Programmed Death Receptor 1 (PD-1)

By regulating effector T cell activity within tissues and tumors, PD-1 functions to protect normal tissues from immune inflammatory responses. PD-1 is expressed by activated T cells and appears to be a more potent inhibitor of T cell response than CTLA-4. When bound to one of its ligands, PD-L1 or PD-L2, PD-1 downregulates the immune system, blocks T cell proliferation, and promotes T cell apoptosis. PD-L1 commonly is overexpressed on melanoma tumors and there is evidence that upregulation of PD-L1 on tumor cells correlates with poor prognosis.5,10


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Table 1. Response Rates and Overall Survival With Ipilimumab15,16

Patients Best Overall Response Median Overall Survival
Previously treated melanoma
Ipilimumab alone (n=137) 10.9% 10.1 mo
Comparator (gp100 vaccine) (n=136) 1.5% 6.4 mo
Hazard ratio for death with ipilimumab
0.66 (P=0.003)
Treatment-naïve advanced/metastatic melanoma
Ipilimumab + dacarbazine (n=250)  15.2%  11.2 mo
Comparator (dacarbazine alone) (n=252)  10.3%  9.1 mo
Hazard ratio for death with ipilimumab 0.72 (P<0.001)

Anti-PD-1 agents are an area of intense research. The furthest along in development are nivolumab (BMS-936558) and lambrolizumab (MK-3475)); both monoclonal antibodies target PD-1 and being studied in patients with advanced melanoma.

Nivolumab is a humanized monoclonal antibody that prevents PD-1 from ligand binding. In a phase 1/2 study, overall response (OR) was 28% among 104 heavily pretreated patients with melanoma. Overall 24-week progression-free survival (PFS) was 41%. Most responding patients had durable (≥1 year) responses. Response appeared to correlate with PD-L1 expression on tumor cells.11Phase 3 trials are under way to confirm these findings.

Phase 1 results from patients with advanced melanoma treated with lambrolizumab were presented in November 2012. In this study, some patients previously had received ipilimumab. The OR rate was 42%, and did not differ between ipilimumab-treated or treatment-naïve patients. Stable disease was seen in 19%.12 A randomized phase 2 study comparing lambrolizumab with dacarbazine is under way.

The antibody BMD-936559 takes a different approach to the PD-1 pathway by blocking PD-L1. In a phase 1 trial, 17% of previously treated advanced melanoma patients (N=55) achieved an OR and 24-week PFS was 42%.13

Novel Challenges with Immunotherapies

Unleashing the immune system presents novel challenges in terms of safety and response assessment. Successful therapy must find a balance to ensure that pumping up response to attack tumors does not excessively harm the patient.5 Unique and potentially severe autoimmune responses have been observed with ipilimumab in clinical practice. Common immune-related adverse events (irAEs) include diarrhea, colitis, rash, vitiligo, pruritis, and damage to nerve or muscle tissue. Grade 3/4 irAEs occur in about 15%. Serious irAEs include enterocolitis, hepatitis, dermatitis, and endocrinopathies.4 A similar pattern is seen with anti–PD-1 and anti–PD-L1 agents; irAEs include pneumonitis, vitiligo, hepatitis, and thyroiditis. These appear to be less frequent than with ipilimumab, however, with grade 3/4 adverse events occurring in 5% to 10% of patients.11-13

Another challenge is that patterns of response differ with these agents than with chemotherapy or tyrosine kinase inhibitors. The pattern with immunotherapies includes a transient worsening of disease (including progression or appearance of new lesions) before disease stabilizes or regresses; a longer time to response; and continued tumor regression for a lengthy period after completion of therapy. Furthermore, some patients who do not meet clinical criteria for OR have clinically relevant long-term stable disease.5,6 Due to the potential of RECIST criteria leading  to premature withdrawal of therapy, specific immune-related response criteria have been proposed to reflect the unique response patterns seen with immunotherapy.14

Conclusion

In blocking CTLA-4 and stimulating T-cell response to melanoma tumor cells, ipilimumab has offered new hope to patients diagnosed with advanced or metastatic disease. It is the first treatment demonstrated to improve survival for these patients. Agents that target the PD-1 pathway are in phase 3 trials after promising results in phase 1/2 studies. Clinical use of ipilimumab has revealed unique challenges with targeted immunotherapies, including unique patterns of response and immune-related adverse events. Going forward, research to identify biomarkers for response or toxicity, optimal response criteria, and additional immune system targets will further elucidate the clinical potential of immunotherapy in treating advanced melanoma.