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

By J. Brahmer, Charles G. Drake, I. Wollner, J. Powderly, J. Picus, W. Sharfman, E. Stankevich, A. Pons, Theresa M Salay, T. McMiller and 10 more. Journal of Clinical Oncology, 2010

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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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/a946a54c5064f5dea98d0692548078c0cee7bae9

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Citations in the corpus

Anti-PD-1 Blockade and Stereotactic Radiation Produce Long-Term Survival in Mice With Intracranial Gliomas (2013, positive): “Clinical trials with anti-PD-1 have suggested that tumorspecific B7-H1 expression may be an important biomarker of anti-PD-1 efficacy (10).”
Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma (2013, methodology): “PD-L1 and PD-1 detection by immunohistochemistry PD-L1 expression analysis was conducted usingmAb 5H1 as previously described (9, 12).”
Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T Cell Rejection Function in Tumors (2013, positive): “The antitumor activity of αPD-1 and αPD-L1 are evident in animal models, and αPD-1 and αPD-L1 antibodies are now under intense clinical evaluation (65-67).”
CDK4/6 Inhibition Augments Anti-Tumor Immunity by Enhancing T Cell Activation (2017, background): “The discovery of immune checkpoint receptors, such as CTLA-4 and PD-1 (5-9), that repress the activity of anti-tumor T cells, led to the development of blocking antibodies directed against these co-inhibitory receptors or their ligands, including ipilimumab (anti-CTLA-4), pembrolizumab (anti-PD-1), ”
Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy (2014, background): “Clinical trials of blocking mAbs against PD-1 and PD-L1 are currently underway for patients with treatment-refractory metastatic melanoma and a variety of epithelial malignancies and have validated this pathway as a therapeutic target((16-19)).”