Melanoma immunotherapy

IL-2 in advanced melanoma

HD IL-2 is administered ranging from 600 000 to 720 000 IU/kg/i. v. every 8 h for up to 14 consecutive doses over 5 d, followed by a second treatment cycle after 6 to 9 d VSports. 2 Treatment of patients with advanced melanoma with HD IL-2 has demonstrated a complete response (CR) rate of 6% and partial response rate of 10%. Among patients who reach CR, the response can be long-lasting. However, HD IL-2 is associated with significant acute toxicity (severe hypotension, pulmonary edema, systemic edema with significant weight gain and renal insufficiency, rash and fatigue). 5 For this reason HD IL-2 requires the hospitalization and is usually reserved for patients in a good performance status. Alternative regimens have been investigated, but were unable to reach comparable response rates. The Society for Immunotherapy for Cancer (SITC) recommends HD IL-2 as first-line treatment in patients with stage IV BRAF-wild type melanoma who have a good performance status and no evidence of central nervous system disease. 6 The genetic background of melanoma might also affect response rates for IL-2 treatment. A recent report7 suggests that neuroblastoma rat sarcoma viral oncogene (NRAS) mutations might predict a better response to IL-2 treatment.

Intralesional IL-2 for in-transit lesions

Surgical resection is the preferred therapeutic approach for in-transit metastases. However, when surgical excision cannot be pursued, another possible option is the intralesional injection of therapeutics. Injecting IL-2 into a metastatic lesion allows for very high intralesional concentrations without systemic toxicity. Several small series have reported promising clinical responses in treated lesions. 8-11 Boyd et al. injected 10 million IU of IL-2 in each lesion twice a week in a total of 39 patients and reported complete and partial responses in 51% and 31%, respectively. 8 Radny et al. used single doses from 0. 6 to 6 million IU, depending on lesion size and injected 2–3 times weekly in a total of 24 patients. They reported complete and partial responses in 63% and 21%, respectively. 10 A systemic effect of this treatment was suggested, with a higher five-year survival in patients with a complete response compared with patients with a partial response (80% vs 50%). 8 To achieve increased local expression of the cytokine over a prolonged period of time, plasmid DNA (pDNA) expression vectors, which deliver the IL-2 gene into tumor cells, are used VSports app下载. 12 The combination of vector delivery via intralesional injection followed by electroporation to facilitate cellular uptake of pDNA is an area of active research. 13.

Several other immunomodulatory gene therapy trials have been conducted; still the most promising results are achieved with administration of pDNA encoding IL-12 along with electroporation. This treatment has also induced responses in untreated lesions, suggesting an induction of systemic response. 14 V体育官网.

IFN in adjuvant treatment

Various systemic therapies have been examined for patients with stage II or III melanoma and a high risk of systemic recurrence after surgery excision. The immunotherapeutics approved by the FDA for the adjuvant treatment of melanoma are interferon α-2b and peginterferon α-2b. The rationale for the use of the pegylated form is to reduce its rate of absorption following subcutaneous injection, to reduce renal and cellular clearance, and to decrease the immunogenicity of the protein. All of these effects tend to enhance the half-life of the pegylated protein. On the other hand, pegylation may interfere with the ability of a protein to bind to its receptor, thereby decreasing its biologic effect. Thus, the true biologic effect of the pegylated protein is determined by the balance of these competing properties of the interferon increases.¹⁹

Stage III melanoma with macroscopic nodal disease (N1b and N2–N3) is generally considered separately from that with microscopically involved lymph nodes (N1a). The SITC suggests one year of interferon α-2b treatment or enrollment in specific clinical trials, for patients with macroscopic lymph node involvement.⁶ On the other hand, in the case of N1a disease, a 1-y course of interferon α-2b, but also no further treatment, or shorter courses of interferon α-2b are suggested. Pegylated interferon α-2b was recommended by a minority of panel members in N1a melanoma with ulcerated primary tumors or for patients unwilling or unable to tolerate the standard regimen of interferon α-2b treatment.⁶ Patients with stage II melanoma are considered at high-risk of recurrence if the primary lesion is ulcerated, larger than 4 mm in diameter, or has mitotic rate ≥1 per mm². Specialists remain divided between recommending interferon α-2b and active surveillance.⁶ A recent randomized study showed a better overall survival in patients treated with a 1-y course of interferon α-2b (20 MIU/m² intravenously daily 5 d per week for 4 wk, followed by IFN-α-2b 10 MIU/m² administered subcutaneously three times per week for 48 wk) compared with a shorter course (20 MIU/m² intravenously daily 5 d per week for 4 wk) in patients from stage IIB to stage IIIC.²⁰ However, most of the patients included had a stage IIIB or IIIC at study entry suggesting once more that 1 y of therapy offers the most benefit to those with macroscopic nodal metastasis and a higher risk of relapse.

