Immunotherapy For Advanced Melanoma Research Articles

Abstract CT329: A Phase I study of IMCgp100: durable responses with a novel first-in-class immunotherapy for advanced melanoma

Abstract Background: IMCgp100 comprises an affinity-enhanced T cell receptor (TCR) specific for the HLA-A2 restricted melanoma gp100 peptide (YLEPGPVTA) fused to an anti-CD3 antibody fragment. Binding of IMCgp100 to melanoma cells redirects T cell cytotoxicity even in the presence of significant levels of PD-1 and PD-L1. Importantly, IMCgp100 enables T cells to kill HLA down-regulated melanoma cells otherwise invisible to cancer specific T cells. A Phase I study was conducted to determine the Maximum Tolerated Dose (MTD) and toxicity of IMCgp100 in patients with metastatic melanoma. Methods: HLA A2 positive patients with Stage IV or unresectable Stage III melanoma, with an ECOG Performance Status (PS) ≤1 and a lymphocyte count of ≥0.5x109/L were enrolled. Those with symptomatic, unstable brain metastases requiring steroids and those who might benefit from immediate vemurafenib treatment were excluded. IMCgp100 was administered on day 1 and patients followed to day 30. Those who tolerated the first dose received repeated cycles of six weekly doses. The dose of IMCgp100 was escalated in cohorts of 3 (+3) patients until criteria for MTD were met. MTD was defined as the highest dose level with an observed incidence of Dose Limiting Toxicity (DLT) in fewer than 33% of patients enrolled at that level. Transient Grade 3 lymphopenia and Grade 3 skin toxicity were excluded from the definition of a DLT. Results: 31 patients were enrolled in 8 cohorts (doses from 5 to 900ng/Kg). 58% were male, median age was 61, ECOG PS 0 in 52% and 1 in 48%. All but 1 patient had stage IV disease. 60% of patients had received systemic treatment with DTIC (29%), ipilimumab (6%), vemurafenib (3%) or one or more experimental therapies (22%) prior to enrolment. At dose 900ng/Kg, 2/4 patients developed Grade 3 hypotension, therefore the MTD was defined at 600ng/Kg. Common toxicities included transient grade 3 pruritic rash and grade 2 pyrexia. Patients experienced profound lymphocyte trafficking to skin as evidenced by immunohistochemical analysis of skin biopsies, accompanied by chemokine/cytokine release. Rash was initially observed at dose level 45ng/Kg. Tumor flare was observed in patients with cutaneous or subcutaneous disease. Four partial responses (PR) and multiple lesser responses (not meeting RECIST PR) have been documented to date. One PR was achieved after a single dose. Two PRs continue after >9 months of continued treatment. One patient continues with stable disease for >10 months. Sites of response included the lung, the liver, the lymphatic system and various soft tissues. Conclusions: Toxicities of IMCgp100 were consistent with the mode of action of the drug i.e. IMCgp100 mediated T cell mobilisation, activation and tumor killing. Objective durable responses were observed. The study has been expanded to accrue additional patients at 600ng/Kg and to explore potentially superior dosing regimens. Citation Format: Mark Middleton, Jeff Evans, Neil Steven, Pippa Corrie, Clive Mulatero, Mario Sznol, William H. Shingler, Dominic Smethurst, Namir Hassan, Yvonne McGrath, Bent Jakobsen. A Phase I study of IMCgp100: durable responses with a novel first-in-class immunotherapy for advanced melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT329. doi:10.1158/1538-7445.AM2014-CT329

Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma.

