Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer

Abstract

Background Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. Methods We enrolled patients with advanced melanoma, non–small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. Results A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Conclusions Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)

Higher preoperative serum levels of PD‐L1 and B7‐H4 are associated with invasive and metastatic potential and predictable for poor response to VEGF‐targeted therapy and unfavorable prognosis of renal cell carcinoma

“…Recent preclinical and clinical studies have demonstrated that checkpoint blockade using anti‐CTLA‐4, anti‐PD‐1, and anti‐PD‐L1 antibodies can be successful for cancer immunotherapy 17, 18, 19. Therefore, it is important to assess whether T‐cell regulatory molecules can be used as biomarkers to predict tumor resistance and guide the choice of therapy, which is why we investigated the preoperative serum levels of B7 family molecules and CD28 family receptors in RCC patients as well as their associations with clinicopatological features.…”

“…reported that PD‐L1 overexpression by tumors in vivo and in vitro leads to immune tolerance, whereas blockade of PD‐L1 or PD‐1 enhances antitumor immunity 24. Blockade of the PD‐L1/PD‐1 interaction achieves a durable response in approximately 30% of patients with ccRCC, and the response seems to be related to the tumor level of PD‐L1 expression 17, 18. However, it remains challenging to select patients who are likely to respond to anti‐PD‐1/PD‐L1 therapy 12.…”

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

“…This indicates that the PD‐1/PD‐L1 axis is present and may be dysregulated in human sepsis 11, 48. In oncology, anti‐PD‐1 and anti‐PD‐L antibody therapy have been used successfully to treat various tumors 49. These data indicate that blocking the PD‐1/PD‐L1 axis is a promising target for restoring immune function in human sepsis.…”

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

“…Within the last decade, treatment of metastatic melanoma (MM) has been revolutionized by a wide array of immunotherapies including checkpoint inhibitors against CTLA-4 1 and PD-1/PD-L1 2 , 3 as well as adoptive cell therapy (ACT). 4-6 However, despite great advances, treatment responses are restricted to a fraction of patients.…”