Getting Personal with Melanoma

Commentary on Rosenberg et al., p. 4550

In this issue of Clinical Cancer Research, Rosenberg and colleagues (1) provide long-term follow-up data on 93 patients with metastatic melanoma who received personalized therapy for their disease, which took the form of infusions of autologous tumor-infiltrating lymphocytes (TIL) after lymphodepletion. They describe three sequential clinical trials in which they progressively increased the intensity of the lymphodepletion regimen by addition of higher doses of total body irradiation to a chemotherapy backbone of fludarabine and cyclophosphamide. The initial reports of outcomes of these studies have been previously published, but this article now describes the results obtained at a median follow-up of 62 months. The increasing intensity of lymphodepletion was associated with increasing objective and complete response (CR) rates (from 49% to 72% and 12% to 40%, respectively). Of particular note, 19 of the 20 patients who attained CR have remained in remission from 3 to 7 years or more (1). This long-term CR rate is particularly impressive given that the trials targeted high-risk populations in which many patients had been heavily pretreated and had visceral metastases at the time of T-cell infusion.

The above results show that adoptive T-cell immunotherapy can produce durable disease control. This effect has also been observed in other studies of T-cell immunotherapy, including donor lymphocyte infusion to treat relapse after allogeneic hematopoietic stem cell transplant (2), infusion of cytotoxic T lymphocytes targeting lymphoma or nasopharyngeal cancer (3–6), and in one patient with melanoma treatment with autologous CD4⁺ T-cell clones with specificity for the melanoma-associated antigen NY-ESO-1 (7). In the TIL studies reported here, factors associated with objective response included longer telomeres of the infused cells, the number of CD8⁺ CD27⁺ cells infused, and the persistence of the infused cells in the circulation at 1 month (1). Rosenberg and colleagues do not provide data on the longer-term persistence of infused cells; however, studies using genetically modified T cells have shown persistence for up to a decade (3, 8), which may contribute to long-term disease control.

Until March 2011, dacarbazine and interleukin-2 were the only two agents that had been approved by the U.S. Food and Drug Administration (FDA) for the therapy of melanoma. However, in the last year, two significant studies of new agents targeting this disease were published, and one resulted in approval of another agent. PLX4032, an inhibitor of mutated BRAF (9), has produced an impressive response rate: 26 of the 32 patients treated at the recommended phase II dose had an objective response (81%), although only 2 of these patients had a CR. These responses, however, were often not complete (2/26 CR) or completely durable, although the median duration of progression-free survival (>7 months) had not been reached at the time the data were submitted for publication. Ipilimumab, a monoclonal antibody against the inhibitory lymphocyte receptor CTLA-4, which downregulates pathways of T-cell activation, also has activity in melanoma. Patients with metastatic melanoma were randomly assigned to receive ipilimumab alone or in combination with a glycoprotein 100 peptide vaccine or the vaccine alone (10). There was an objective response rate of 7% in the 540 patients who received one of the two ipilimumab-containing regimens, but responses to ipilimumab continued to improve for several months, and a significant proportion of these patients maintained an objective immune response for more than 2 years (10). Moreover, improvements in both overall survival and progression-free survival were seen in the patients who received anti–CTLA-4 therapy compared with control patients who received only the vaccine. The median overall survival was 10.0 months in patients who received ipilimumab plus the vaccine and 10.1 months in those who received ipilimumab alone, compared with 6.4 months in patients who received only the vaccine. Based on these results, the FDA approved the use of ipilimumab to treat patients with late-stage (metastatic) melanoma on March 25, 2011.

The observation that sustained CRs can be achieved both by infusion of TILs and administration of ipilimumab supports the contention that immune modulation can effectively control disease in at least a subset of patients with advanced melanoma. Therapy with TILs is not an option for all patients with metastatic melanoma, because manufacture of this product requires both that a suitably sized tumor lesion is accessible for resection to obtain TILs and that a cell product can be generated by ex vivo culture and expansion, a requirement that is currently met by approximately 45% of patients with metastatic melanoma (1). The manufacturing protocols for TIL generation are exportable to other institutions (11) and have been facilitated by recent changes in manufacturing that incorporate newer cytokine and costimulatory molecule technology in improved bioreactors. A recent white paper proposed a randomized multicenter study of TIL therapy. For this study to be feasible, investigators will need to develop a consensus about the optimal lymphodepletion regimen and control group, define manufacturing processes, and decide on the postinfusion cytokine support (11). Given the sustained CRs described in this report, the development and design of such a study should be a priority.

The long-term benefit of TIL infusions described in this report also justifies exploration of other T-cell therapy approaches in patients with metastatic melanoma. Figure 1 summarizes T-cell strategies that are currently undergoing clinical testing. Several investigators have described a methodology for generating CD8⁺ or CD4⁺ antigen-specific T-cell clones by stimulating responding T cells with antigen-presenting cells pulsed with peptides derived from tumor antigens expressed by melanoma cells (7). An alternative strategy is to genetically modify nonspecifically activated T cells with artificial receptors specific for tumor antigens. The National Cancer Institute group has identified T-cell receptors (TCR) that are highly reactive to melanoma/melanocyte antigens from screens in immunized transgenic mice and from cloning TIL lines, and undertaken clinical trials in which these TCRs are transferred to activated peripheral blood lymphocytes (8). Objective response rates of 19% to 30% have been reported (8). An alternative strategy is to transduce T cells with chimeric antigen receptors consisting of an antigen-binding exodomain and a T-cell signaling endodomain so that the antigen specificity of an antibody and the cytotoxic properties of a T cell are combined in a single fusion molecule. Preclinical studies have evaluated the nonprotein tumor antigen disialoganglioside 2 (GD2) because it is expressed by the majority of melanoma cells and cannot be targeted by conventional TCRs (12). For individuals in whom TIL manufacture fails or TIL infusions do not produce clinical benefit, adoptive immunotherapy with such other T-cell products may be considered.

All the above adoptive T-cell therapies may be further improved by combining them with antibodies that target downregulators of T-cell activation, such as CTLA-4, or block other negative regulators of immune function, such as PD1, or immunosuppressive cells and cytokines in the tumor microenvironment. In the longer term, the optimal personalized therapy for melanoma may be to combine therapies that act by different mechanisms. For example, it may be possible to combine T-cell immunotherapy approaches directed to melanoma antigens with targeted small molecules that inhibit aberrantly activated pathways in the individual's tumor.

No potential conflicts of interest were disclosed.