| Abstract |
Background: HuMax-IL8 (now known as BMS-986253) is a novel, fully human monoclonal antibody that inhibits interleukin-8 (IL-8), a chemokine that promotes tumor progression, immune escape, epithelial-mesenchymal transition, and recruitment of myeloid-derived suppressor cells. Studies have demonstrated that high serum IL-8 levels correlate with poor prognosis in many malignant tumors. Preclinical studies have shown that IL-8 blockade may reduce mesenchymal features in tumor cells, making them less resistant to treatment.
Methods: Fifteen patients with metastatic or unresectable locally advanced solid tumors were enrolled in this 3 + 3 dose-escalation trial at four dose levels (4, 8, 16, or 32 mg/kg). HuMax-IL8 was given IV every 2 weeks, and patients were followed for safety and immune monitoring at defined intervals up to 52 weeks.
Results: All enrolled patients (five chordoma, four colorectal, two prostate, and one each of ovarian, papillary thyroid, chondrosarcoma, and esophageal) received at least one dose of HuMax-IL8. Eight patients had received three or more prior lines of therapy and five patients had received prior immunotherapy. Treatment-related adverse events occurred in five patients (33%), mostly grade 1. Two patients receiving the 32 mg/kg dose had grade 2 fatigue, hypophosphatemia, and hypersomnia. No dose-limiting toxicities were observed, and maximum tolerated dose was not reached. Although no objective tumor responses were observed, 11 patients (73%) had stable disease with median treatment duration of 24 weeks (range, 4-54 weeks). Serum IL-8 was significantly reduced on day 3 of HuMax-IL8 treatment compared to baseline (p = 0.0004), with reductions in IL-8 seen at all dose levels.
Conclusions: HuMax-IL8 is safe and well-tolerated. Ongoing studies are evaluating the combination of IL-8 blockade and other immunotherapies.
Trial registration: NCTN, NCT02536469. Registered 23 August 2015, https://clinicaltrials.gov/ct2/show/NCT02536469?term=NCT02536469&rank=1 .
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| MeSH term(s) |
Adult ; Aged ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized/immunology ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents, Immunological/immunology ; Antineoplastic Agents, Immunological/pharmacokinetics ; Antineoplastic Agents, Immunological/therapeutic use ; Cohort Studies ; Female ; Follow-Up Studies ; Humans ; Interleukin-8/antagonists & inhibitors ; Interleukin-8/immunology ; Male ; Maximum Tolerated Dose ; Middle Aged ; Neoplasm Metastasis ; Neoplasms/drug therapy ; Neoplasms/immunology ; Neoplasms/pathology ; Prognosis ; Tissue Distribution |
| Chemical Substances |
Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents, Immunological ; CXCL8 protein, human ; Interleukin-8 ; HuMax-IL8 (N0YWS8X3S9) |
| Language |
English |
| Publishing date |
2019-09-05 |
| Publishing country |
England |
| Document type |
Clinical Trial, Phase I ; Journal Article ; Research Support, N.I.H., Intramural |
| ZDB-ID |
2719863-7 |
| ISSN |
2051-1426 ; 2051-1426 |
| ISSN (online) |
2051-1426 |
| ISSN |
2051-1426 |
| DOI |
10.1186/s40425-019-0706-x |
| Database |
MEDical Literature Analysis and Retrieval System OnLINE |