Anti-CTLA-4 antibodies in metastatic melanoma

Clinical studies confirm that the CTLA-4 inhibitor ipilimumab can induce durable responses and improve overall survival in patients with advanced melanoma. A phase II study comparing different dose regimens (0.3, 3, or 10 mg/kg IV every 3 wk) established that the best response was obtained with 10 mg/kg. However, at this dose, a significant increase in immune-related adverse effects (irAEs) was observed.³⁸ In the first phase III trial, ipilimumab +/− glycoprotein 100 peptide (gp100) vaccine was compared with gp100 vaccine monotherapy in patients with unresectable stage III or stage IV melanoma. Ipilimumab in monotherapy improved overall survival (OS) compared with gp100 vaccine monotherapy (10.1 mo vs. 6.4 mo). However, more irAEs were noticed with ipilimumab treatment. The combination of ipilimumab and gp100 did not improve OS as compared with ipilimumab alone.³⁹ In another randomized phase III trial ipilimumab (10 mg/kg) combined with dacarbazine (850 mg/mq) demonstrated a modest but statistically significant improvement in OS compared with dacarbazine (850 mg/mq) plus placebo (11.2 mo vs. 9.1 mo). A higher incidence of total adverse events was recorded in the ipilimumab–dacarbazine group compared with dacarbazine–placebo including elevation of alanine aminotransferase levels (in 29.1% of patients vs. 4.4%), elevation of aspartate aminotransferase levels (26.7% vs. 3.2%), diarrhea (32.8% vs. 15.9%), pruritus (29.6% vs. 8.8%), and rash (24.7% vs. 6.8%). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P < 0.001).⁴⁰

Subsequently, ipilimumab was approved by the FDA in 2011 for the treatment of unresectable or metastatic melanoma. Similar to other types of immunotherapy, ipilimumab demonstrates durable responses in a small subset of patients. Prieto et al. reported on 177 patients treated with ipilimumab in three different trials. 56 patients received ipilimumab with gp100 peptides, 36 patients received ipilimumab with interleukin-2, and 85 patients received ipilimumab with intrapatient dose-escalation and were randomized to receive gp100 peptides. Out of these 177 patients, 9% experienced a complete response and all but one were durable during follow-up ranging from 54 to 99 mo. Responses were most frequently observed in patients who received a combination of HD-IL2 (720 000 IU/kg) and ipilimumab.⁴¹

First results with tremelimumab showed promising activity in phase I and phase II studies. Although, a subsequent phase III randomized trial comparing tremelimumab to chemotherapy (dacarbazine or temozolamide) in 655 patients with advanced melanoma revealed a not significant prolonged overall survival among patients treated with tremelimumab (11.8 mo with tremelimumab vs. 10.7 mo with chemotherapy, P = 0.73).⁴² The failure of tremelimumab to improve outcome may be attributed to restrictive inclusion criteria of the study: patients with elevated LDH >2× upper limit of normal, a known negative prognostic indicator, were excluded from the control cohort, making the study populations unbalanced in terms of baseline prognostic factors. This restriction was not present in the ipilimumab phase III trial.⁴³

Anti-CTLA-4 antibody in adjuvant therapy

In a phase II trial, 75 patients with resected stage IIIC/IV melanoma were treated with ipilimumab to assess the safety and feasibility of this drug in an adjuvant setting.⁴⁴ Improved outcomes in terms of relapse-free survival and overall survival were reported compared with historical data; irAEs were generally reversible and appeared to be associated with improved relapse-free survival.⁴⁴ The European Organisation for Research and Treatment of Cancer (EORTC) melanoma group is conducting a phase III trial (EORTC 18071) where resected high-risk patients are randomized to ipilimumab treatment (dose 10 mg/kg every 3 wk for 4 cycles, then every 12 wk for a total of 3 y treatment) or to placebo in order to determine whether adjuvant ipilimumab can prevent disease recurrence. Recruiting has been completed and the results are pending.³⁵ In addition, a cooperative group trial is currently open to compare adjuvant ipilimumab to high-dose interferon α-2b in treating patients with high-risk stage III or stage IV melanoma (ECOG 1609).³⁵ Given the minimal impact of interferon in reducing disease recurrence, this study could provide additional evidence if immunotherapies have the potential to positively influence the immune system to eradicate minimal to microscopic residual disease resulting in prolonged OS.

