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Supplements The Role of Immuno-Oncology in the Treatment of Advanced Melanoma

Current Landscape of Immuno-Oncology in Advanced Melanoma

T-VEC is also being evaluated in combination with pembrolizumab in a multicenter, double-masked, phase lb/3 study in patients with unresectable stage IIIB or IVM1c melanoma with no previous systemic treatment. In phase 1b, all patients received T-VEC plus pembrolizumab (N = 21). The confirmed ORR was 48%, with 14% of patients achieving a CR. The median time to response was 17 weeks. During treatment with T-VEC, circulating CD8+ cells were elevated, but decreased after pembrolizumab was initiated. Most common AEs were fatigue, fever, and chills. All patients experienced treatment-related AEs, with 33% experiencing grade 3 or 4 AEs.54 In phase 3 (estimated N = 660), patients will be randomized to receive T-VEC plus pembrolizumab or pembrolizumab and placebo. This study is expected to be completed by September 2022.55

DC Vaccines

Upon infection or inflammation, DCs collect and present antigens to naïve T cells, activating them against an antigen-specific target. DC vaccines aim to take advantage of this key role in the immune response. In the past, researchers matured undifferentiated DC cells from a progenitor line in vitro, yielding limited clinical responses. However, recent advances show that by using naturally occurring DCs, a measurable clinical effect can be achieved. Therefore, DC vaccines currently in development are created by loading tumor-specific peptides into patients’ own harvested DCs for individualized therapy.56,57

In a first-in-human feasibility study evaluating the ability of plasmacytoid DCs (pDCs) to initiate an antitumor response, 16 patients with metastatic melanoma received autologous activated pDCs loaded with tumor-associated peptides. To evaluate the clinical outcomes, investigators identified matched historical controls who received standard dacarbazine chemotherapy. The number of patients in the study did not allow investigators to draw conclusions of clinical significance; however, compared with the historical control group, the median OS showed notable improvement over the matched controls: 22.0 months (95% CI, 1.8-42.2) versus 7.6 months (95% CI, 5.8-9.4; P = .001), respectively. Vaccines were well tolerated and no severe toxicities were observed.56

In another safety and feasibility study, patients with metastatic melanoma were administered tumor antigen–loaded autologous CD1c+ myeloid DCs (mDCs) isolated from peripheral blood and cultured overnight. After the first cycle of therapy, 5 patients showed at least stable response; these patients received a second cycle of therapy, of whom 2 experienced disease progression and the remaining 3 received a third cycle of therapy. Of these 5 remaining patients, 2 also showed an objective response that was correlated with the presence of functional T cells. One patient converted to a CR, and at the time of study publication (2016) was in remission after 35 months. The median OS for patients with functional T cells was 29.0 months compared with 10.9 months in patients who did not have functional T cells (HR, 0.43; 95% CI, 0.12-1.54; P = 0.103). The median OS for all patients was 13.3 months. Vaccines were well tolerated and no serious toxicities were observed.57

Other elements within the immune system are being explored for possible applications in cancer. One such component is LAG-3, a cell-surface molecule expressed on activated T cells, NK cells, and B cells.58 LAG-3 is interesting

because several approaches to manipulating its role in the immune process appear to have clinical use. In preclinical studies, blocking LAG-3 with a LAG-3 antibody resulted in more persistent proliferation of T cells in vitro, potentially increasing antitumor activity, whereas upregulating LAG-3 with LAG-3–Ig increased the expression of co-stimulatory molecules and interleukin-12 in DCs.58 Both of these approaches are being evaluated in early clinical trials: LAG-3–Ig (IMP321, Immutep, France) and LAG-3 mAb (NCT01968109, Bristol-Myers Squibb, United States).59

Conclusions

The incidence of advanced melanoma is steadily increasing and comes at considerable economic cost and emotional burden. However, in the recent past, the number of useful treatment options and bourgeoning fields of research for these patients have increased considerably. Accordingly, patients should be informed of ongoing clinical trials that may alter their individual treatment journeys.

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