Numerous most successful strategies in immunotherapy have been conducted in melanoma, used either as single agents or in synergistic treatment combinations. These include adoptive transfer of ex vivo activated T cells, immunomodulatory monoclonal antibodies (mAbs), and cancer vaccines. The most encouraging results in stabilizing the melanoma and increasing the overall survival have been obtained by using immunotherapeutic approaches, which transformed the once unbeatable melanoma beast into a curable bet.
One approach that demonstrated efficacy in a subset of patients is high-dose intravenous administration of interleukin-2 (IL-2), a potent T-cell growth factor, and this therapy was approved for use in metastatic melanoma in 1998. The overall response rate (RR) with high-dose IL-2 treatment was 16%, with a 6% complete RR and durable responses observed. However, given the potential for substantial toxicity, this therapy is limited to carefully selected patients with good performance status and adequate cardiopulmonary function. IL-2 therapy should be administered by experienced clinicians at established cancer treatment centers. Dose-related toxicities of IL-2, some of which result from a capillary leak syndrome, include hypotension, renal dysfunction with oliguria, respiratory failure, fever, chills, diarrhea, and vomiting. Although most of the side effects are self-limiting and resolve after discontinuation of therapy, intensive supportive care is often required. High dose IL-2 has been combined with a gp100 vaccine therapy. One study evaluated IL-2 with gp100 vaccine compared to IL-2 alone in a randomized phase III clinical trial, and RRs were significantly improved in the combined IL-2 and gp100 vaccine arm (16% vs. 6%; P = 0.03) as well as longer progression-free survival (PFS) in favor of the combination.
In melanoma, it has been shown that numerous tumor antigen-specific T cells can be isolated from excised material of a tumor mass, dissociating cells into single cell suspensions and adding the T-cell growth factor interleukin-2 (IL-2). Several clinical trials using this approach have provided highly promising results, especially in melanoma. For instance, a series of studies collectively involving 93 patients with stage IV melanoma were treated with the adoptive transfer of autologous TILs administered in conjunction with IL-2 following a lymphodepleting preparative regimen on three clinical trials. Objective-response rates in the three trials using lymphodepleting preparative regimens (chemotherapy alone or with 2 or 12 Gy total body irradiation) were 49, 52, and 72%, respectively. Of particular note, 22% of patients had a complete tumor regression and most of these patients have been alive and disease-free for longer than 8 years. Encouraging results were also shown in another study by treating 57 patients with IV stage melanoma with unselected/young TIL and high-dose IL-2 following non-myeloablative lymphodepletion. Overall response rates (ORR) were observed up to 40% with 23 patients achieving complete or partial remission.
This treatment strategy involves the therapeutic manipulation of inhibitory signaling pathways that normally function to maintain T-cell homeostasis and prevent autoimmunity. CTLA-4 is one such inhibitory receptor that is induced on activated T cells and provides negative feedback by binding to its ligands CD80 and CD86 (also known as B7.1 and B7.2) on antigen-presenting cells (APCs), outcompeting the costimulatory receptor CD28, which also shares these ligands but binds with lower affinity. Early studies in animal models identified the ability of CTLA-4 blockade to promote antitumor immunity and led to the eventual clinical development of ipilimumab, a fully human immunoglobulin G (IgG)1 mAb, as well as a second blocking anti–CTLA-4 mAb tremelimumab (human IgG2 isotype). Although their precise mechanism of action in patients is not completely understood, studies in mice indicate that CTLA-4 blockade both enhances effector T-cell function and inhibits immunosuppressive T regulatory cells (Treg) (which constitutively express high levels of CTLA-4), possibly through Treg depletion from the tumor microenvironment via antibodydependent cell-mediated cytotoxicity (ADCC).
A second inhibitory pathway on T cells involves PD-1, a receptor expressed on antigen-stimulated T cells, which upon binding to its ligands programmed cell death-ligand 1(PD-L1) and PD-L2 (also known as B7-H1 and B7-DC) leads to impairment in effector T-cell functions including cytotoxicity, cytokine production, and proliferation.18 PD-L1 is expressed broadly in the parenchymal cells of many tissues as well as on hematopoietic cells, whereas PD-L2 expression is confined to APCs. The PD-1 receptor is believed to operate in the maintenance of peripheral immune tolerance and to limit excessive tissue damage during acute infection. Importantly, this pathway can be co-opted by tumors to suppress antitumor immunity through tumor cell expression of PD-L1. Several antibodies have been developed for clinical use, including approved agents pembrolizumab and nivolumab (both humanized IgG4 mAbs to PD-1) and the anti- PD-L1 mAbs BMS-936559 and MPDL-3280A, which are not approved but have demonstrated efficacy in early phase trials.
With the success of checkpoint inhibitors as monotherapy, a multitude of trials have been initiated to test these agents in combination, when administered concurrently with other immunomodulatory agents or targeted BRAF/MEK inhibitors, or in conjunction with other treatment modalities such as radiotherapy. Approaches combining two immunotherapies with different mechanisms of action, or an immunotherapy along with agents that promote immunogenic tumor cell death might be expected to act synergistically.
Many new methods are under research now, which will bring more success in melanoma immunotherapy.
Diamond M et al. Immunotherapy for melanoma[J]. Abeloff's Clinical Oncology. 5th ed. Philadelphia, PA: Elsevier, 2015.
Ascierto M L et al. Melanoma: from incurable beast to a curable bet. The success of immunotherapy[J]. Frontiers in oncology, 2015, 5.