Merkel Cell Carcinoma: Hints of Immune Mediation May Enhance Treatment Options 


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Merkel cell carcinoma is a rare but aggressive skin cancer with poor outcomes and suboptimal therapeutic options. With a 46% mortality rate, it is three times more lethal than melanoma, and its reported incidence is rising.

“Merkel cell carcinoma is a nasty cancer and we have zero FDA-approved therapies for it. We are cautiously optimistic that this will change in the next few years,” said Paul Nghiem, MD, PhD, the Michael Piepkorn Endowed Chair in Dermatology Research at the University of Washington and Fred Hutchinson Cancer Research Center, Seattle. Dr. Nghiem and his colleague at the university and cancer center, Shailender Bhatia, MD, Assistant Professor of Medical Oncology, described emerging insights into Merkel cell carcinoma at the 2013 World Cutaneous Malignancies Congress in La Jolla, California.

An Infectious Etiology?

The fact that Merkel cell carcinoma occurs in the elderly and in immunosuppressed persons suggests an infectious origin. This hypothesis was strengthened in 2008 by the observed association between Merkel cell carcinoma and the genome of a previously unknown polyomavirus, now dubbed Merkel cell polyomavirus.1 Sequences of Merkel cell polyomavirus were detected in 80% of Merkel cell tumors, compared with 16% of control skin tissue samples. The clonal pattern of chromosomal integration into Merkel cell carcinomas pointed to a contributing role for Merkel cell polyomavirus in the pathogenesis of the carcinoma.

“However, while [Merkel cell polyomavirus] exists in the skin of most of us, only 1 in 3,000 persons will get [Merkel cell carcinoma],” Dr. Nghiem noted. He attributed this to a “perfect storm” that involves viral infection, integration mutation, and truncation mutation, perhaps mediated by ultraviolet light or radiation, and blossoming into cancer late in life as a result of immune suppression or senescence.

“The bottom line is that [Merkel cell polyomavirus] often plays a role, but it’s not necessary or sufficient for Merkel cell,” he said. “The question is, are the viral oncoproteins recognized by the immune system?”

Role of the Immune System

The immune system appears to be dysfunctional in the Merkel cell tumor microenvironment. There is downregulation of major histocompatibility complex class 1 on tumor cells, sparse intratumoral CD8-positive T-cell infiltration, and immune exhaustion of tumor-infiltrating lymphocytes. “This provides a strong rationale for immunotherapy,” Dr. Bhatia said.

Genes related to immune responsiveness are upregulated in Merkel cell carcinoma, and infiltration of CD8-positive lymphocytes into the tumor is associated with improved survival. In a study of 146 Merkel cell tumors, Dr. Nghiem and his team showed that patients who demonstrated robust intratumoral CD8-positive infiltration had 100% disease-specific survival, compared with 60% for those with sparse infiltration.2

“If CD8-positive cells have entered and moved at least one cell diameter away from a vessel, that is incredibly protective,” Dr. Nghiem noted. Dr. Bhatia added, “Unfortunately, the majority (~80%) of patients do not have these infiltrates. Even when there is infiltration, those cells appear exhausted. It’s important to understand this immune evasion, in order to be able to harness the immune system for therapeutic use.”

This is indeed supported by the recent findings of increased programmed cell death ligand 1 (PD-L1) in Merkel cell tumors with Merkel cell polyomavirus–specific CD8-positive T cells. This probably represents an important mechanism of immune evasion by the tumor cells, Dr. Nghiem said, suggesting a role for the anti–programmed death (PD)-1/PD-L1 antibodies in treatment.

Harnessing the immune system in treating Merkel cell carcinoma will be important, the speakers predicted. Ongoing or planned immunotherapeutic efforts for treating the disease include adoptive cell therapy using Merkel cell polyomavirus–specific T cells; systemic therapy with ipilimumab (Yervoy), anti–PD-1/PD-L1 antibodies, and 4-1BB (a T-cell activator); and intratumoral injections with the toll-like receptor 4 agonist glucopyranosyl lipid adjuvant–stable emulsion (GLA-SE), interferon beta, and interleukin-12.