Historically, the median overall survival for patients with stage IV melanoma was less than 1 year and the 5-year survival rate was ∼10%. Recent advances in therapy have raised 5-year survival expectations to ∼20%. Notably, a subset of melanoma patients who receive immunotherapy with high-dose interleukin-2, and now ipilimumab, can achieve long-term survival of at least 5 years. A major goal in melanoma research is to increase the number of patients who experience this overall survival benefit. In this review, we discuss the attributes of immunotherapy and newer targeted agents, and consider how combination strategies might improve the chances of achieving durable benefit and long-term survival. We also discuss three areas that we believe will be critical to making further advances in melanoma treatment. To better understand the clinical profile of patients who achieve long-term survival with immunotherapy, we first present data from ipilimumab clinical trials in which a subset of patients experienced durable responses. Second, we discuss the limitations of traditional metrics used to evaluate the benefits of immunotherapies. Third, we consider emerging issues that clinicians are currently facing when making treatment decisions regarding immunotherapy. A better understanding of these novel treatments may improve survival outcomes in melanoma, increase the number of patients who experience this overall survival benefit, and inform the future use of these agents in the treatment of other cancer types.

Current and future roles of targeted therapy and immunotherapy in advanced melanoma.

Melanoma is an aggressive disease that accounts for approximately 75% of skin cancer-related deaths. Historically, treatment options for patients with advanced stage melanoma have been limited by modest response rates and failure to improve overall survival. The treatment landscape for advanced stage melanoma was revolutionized in 2011 with the approval of ipilimumab and vemurafenib, both of which improved overall survival in phase III clinical trials. More recently, the targeted inhibitors dabrafenib and trametinib have demonstrated similar therapeutic profiles. To (a) discuss emerging treatment options for advanced melanoma, specifically ilpilimumab, vemurafenib, dabrafenib, and trametinib, in the context of their mechanisms of action and their potential for long-term improvement in patient outcome, and (b) to consider the impact of these agents on the current treatment landscape. A literature search was conducted to collect data from clinical trials involving ipilimumab, vemurafenib, dabrafenib, and trametinib. Emphasis was placed on outcome measures related to long-term clinical benefit. Ipilimumab, a fully human monoclonal antibody, exploits the natural ability of the immune system to eradicate primary cancer cells. It inhibits the binding of cytotoxic T-lymphocyte antigen-4 to its ligands, thereby potentiating T-cell response and antitumor immunity. In a phase III clinical trial, ipilimumab at 3 mg/kg improved overall survival in previously treated patients with metastatic melanoma. Components of the mitogen-activated protein kinase (MAPK) pathway are particularly relevant in melanoma and have been targeted by small molecular inhibitors. Vemurafenib and dabrafenib inhibit the BRAF V600 mutation, which prevents oncogenic activities such as uncheck proliferation and evasion of immune response. Data from phase III clinical trials suggest that both vemurafenib and dabrafenib improve patient outcomes, with vemurafenib showing an overall survival benefit and dabrafenib showing improved median progression-free survival. The targeted-therapy approach in melanoma continued to gain momentum with the development of trametinib, which inhibits the MEK protein, the only known substrate of the BRAF V600 protein. Inhibition of MEK leads to decreased cell signaling and proliferation in cancer cells. In phase III trials, trametinib demonstrated significant improvement in median progression-free survival and median overall survival compared with chemotherapy treatment, making this treatment a valuable addition to the current armamentarium. The adverse events associated with these new treatments are generally tolerable and mild to moderate in severity; however, care should be taken when selecting a therapy, since the specific adverse events associated with these treatments are unique, and serious events have been reported. The immunotherapy ipilimumab and the MAPK-targeted inhibitors vemurafenib, dabrafenib, and trametinib have forever changed the treatment landscape for melanoma. Indeed, these new therapies have demonstrated long-term improvement in patient outcome, a benefit not afforded by traditional therapeutics. Important research continues on the molecular basis of melanoma, and new targets are likely to emerge. Other areas of work include optimization of sequencing and/or combination of current treatments, which may increase the number of patients who experience clinical benefit.

