Phase I Study of Single-Agent Anti–Programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates

Abstract

Purpose Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti–PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates. Patients and Methods Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non–small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti–PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy. Results Anti–PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti–PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells ≥ 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment. Conclusion Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

“…However, PD-1 and PD-L1 blocking antibodies were proven unsuccessful in CRC, with the exception of MMR-deficient CRC. 23-25 , 27 , 28 The first aim of this study was to investigate whether the composition of the immune infiltrates and the intra-tumoral expression levels of inhibitory molecules in CRC metastases in the liver environment differ from those in primary CRC tumors and metastases outside the liver, which would suggest potential differences in sensitivity to checkpoint inhibitors among CRC tumors at different anatomical locations. The second objective was to determine whether targeting of inhibitory checkpoint pathways by antagonistic antibodies can enhance the functionality and anti-tumor responses of tumor-infiltrating T cells in LM-CRC.…”

“…17-21 Targeting the PD-1/PD-L1 inhibitory pathway has resulted in objective responses in 17%-28% of advanced melanoma patients, 12%-27% of renal cell cancer patients, 10%-18% of non-small cell lung cancer patients and 20% of advanced hepatocellular carcinoma patients. 22-25 In contrast, CRC patients hardly respond to PD-1 and PD-L1 blocking antibodies, 23-26 except for the minority of patients who are with mismatch repair (MMR)-deficient CRC. 27 , 28 A defective MMR enzyme system occurs in 10%-20% of CRC tumors and results in microsatellite instability, which is used as a molecular marker of MMR-deficiency.…”

Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development

“…In this format, the detection reagent is generally an anti‐receptor antibody that binds to an epitope distinct from that of the drug (i.e., a non‐competing antibody). An alternative approach is to detect drug‐occupied receptors as described above following the incubation of the specimen with excess drug to saturate all receptors 2, 3, 22.…”

“…A fluorescence‐labeled, non‐neutralizing anti‐idiotypic antibody or an antibody with specificity for Fc 2, 3, 22 or a modified Fc region 38, 39, 40 can be used for detection. Selection of specific, high affinity reagents is essential for robust detection sensitivity.…”

“…The anti‐receptor antibody must have sufficient affinity for the receptor to ensure detection sensitivity and must not compete with the drug for receptor binding. Another option is to add excess drug and then use ADA as detection reagent 2, 3, 22. When a drug‐occupied receptor method with addition of excess drug is used to assess total receptor, the concentration of drugs added to the assay should be optimized to ensure full occupancy of the receptor and the dissociation of drug from receptor should be minimized during washing steps of staining procedures.…”