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The science and practice of human immunology

The science and practice of human immunology

Letter From the Website Medical Editor - What's New in Immunotherapeutics

Advanced melanoma treatment by immunotherapy

Melanoma is the most lethal form of skin cancer. Metastasis represents the most significant cause of death from the disease. Advanced metastatic melanoma has been resistant to conventional cytotoxic chemotherapy, indicating the urgent need for new treatments.

The concept of using immunotherapeutic approaches to treat melanoma has long been considered. The rationale comes from the knowledge that clinically meaningful tumor regression can be achieved in a minority of patients using high-dose IL-2 for metastatic melanoma1 and high-dose IFN-a for resected, high-risk melanoma.2 Despite these treatments, no consistent survival improvement had been demonstrated and the need for more effective immune-based therapies remained a clear priority.

Recently, immune checkpoint blockade has become a major focus in the immune-based therapy of cancer, particularly melanoma. This concept involves inhibition of immune checkpoints that normally function to control excessive immune activation but also appear to be a means by which tumors evade the immune system. Over the past few years, with the identification of novel therapeutic targets for immune checkpoint blockade, immunotherapy has dramatically changed the landscape for late-stage treatment options of melanoma.

A particularly important immune checkpoint receptor is cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a negative regulator of the activated immune system. The immune-based treatment with ipilimumab (Yervoy®), a monoclonal antibody against CTLA-4, has extended survival of patients with metastatic melanoma. In a vaccine-controlled phase III trial of patients with metastatic melanoma, second-line administration of ipilimumab significantly extended overall survival from 6.4 months to 10.1 months. Although the objective response rate was 10.9%, 60% of these responders controlled their disease at 2 years.3 In the first-line setting, administration of ipilimumab with the chemotherapeutic agent dacarbazine led to a statistically significant median survival benefit of 2 months compared with dacarbizine monotherapy and the response rate 15% in a phase III trial of patients with advanced melanoma.4 These studies led to the FDA approval of ipilimumab in 2011 as the first immune checkpoint inhibitor. More recently, pooled analysis of survival among patients with advanced melanoma treated with ipilimumab monotherapy in either phase II or phase III trials demonstrated a 3-year survival rate of 22% which is further stratified as 20% for pretreated patients and 26% for treatment-naïve patients, suggesting that durable benefit is achieved in a minority of patients.5 Toxicity with this treatment was high and included severe immune-related adverse events occurring in 10-20% of patients such as colitis, endocrinopathies, dermatitis, hepatitis and neurotoxicity. However, these adverse events are quite distinct from the toxicity profile of cytotoxic chemotherapy and are generally reversible with corticosteroids, anti-TNF monoclonal antibodies and mycophenylate mofetil.

Another key inhibitory receptor present on activated T cells is a molecule called programmed death 1 (PD-1). Its ligands, PD-L1 and PD-L2, found on antigen-presenting cells, macrophages, T cells and B cells are upregulated at the time of T cell activation. PD-L1 is also expressed by many tumors including melanoma.6 The interaction between PD-1 and PD-L1 in cancer causes T-cell apoptosis, limits T-cell expansion and inhibits production of IL-2 and IFN-g.7 Inhibiting this immune modulatory axis, therefore, was hypothesized to induce more specific antitumor responses and mitigate autoimmune toxicity. Indeed, targeting the PD-1/PD-L1/PD-L2 axis with antibodies against PD-1 such as nivolumab (OPDIVO®), pembrolizumab/lambrolizumab (KEYTRUDA®) has offered results that are more promising than anything observed with melanoma immunotherapy in early phase clinical trials before and represented a new era in cancer care. A 31% objective response rate was reported in advanced melanoma patients treated in a phase I/II trial of nivolumab, with estimated median response duration of 2 years.8 A phase III study with nivolumab versus dacarbizine as first-line treatment in melanoma demonstrated significant improvements in overall survival and progression-free survival in previously untreated patients with metastatic melanoma without the serine/threonine-protein kinase B-raf proto-oncogene BRAF mutation.9 Although the objective response rate was greater in the PD-L1+ subgroup (52.7%) than in PD-L1- subgroup (33.1%), a survival benefit compared with dacarbazine was observed in both subgroups. Similarly, early phase results with lambrolizumab with varying dosing schedules in 135 patients with advanced melanoma showed response rate as high as 81%.10 These striking results have led the FDA approval of pembrolizumab (September 2014) and nivolumab (December 2014) for the treatment of patients with unresectable or metastatic melanoma. Less frequent than with anti-CTLA-4 therapy, grade 3/4 immune-related adverse events with anti-PD-1 therapy included pneumonitis, colitis, hepatitis, renal and thyroid dysfunction. Toxicity was not cumulative and almost exclusively occurred in the first 6 months of therapy and could be reversed with close monitoring and appropriate management.

Moreover, combination of CTLA-4 and PD-1 blockade (based on their distinct mechanisms of action) was tested in a phase I study where ipilimumab and nivolumab were administered either concurrently or sequentially. Both regimens showed promising clinical activity, but more interestingly, the concurrent treatment achieved deep tumor regressions of more than 80% in 53% of patients who received the highest acceptable dose.11 Multiple phase III trials in patients with melanoma are currently underway and will likely shed light on the optimal sequencing versus combining of PD-1- and CTLA-4-directed therapies. The progress seen in melanoma so far would suggest that the long-term gains from such an approach could be promising. Considering that patients with melanoma brain metastases have been almost universally excluded from clinical trials, immunotherapy efficacy suggests that in the future more specific clinical trials will be necessary for these patients if the eligibility criteria are not changed. There are now greater numbers of clinical trials studying anti-PD-1 or anti-PD-L1 monotherapy or combinations in patients with bladder, non-small cell lung and renal cancers that may result in additional indications for this approach. This therapy has also achieved promising results in patients with hematological malignancies: nivolumab resulted in the response rate of 87% in a small phase I study in the patients with relapsed/refractory Hodgkin’s lymphoma.12

CTLA-4 and PD-1 are undoubtedly the “godfathers” of immune checkpoint13 but a plethora of co-stimulatory (ICOS, 4-1BB, OX-40) and co-inhibitory (BTLA, LAG3, TIM3) molecules have now been identified. The addition of co-stimulatory signals to T cells using agonists to OX-40 or 4-1BB in conjunction with checkpoint inhibition could add significantly more anti-tumor efficacy. Some of these molecules are still in preclinical development, whereas others have already entered early phase clinical trials in cancer immunotherapy. Personalizing immunotherapy based on quantification of immune infiltrates for co-stimulatory and co-inhibitory molecules may help to optimize treatment choices and sequencing in individual patients and will be the beginning of another new era in the fight against cancer.


1.         Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 1994; 271:907-13.

2.         Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14:7-17.

3.         Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711-23.

4.         Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364:2517-26.

5.         Ascierto PA, Simeone E, Sileni VC, Pigozzo J, Maio M, Altomonte M, et al. Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort. J Transl Med 2014; 12:116.

6.         Haile ST, Bosch JJ, Agu NI, Zeender AM, Somasundaram P, Srivastava MK, et al. Tumor cell programmed death ligand 1-mediated T cell suppression is overcome by coexpression of CD80. J Immunol 2011; 186:6822-9.

7.         Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ, Mor A. Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol 2014; 153:145-52.

8.         Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443-54.

9.         Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372:320-30.

10.       Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369:134-44.

11.       Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369:122-33.

12.       Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015; 372:311-9.

13.       Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12:252-64.