti–PD-1 and anti–PD-L1 antibodies in ongoing clinical trials.
1. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704.
2. 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.
3. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064-74.
4. Schalper KA, Velcheti V, Carvajal D, et al. In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res. 2014;20:2773-82.
5. Velcheti V, Schalper KA, Carvajal DE, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest. 2014;94:107-16.
6. Mahoney KM, Atkins MB. Prognostic and predictive markers for new immunotherapy. Oncology (Williston Park). 2014;28(suppl 3):39-48.
7. 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;366:2443-54.
8. Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 2001;22:265-8.
9. Hodi FS, Sznol M, Kluger HM, et al. Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial. J Clin Oncol. 2014;32(suppl 5S):abstr 9002.
10. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32:1020-30.
11. Sznol M, Kluger HM, Callahan MK, et al. 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). J Clin Oncol. 2014;32(suppl 5S):abstr LBA9003.
12. Ribas A, Hodi FS, Kefford R, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). J Clin Oncol. 2014;32(suppl 5S):abstr LBA9000.
13. Joseph RW, Elassaiss-Schaap J, Wolchok JD, et al. Baseline tumor size as an independent prognostic factor for overall survival in patients with metastatic melanoma treated with the anti-PD-1 monoclonal antibody MK-3475. J Clin Oncol. 2014;32(suppl 5S):abstr 3015.
14. Hamid O, Robert C, Ribas A, et al. Randomized comparison of two doses of the anti-PD-1 monoclonal antibody MK-3475 for ipilimumab-refractory (IPI-R) and IPI-naive (IPI-N) melanoma (MEL). J Clin Oncol. 2014;32(suppl 5S):abstr 3000.
15. Atkins MB, Kudchadkar RR, Sznol M, et al. Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma. J Clin Oncol. 2014;32(suppl 5S):abstr 9001.
16. Hamid O, Sosman JA, Lawrence DP, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). J Clin Oncol. 2013;31(suppl):abstr 9010.
17. 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;366:2455-65.
18. Lutzky J, Antonia SJ, Blake-Haskins A, et al. A phase 1 study of MEDI4736, an anti–PD-L1 antibody, in patients with advanced solid tumors. J Clin Oncol. 2014;32(suppl 5S):abstr 3001.
19. Segal NH, Antonia SA, Brahmer JR, et al. Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody. J Clin Oncol. 2014;32(suppl 5S):abstr 3002.
20. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci USA. 2010;107:4275-80.
21. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-33.
22. Weber JS, Kudchadkar RR, Yu B, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013;31:4311-8.
23. Klapper JA, Downey SG, Smith FO, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008;113:293-301.
24. Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30:825-30.
25. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma (mRCC): results of a randomized, dose-ranging phase II trial. J Clin Oncol. 2014;32(suppl 5S):abstr 5009.
26. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14:552-62.
27. Hutson TE, Escudier B, Esteban E, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32:760-7.
28. Cho DC, Sosman JA, Sznol M, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2013;31(suppl):abstr 4505.
29. Hammers HJ, Plimack ER, Infante JR, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32(suppl 5S):abstr 4504.
30. Johnson BF, Clay TM, Hobeika AC, et al. Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy. Expert Opin Biol Ther. 2007;7:449-60.
31. Gettinger SN, Shepherd FA, Antonia SJ, et al. First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in advanced NSCLC: safety, efficacy, and correlation of outcomes with PD-L1 status. J Clin Oncol. 2014;32(suppl 5S):abstr 8024.
32. Rizvi NA, Garon EB, Patnaik A, et al. Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32(suppl 5S):abstr 8007.
33. Brahmer JR, Horn L, Gandhi L, et al. Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients (pts) with advanced non-small-cell lung cancer (NSCLC): survival and clinical activity by subgroup analysis. J Clin Oncol. 2014;32(suppl 5S):abstr 8112.
34. Garon EB, Leighl NB, Rizvi NA, et al. Safety and clinical activity of MK-3475 in previously treated patients (pts) with non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32(suppl 5S):abstr 8020.
35. Soria JC, Cruz C, Bahleda R, et al. Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC): additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1). Eur J Cancer. 2013;49(suppl):abstr 3408.
36. Brahmer JR, Rizvi NA, Lutzky J, et al. Clinical activity and biomarkers of MEDI4736, an anti-PD-L1 antibody, in patients with NSCLC. J Clin Oncol. 2014;32(suppl 5S):abstr 8021.
37. Antonia SJ, Gettinger SN, Chow L, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: interim phase I results. J Clin Oncol. 2014;32(suppl 5S):abstr 8023.