Clinical benefit of high dose IL-2 (HD IL-2) therapy: evidence for improved overall survival in patients with stable disease

Background HD IL-2 is an approved immunotherapy for advanced melanoma and renal cell carcinoma with a reported objective response rate (ORR) up to 20%. Patients with stable disease (SD) following treatment are not considered objective responders and thus are not included in reported response rates. Since the initial reports of IL-2 our understanding of the delayed pharmacokinetics of immunotherapy has improved. The purpose of this study is to report the clinical outcomes for patients with stable response to HD IL-2. Methods A retrospective chart review of 305 patients diagnosed with metastatic renal cell carcinoma or melanoma and treated with HD IL-2 therapy over a 12-year period was conducted. Age, response to HD IL-2 (based on RECIST criteria) and survival data were available in 215 patients at the time of analysis. Survival analysis was conducted on all patients for whom complete data was available and Kaplan-Meier curves were generated based on overall survival. Results Among the 215 patients with complete data, 62% had progressive disease (PD), 24% had SD and the objective response rate was 14%. Median overall survival was 16.8 months among all 215 patients. Patients with a PR or CR (median survival not reached in the study period) had significantly prolonged survival than the remaining patients (median survival 13.9 months, log-rank p < 0.01). Patients with SD (median survival of 38.2 months) had improved survival compared to patients with progressive disease (median survival of 7.9 months, log-rank p< 0.01). Discussion The IL-2 literature has focused on partial or complete responders when reporting objective response rates. In our data, as well as elsewhere in the literature, there are a large number of patients who have as table response to HD IL-2 that have not been included in the ORR. Our data supports a significant survival benefit associated with stable disease following IL-2, which suggests that HD IL-2 may result in a clinical benefit in a larger number of patients than has previously been reported. Consideration of ad isease control rate (DCR) inclusive of objective responders and stable responses may be more appropriate to better define the clinical benefit of IL-2.

Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm.

Metastatic melanoma is one of the most challenging malignancies to treat and often has a poor outcome. Until recently, systemic treatment options were limited, with poor response rates and no survival advantage. However, the treatment of metastatic melanoma has been revolutionized by developments in targeted therapy and immunotherapy; the BRAF inhibitor, vemurafenib, and anticytotoxic T-lymphocyte antigen 4 antibody, ipilimumab, are the first agents to demonstrate a survival benefit. Despite the success of these treatments, most patients eventually progress, and research into response and resistance mechanisms, rationally designed combination therapies and evaluation of the role of these agents in the adjuvant setting is critically important.

Kinesin Family Member 20A is a Novel Melanoma-associated Antigen

It has been shown recently that immunotherapy for advanced melanoma is effective. However, in order to improve the efficacy of immunotherapy, the identification of more specific melanoma-associated antigens is urgently needed. Kinesin family member 20A (KIF20A) has been reported to be a promising immunotherapeutic target for pancreatic cancer. To investigate the expression of KIF20A in melanoma, we performed quantitative reverse transcript (RT)-PCR and western blotting analyses of melanoma cell lines. We also investigated primary melanomas and naevus tissues with immunohistochemistry and real-time RT-PCR. KIF20A expression was detected in 59% of melanomas and 12% of naevi by immunohisto-chemistry, and 64% of melanomas and 60% of naevi by real-time RT-PCR. The primary melanomas that were positive for KIF20A showed a significantly greater thickness than those that were negative, and patients with KIF20A+ melanoma tended to develop recurrence earlier. These results suggest that immunotherapy with KIF20A may be a novel treatment option for advanced melanoma.

Immunotherapy of advanced melanoma by intratumoral injections of autologous, purified dendritic cells transduced with gene construct of interleukin-12, with dose-dependent expression under the control of an oral activator ligand.