Injections of interleukin-12 DNA, facilitated by electroporation, can regress not only the injected lesions but those at distant sites as well, with few side effects. Studies have shown that CD8-positive infiltration occurs in about 50% of patients after treatment, suggestive of a successful immune response, Dr. Bhatia added.

The findings have also led to the development of a serum assay that monitors for recurrence by measuring the concentration of antibodies to the Merkel cell polyomavirus oncoprotein. The test is being validated and should become clinically available soon.

Proper Staging Is Important

Meanwhile, lacking these novel approaches, clinicians need to understand some of the nuances of treating Merkel cell carcinoma with conventional approaches.

Proper staging of disease is important, as one-third of clinically negative nodes are actually microscopically positive. “Stage IA patients still do not have a normal survival time. Even with early-stage disease there are reasons to be concerned,” Dr. Nghiem said.

Dr. Bhatia agreed, noting that 35% of patients diagnosed with local disease die from Merkel cell carcinoma, despite its being potentially curable with surgery and radiotherapy.

In an analysis of 5,823 Merkel cell carcinoma patients from the National Cancer Data Base, 5-year relative survival was 54% (compared to matched controls).3 In the two-thirds of patients who presented with local disease only, even those with tumors ≤ 2 cm had only a 66% relative survival.

“Sentinel lymph node biopsy results in more accurate staging, may have therapeutic implications, and should be considered in all patients,” Dr. Nghiem said. It may not be necessary when the procedure would not change management, when a false-negative result would be more likely, or when prognostic data are not important to the patient.

Additionally, the absence of positive surgical margins should not be falsely reassuring. “Disease can occur several centimeters away from the primary, so negative margins do not ensure a cure, and surgical treatment alone is often not a good plan,” he said.

Excision, usually with radiotherapy, is the recommended local approach. With surgery alone, local recurrence is almost four times greater and regional recurrence is almost three times greater than when radiotherapy is also given.4 But the risk of recurrence is important to determine. Five favorable features likely lower the need for adjuvant radiotherapy: primary tumor ≤ 1 cm, margins pathologically negative, lack of lymphovascular invasion in the primary, lack of profound immune suppression, and negative sentinel node biopsy.

In the adjuvant setting, chemotherapy has not been shown to improve outcomes.

Salvage Therapy

A number of approaches can palliate symptoms or serve as a bridge to enrollment in an immunotherapy trial.

In stage IV disease, chemotherapy remains the standard of care. Although response rates may be high, they are seldom durable and progression-free survival is short. Toxicity can also be significant, especially in the elderly, and there is also the potential for immune suppression. Pazopanib (Votrient) appears to be effective in some patients. When there is evidence of somatostatin receptor expression, somatostatin analogs may produce disease stabilization, without major side effects, Dr. Bhatia said.

Radiotherapy can be effective as salvage treatment. At the University of Washington, a single-fraction 8-Gy approach has resulted in rapid-onset palliation after a convenient 1-day treatment (Fig. 1). In a study of 9 patients with 29 lesions, durable complete responses were achieved in 89% of lesions in patients who were not immunosuppressed and in 36% of lesions among immunosuppressed patients.5

“Merkel cell is a radiosensitive tumor. When we use fractionated radiotherapy, it is possible that subsequent fractions may kill immune cells infiltrating into the tumors from the radiation,” he said. “A high-dose single fraction may be more immunogenic. It’s an exciting approach, especially if we can combine this with systemic immunotherapy.” ■

Disclosure: Drs. Nghiem and Bhatia reported no potential conflicts of interest.

References

1. Feng H, Shuda M, Chang Y, et al: Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319:1096-1100, 2008.

2. Paulson KG, Iyer JG, Tegeder AR, et al: Transcriptome-wide studies of Merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol 29:1539-1546, 2011.

3. Lemos BD, Storer BE, Iyer JG, et al: Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma. J Am Acad Dermatol 63:751-761, 2010.

4. Lewis KG, Weinstock MA, Weaver AL, et al: Adjuvant local irradiation for Merkel cell carcinoma. Arch Dermatol 142:693-700, 2006.

5. Parvathaneni U, Iyer J, Nagase K, et al: Effective and durable palliation using a novel single fraction radiation therapy approach for Merkel cell carcinoma metastatic lesions (abstract). Int J Radiat Oncol Biol Phys 84(suppl):S631, 2012.



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