Single‐institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting

Abstract

BACKGROUNDIpilimumab 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.METHODSPatients 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.RESULTSA 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.CONCLUSIONSThe 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.

The Role of Regulatory T Cells in Mesothelioma

“…This "triple immunotherapy" looks particularly promising especially as all components of the "triple immunotherapy" have approved human equivalents or are undergoing clinical trials. Clinical trials have investigated TGF-β blockade [52] and denileukin diftitox (Ontak) to deplete Treg cells in a number of different cancers [53][54][55] while the use of anti-CTLA4 Ig (Ipilimumab, Bristol Myers Squibb) was approved for the treatment of melanoma based on a recent phase III clinical trial [56]. Although many of these Treg cell depletion strategies are showing promise, it is unlikely that they will be used as a single modality to treat an advanced stage mesothelioma patient.…”

Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response

“…Our data reinforce previous results from clinical trials involving either ipilimumab at a higher dose or another CTLA-4 abrogating antibody, tremelimumab. 21,22,23,38 Prior to treatment, patients' circulating T cells displayed a phenotype compatible with a chronic activation by the tumor, with a lower expression of the costimulatory molecule CD28 and increased percentage of HLA-DR and granzyme B positive CD8 C T cells, when compared to HD. In addition, although not significant, a trend toward higher percentages of TCD8 C T cells expressing CTLA-4 by was also observed, suggesting a post-activation status of T cells.…”

“…Increased absolute lymphocyte count (ALC) during the therapy is found to be associated with clinical benefit and overall survival (OS) in uncontrolled studies. 21,22,23,24 In a clinical trial using tremelimumab, another humanized anti-CTLA-4, increased levels of memory and activated T cells were reported in 3 out of 12 patients achieving disease control (DC). 25 Several reports demonstrate immunological changes under ipilimumab therapy, shedding light on in vivo mechanisms of anti-CTLA-4, but their pertinence to predict clinical responses and OS remains to be clarified.…”

Anticorps anti-CTLA-4

“…Plus simple encore, le nombre absolu de lymphocytes après quelques semaines de traitement pourrait être un marqueur pré-dictif d'efficacité. Un taux de lymphocytes supérieur ou égal à 1000 par mm 3 après sept semaines de traitement serait associé à un bénéfice thérapeutique [42]. Avec le tremelimumab, une analyse rétrospective portant sur les patients inclus dans l'essai de phase III tremelimumab versus chimiothérapie suggérait que le taux bas de CRP pouvait sélectionner des patients susceptibles de répon-dre au traitement, mais cela n'a pas encore été confirmé au cours d'une étude prospective [13].…”