2540 Background: RTS-IL12 is a novel synthetic gene construct in an adenovirus vector, with IL-12 expression only turned on when an oral small molecule activator ligand (AL) triggers the promoter of the gene. Syngeneic dendritic cells (DC) transduced with RTS-IL-12 injected intra-tumorally + oral AL induced IL-12 and associated genes only locally, triggering systemic, specific anti-tumor cytotoxic T cells and regression of B16 melanoma and other mouse tumors. A Phase 1 trial was initiated to evaluate safety, mechanism of action (MOA) and clinical activity of DC-RTS-IL12 in patients with advanced melanoma. Methods: Autologous immature DC-RTS-IL-12s (5x107) are injected intra-tumorally, in combination with 14 days of AL (0.6, 20, 60 or 200 mg /day), for ≤ 5 treatment cycles. Safety, MOA (genomic and immunologic) and clinical responses (CT evaluation by RECIST) are being assessed. Results: Among 7 patients treated, partial or complete regression of injected and some uninjected lesions was observed by CT in 2 patients, with 1 patient having RECIST PR of >11 months. These 2 patients had intratumoral changes in IL-12 associated gene expression, and circulating CD8+ and/or CD4+T cells reactive against several melanoma-associated peptides by ELISPOT. Treatment was generally well tolerated and MTD has not yet been reached. Accrual will end early if there are 4 or more responses. Conclusions: This phase I trial in patients with advanced melanoma has confirmed key findings from mouse tumor models: regression of some uninjected as well as injected tumor lesions, and induction of systemic, specific anti-tumor T cell immunity even at dose levels of AL that do not trigger increases in circulating IL-12 or its associated cytokines.

Restoration of tumor equilibrium after immunotherapy for advanced melanoma

Metastatic melanoma runs a predictable detrimental course in the vast majority of patients. New modalities of immunotherapy, such as melanoma antigen-specific therapeutic vaccination and cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor blockade by monoclonal antibodies (mAbs), have been associated with atypical kinetics of tumor response that differ from those observed during cytotoxic treatment. Recently, new tumor response criteria have been proposed based on the tumor response characteristics observed in clinical studies with ipilimumab (the so-called 'immune-related response criteria'). We report three illustrative cases of the American Joint Committee on Cancer stage IV-M1c melanoma patients who experienced atypical kinetics of tumor response to the treatment with the CTLA-4-blocking mAb, ipilimumab (case 1), or an autologous dendritic cell vaccine in combination with interferon α-2b (cases 2 and 3). These cases show that atypical response patterns not only relate to the outcome of CTLA-4-blocking mAb therapy but also to the treatment with therapeutic vaccines and interferon α-2b.

Histamine in immunotherapy of advanced melanoma: a pilot study.

Sixteen patients with advanced metastatic malignant melanoma were treated with a high-dose infusion of interleukin-2 (IL-2; 18 x 10(6) IU/m-2 day-1) together with daily subcutaneous (s.c.) injections of interferon alpha (IFN alpha; 3 x 10(6) U/m-2 day-1) in 5-day cycles. Nine of these patients were given histamine (1 mg s.c.) twice daily during treatment with IL-2 and IFN alpha. In the seven patients who did not receive histamine, one partial response (that is a reduction of more than 50% in the total tumour burden) was observed in a patient with skin and lymph node melanoma. In the eight histamine-treated patients evaluable for response, four partial responses were observed. Two other patients showed regression at one site of metastasis but tumours remained unchanged at other sites. Two histamine-treated patients showed complete resolution of extensive liver metastasis. Sites of response in histamine-treated patients also included the subcutis, lymph nodes, skeleton, spleen and muscle. Lung melanoma did not respond to histamine/IL-2/IFN alpha. Three patients with lung tumours responded with significant (more than 50%) reduction of the volume of soft-tissue tumours, suggesting that the response to histamine may be organotropic. Survival was significantly prolonged in patients receiving histamine. Our data suggest that treatment with histamine may improve the antitumour efficacy of immunotherapy in metastatic melanoma.

THE SURVIVAL OF PATIENTS WITH MALIGANT MELANOMA RECEIVING BCG WITH OR WITHOUT CHEMOTHERAPY

The effects of treatment by immunotherapy and chemoimmunotherapy were assessed in 31 non-randomized patients with melanoma; 16 received only BCG and 15 BCG and chemotherapy. For advanced cases, the times of survival for the two treatment groups did not differ significantly, nor did there appear to be any improvement in survival over that recorded for the natural course of the disease. The pretreatment immune status as judged by hyporeactivity or normal reactivity to skin tests for delayed type hypersensitivity did not appear to influence survival. This study, together with other reports, does not support the use of immunotherapy in advanced melanoma. Immunotherapy for early melanoma is still to be assessed.