Metastatic melanoma is the most aggressive skin cancer.,Recently, phenotypically distinct subpopulations of tumor cells were identified.,Among them, ABCB5-expressing cells were proposed to display an enhanced tumorigenicity with stem cell-like properties.,In addition, ABCB5+ cells are thought to participate to chemoresistance through a potential efflux function of ABCB5.,Nevertheless, the fate of these cells upon drugs that are used in melanoma chemotherapy remains to be clarified.,Here we explored the effect of anti-melanoma treatments on the ABCB5-expressing cells.,Using a melanoma xenograft model (WM266-4), we observed in vivo that ABCB5-expressing cells are enriched after a temozolomide treatment that induces a significant tumor regression.,These results were further confirmed in a preliminary study conducted on clinical samples from patients that received dacarbazine.,In vitro, we showed that ABCB5-expressing cells selectively survive when exposed to dacarbazine, the reference treatment of metastatic melanoma, but also to vemurafenib, a new inhibitor of the mutated kinase V600E BRAF and other various chemotherapeutic drugs.,Our results show that anti-melanoma chemotherapy might participate to the chemoresistance acquisition by selecting tumor cell subpopulations expressing ABCB5.,This is of particular importance in understanding the relapses observed after anti-melanoma treatments and reinforces the interest of ABCB5 and ABCB5-expressing cells as potential therapeutic targets in melanoma.
Ipilimumab is a monoclonal antibody that antagonizes cytotoxic T lymphocyte antigen-4, a negative regulator of the immune system.,The authors report on advanced refractory melanoma patients treated in a compassionate use trial of ipilimumab at the Memorial Sloan-Kettering Cancer Center.,Patients with advanced refractory melanoma were treated in a compassionate use trial with ipilimumab 10 mg/kg every 3 weeks for 4 doses.,Those with evidence of clinical benefit at Week 24 (complete response [CR], partial response [PR], or stable disease [SD]) then received ipilimumab every 12 weeks.,A total of 53 patients were enrolled, with 51 evaluable.,Grade 3/4 immune-related adverse events were noted in 29% of patients, with the most common immune-related adverse events being pruritus (43%), rash (37%), and diarrhea (33%).,On the basis of immune-related response criteria, the response rate (CR + PR) was 12% (95% confidence interval [CI], 5%-25%), whereas 29% had SD (95% CI, 18%-44%).,The median progression-free survival was 2.6 months (95% CI, 2.3-5.2 months), whereas the median overall survival (OS) was 7.2 months (95% CI, 4.0-13.3 months).,Patients with an absolute lymphocyte count (ALC) ≥1000/μL after 2 ipilimumab treatments (Week 7) had a significantly improved clinical benefit rate (51% vs 0%; P = .01) and median OS (11.9 vs 1.4 months; P < .001) compared with those with an ALC <1000/μL.,The results confirm that ipilimumab is clinically active in patients with advanced refractory melanoma.,The ALC after 2 ipilimumab treatments appears to correlate with clinical benefit and OS, and should be prospectively validated.,Cancer 2010.,© 2010 American Cancer Society.,This description of 51 patients with advanced, treatment-refractory melanoma who were enrolled in a compassionate use trial of ipilimumab at Memorial Sloan-Kettering Cancer Center confirms that ipilimumab is active in this disease setting.,In addition, the results suggest that the absolute lymphocyte count after 2 ipilimumab treatments (at Week 7) highly correlates with the rate of clinical benefit at Week 24 and overall survival.