38. Antonia SJ, Brahmer JR, Gettinger SN, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with platinum-based doublet chemotherapy (PT-DC) in advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32(suppl 5S):abstr 8113.
39. Rizvi NA, Chow L, Borghaei H, et al. Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC. J Clin Oncol. 2014;32(suppl 5S):abstr 8022.
40. Brandau S, Suttmann H. Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: a success story with room for improvement. Biomed Pharmacother. 2007;61:299-305.
41. Mullane SA, Werner L, Callea M, et al. PD-L1 expression in mononuclear cells and not in tumor cells, correlated with prognosis in metastatic urothelial carcinoma. J Clin Oncol. 2014;32(suppl 5S):abstr 4552.
42. Sharma P, Shen Y, Wen S, et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA. 2007;104:3967-72.
43. Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333-9.
44. Powles T, Eder JP, Petrylak DP, et al. Inhibition of PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer (UBC). J Clin Oncol. 2014;32(suppl 5S):abstr 5011.
45. Plimack ER, Gupta S, Bellemunt J, et al. A phase 1b study of pembrolizumab (Pembro; MK-3475) in patients (pts) with advanced urothelial tract cancer. Presented at the Proffered Papers session of ESMO 2014. September 26-30, 2014; Madrid, Spain. LBA23. Available from: https://www.webges.com/cslide/library/esmo/browse/itinerary/478/2014-09-.... Accessed October 20, 2014.
46. Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013;73:1733-41.
47. Saloura V, Zuo Z, Koeppen H, et al. Correlation of T-cell inflamed phenotype with mesenchymal subtype, expression of PD-L1, and other immune checkpoints in head and neck cancer. J Clin Oncol. 2014;32(suppl 5S):abstr 6009.
48. Seiwert TY, Burtness B, Weiss J, et al. A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)-associated and non-HPV–associated head and neck (H/N) cancer. J Clin Oncol. 2014;32(suppl 5S):abstr 6011.
49. Herbst RS, Gordon MS, Fine GD, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. J Clin Oncol. 2013;31(suppl):abstr 3000.
50. 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;28:3167-75.
51. Lipson EJ, Sharfman WH, Drake CG, et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res. 2013;19:462-8.
52. Llosa NJ, Housseau F, Wick EC, et al. Immune checkpoints expression in MSI versus MSS colorectal cancers and their potential therapeutic implications. J Clin Oncol. 2014;32(suppl 5S):abstr 3620.
53. Gatalica Z, Snyder CL, Yeatts K, et al. Programmed death 1 (PD-1) lymphocytes and ligand (PD-L1) in colorectal cancer and their relationship to microsatellite instability status. J Clin Oncol. 2014;32(suppl 5S):abstr 3625.
54. Tabernero J, Powderly JD, Hamid O, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic CRC, gastric cancer (GC), SCCHN, or other tumors. J Clin Oncol. 2013;31(suppl):abstr 3622.
55. Powderly JD, Koeppen H, Hodi FS, et al. Biomarkers and associations with the clinical activity of PD-L1 blockade in a MPDL3280A study. J Clin Oncol. 2013;31(suppl):abstr 3001.
56. Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19:1021-34.
57. Gajewski TF, Fuertes M, Spaapen R, et al. Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment. Curr Opin Immunol. 2011;23:286-92.
58. Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA. 2003;100:4712-7.
59. Ribas A, Comin-Anduix B, Economou JS, et al. Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in patients with melanoma undergoing CTLA4 blockade. Clin Cancer Res. 2009;15:390-9.
60. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-33.
61. Mok S, Koya RC, Tsui C, et al. Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res. 2014;74:153-61.
62. Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res. 2013;19:997-1008.
63. Moran AE, Kovacsovics-Bankowski M, Weinberg AD. The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol. 2013;25:230-7.
64. Curti BD, Kovacsovics-Bankowski M, Morris N, et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 2013;73:7189-98.
65. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134-44.
66. Infante JR, Powderly JD, Burris HA, et al. Clinical and pharmacodynamic (PD) results of a phase I trial with AMP-224 (B7-DC Fc) that binds to the PD-1 receptor. J Clin Oncol. 2013;31(suppl):abstr 3044.
67. Heery CR, O’Sullivan-Coyne GH, Madan RA, et al. Phase I open-label, multiple ascending dose trial of MSB0010718C, an anti-PD-L1 monoclonal antibody, in advanced solid malignancies. J Clin Oncol. 2014;32(suppl 5S):abstr 3064.
68. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23..
69. Hamanishi J, Mandai M, Ikeda T, et al. Efficacy and safety of anti-PD-1 antibody (nivolumab: BMS-936558, ONO-4538) in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2014;32(suppl 5S):abstr 5511.