Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases

Abstract

The management of unresectable metastatic melanoma is a major clinical challenge because of the lack of reliably effective systemic therapies. Blocking cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) has recently been proposed as a strategy to enhance cell-mediated immune responses to cancer, and clinical trials have demonstrated that anti-CTLA-4 therapy can produce durable outcomes with different response patterns than cytotoxic chemotherapy. We enrolled eight out of 155 patients with advanced melanoma in a multicentre phase II trial that evaluated the activity and tolerability of ipilimumab, a fully human, anti-CTLA-4 monoclonal antibody ( www.clinicaltrials.gov ; NCT00289627; CA184-008). Here we report our experience with three of these patients, who experienced progressive disease after a variety of previous therapies, including prior immunotherapies, and who achieved good outcomes with ipilimumab. One patient had a partial response ongoing at 17+ months on ipilimumab despite failure with four prior therapies, and the other two patients showed durable stable disease, both still ongoing at 17+ and 20+ months, respectively. The patient achieving a partial response experienced no side effects while receiving ipilimumab. The other two patients developed immune-related adverse events (irAEs) including rash (one case; grade 2) and diarrhoea (both cases; grades 1 and 2, respectively); the histopathology of colon biopsy samples from both was suggestive of colitis, with an abundant CD8+ T-cell infiltrate. Nausea, vomiting and acute pancreatitis were also observed in one patient. In addition, immunohistochemical findings of a dense CD8+, TIA1+ and granzyme B+ lymphoid infiltrate within a biopsied lesion provide indirect evidence of functional T-cell activation induced by treatment. These case reports highlight the potential for anti-CTLA-4-based therapy in previously treated patients with advanced melanoma. Moreover, because the patterns of response to ipilimumab differ from chemotherapy, we need to understand how and when patients may respond to treatment so that appropriate clinical decisions can be made.

Fig. 1

Case 1 Cutaneous leg lesions showing a pretreatment sessile base (b) evolved into a single lesion during therapy with ipilimumab (week 12 of trial CA184-008; c with a progressive tendency to become semi-pedunculated (week 12 of trial CA184-025 and 14 months after starting treatment; d During treatment, there was re-epithelialisation of the lesion stalk and a dense mononuclear infiltrate confined to the body of the tumour (a; H&E; ×25). Four months after surgical excision, the lesion’s base completely re-epithelialised showing no macroscopic evidence of disease (week 36 of trial CA184-025 and 19 months after starting treatment; e)

Fig. 2

Case 1 Cutaneous leg lesion excised during the maintenance phase of ipilimumab therapy in the CA184-025 roll-over trial, illustrating a dense inflammatory infiltrate (a) containing a high proportion of activated cytotoxic lymphocytes tending to dissociate individual melanoma cells (b–d: CD8, TIA-1 and granzyme-B immunostainings, respectively; ×400). Small haemorrhages were also detected within the lesion (indicated by the arrow in a; H&E; ×100)

Fig. 3

Case 1 Colon biopsies taken after completing induction therapy with ipilimumab (week 18). Histopathology was reminiscent of ulcerative colitis with moderate to severe inflammatory infiltrates confined exclusively to the mucosa and submucosa (a; H&E; ×100). Higher magnification demonstrated neutrophils infiltrating crypts and forming crypt microabscesses (b; H&E; ×400). Consistent levels of intraepithelial CD8+ T-lymphocytes were evident (c; CD8 immunostaining; ×400)

Fig. 4

Case 2 CT scans illustrating the disease status before (a, b) treatment with ipilimumab, at week 12 from the beginning of treatment (c, d), and at week 24 of the CA184-025 roll-over trial (e, f). After the induction phase, the patient experienced substantial shrinkage of liver metastases at segments II and VI (c), while two pre-existing splenic lesions progressed (d). At week 24 of the roll-over trial, he experienced further shrinkage of hepatic lesions (e), disappearance of one splenic nodule and significant shrinkage of the second one (f)

Fig. 5

Case 2 CT and PET scans illustrating the status of subcutaneous metastases before (a, c) and after treatment (week 20; b, d) with ipilimumab. The arrows on the pretreatment scans show the sites of metastases. The patient achieved a PR, with the disappearance of many subcutaneous lesions on the left thigh

Fig. 6

Case 3 Cutaneous thigh lesion resected at week 32. Melanoma-cell nests are intermingled with an abundant mononuclear cell infiltrate (a, H&E; ×100), comprising a relatively high number of activated cytotoxic lymphocytes, as shown by CD8 (b), the apoptosis promoting protein TIA-1 (c) and granzyme B (d) immunohistochemical staining; ×400