CD40 agonist

CD40 is a co-stimulatory molecule expressed on dendritic cells, B cells, and monocytes (Fig. 3). Its ligand, CD40L, is expressed on CD4⁺ T cells. The interaction of CD40–CD40L triggers T-cell activation. CD-870 873 is a monoclonal antibody targeting CD40. In a phase I study, the administration of CD-870 873 was associated with the induction of melanoma antigen-specific T cells, which is believed to be the mechanism of action leading to partial responses which were observed in 27% of patients with metastatic melanoma. The most common adverse event was cytokine release syndrome (grade 1 to 2) which included chills, rigors, and fever.⁵³ Preclinical data suggest a synergy between chemotherapy and CD40 agonists.⁵⁴ In a phase I 32 patients affected by advanced solid tumors were treated with a combination of CP-870 893, paclitaxel and carboplatin. Out of them, 25 patients were affected by metastatic melanoma. Six of the 30 evaluable patients (20%) had a partial response and half of them were melanoma patients.⁵⁵ An ongoing trial is recruiting patients with stage IV melanoma in order to assess the most effective dose of CP-870 893 in combination with tremelimumab and the related side effects (NCT01103635).³⁵

CD137 agonist

CD137 is an inducible T-lymphocyte surface molecule of the tumor necrosis factor (TNF) receptor superfamily. Its ligand, CD137L, can be expressed by most immune and many non-immune cells as a transmembrane protein (Fig. 3). CD137 signaling enhances T-lymphocyte proliferation and T-helper-1 cytokine production, protecting CD8⁺ T-lymphocytes from apoptosis. A phase I–II study of BMS663513, a human monoclonal antibody agonist of CD137, showed clinical activity with partial remission and stable disease in a subset of patients. However, a high incidence of grade 4 hepatitis was reported and the study had to be discontinued.⁵⁶

Agonistic antibodies targeting OX40

OX40 and its ligand, OX40L (Fig. 3), are key TNF members that augment T-cell expansion, cytokine production, and cell survival. OX40 is a co-stimulatory molecule expressed transiently on the surface of T cells. Agonistic antibodies targeting OX40 have been shown to have antitumor activity.⁵⁷ A phase I with a proof-of-concept phase II trial was initiated to study in patients with unresectable or metastatic melanoma the combination of OX40 and ipilimumab, but the phase II trial to assess the immune system response to treatment with OX40 antibodies in monotherapy was withdrawn prior to enrollment due to changes in the development plan for the OX40 antibody (NCT01416844).³⁵

Anti-LAG-3 antibody

Lymphocyte activation gene-3 (LAG-3) is a transmembrane protein that binds MHC class II molecules, enhances regulatory T-cell activity, and negatively regulates cellular proliferation, activation, and homeostasis of T cells (Fig. 3).⁵⁸ Further studies revealed a synergy between PD-1 and LAG-3 pathways to induce tolerance to self and tumor antigens.⁵⁹ Therefore, the dual blockade of these molecules might be a promising combinatorial strategy for cancer treatment. Moreover, melanoma cells often express MHC class II molecules, and the LAG-3-MHC II interaction protects tumor cells from apoptosis.⁵⁹ Targeting LAG-3 could serve as a bidirectional way to prevent tumor immune escape; however, the effects on autoimmunity are yet to be explored. A clinical trial to assess safety of anti-LAG-3 with or without anti-PD-1 in patients with solid tumors is currently recruiting patients (NCT01968109).³⁵

Anti-TIM-3 antibody

T-cell immunoglobulin mucin-3 (TIM-3) is another inhibitory receptor expressed on a subset of tumor reactive T cells. Blockage of TIM-3 has been shown to improve the function of anti-tumor T cells in different experimental models (Fig. 3). These findings provide the rationale for the clinical development of agents targeting these molecules. Interestingly, TIM-3 is frequently co-expressed with PD-1, and TIM-3/PD-1 expressing cells represented the majority of tumor-infiltrating T cells.⁶⁰ Combined targeting of the TIM-3 and PD-1 pathway will be an interesting future treatment approach, but to date clinical trials are not on going yet.