Case: Dual Immunotherapy Induced Remission in Metastatic Melanoma

Details of a first-in-human case report showed that a patient with melanoma was able to achieve a durable complete response with the combination of two types of immunotherapy.

Researcher Aude G. Chapuis, MD, of Fred Hutchinson Cancer Research Center, and colleagues combined treatment with a bolus of enhanced IL-21-primed polyclonal antigen-specific cytotoxic T lymphocytes and CTLA-4 blockade with the drug ipilimumab. According to the case report, published in the Journal of Experimental Medicine, the patient was refractory to both monoclonal cytotoxic T lymphocytes and anti-CTLA4.

According to the report, research has shown that neither immunotherapy method alone is able to achieve complete and durable remissions in patients with metastatic melanoma. Adoptive transfer of peripheral blood-derived melanoma-reactive CD8-positive cytotoxic T cells alone are not powerful enough to eliminate bulky tumors and treatment with anti–CTLA-4 drugs alone does not sustain remissions.

In the case of this patient, the researchers hypothesized whether combining the two approaches would yield improved response. The patient was a 53-year-old man with melanoma. He had initially undergone wide local excision and inguinal node dissection and was treated with 12 months of adjuvant interferon-alfa. Four years later the patient developed metastases.

His peripheral blood mononuclear cells were collected in anticipation of him undergoing adoptive cell transfer, and he received 4 cycles of high-dose interleukin-2, but his disease progressed. Next, the patient received two infusions of monoclonal MART-1–specific T cells each followed by low-dose interleukin-2; however, the melanoma progressed again. The patient then underwent treatment with ipilimumab and experienced a partial slowing in the growth of the tumor, but developed new metastases within 4 months.

Finally, the patient underwent an infusion with enhanced IL-21-primed anti-tumor T cells, and then received treatment with ipilimumab. According to the report, the patient’s tumor began to respond within weeks of treatment initiation and at year 3, the patient achieved a complete response by response evaluation criteria in solid tumors (RECIST) and immune-related response criteria. The researchers reported that the patient has been disease free for more than 5 years.

The combined approach boosted the number of antitumor T cells circulating in the patient's blood in both the short and long term. Moreover, the enhanced immune response induced by this treatment allowed the patient to develop new types of T cells that attacked the melanoma in additional ways, a phenomenon known as epitope spreading.

“The targeted immune response provided by tumor-specific [cytotoxic T lymphocytes], plus the proinflammatory context fostered by anti–CTLA-4 blockade, were both required for epitope spreading,” the researchers wrote. “Whereas epitope spreading has been demonstrated in some patients receiving anti–CTLA-4 antibody monotherapy, no evidence of antigen spreading or a clinical response was evident in this patient before receiving the combination therapy.”

The patient experienced no serious adverse events. At 12 weeks after initiation of the combined therapy, the progressive reduction in tumor size was associated with the development of vitiligo. The patient had depigmentation of the eyebrows and eyelashes.

“We conclude that combining CTLA-4 blockade with the transfer of well-characterized, robust antitumor [cytotoxic T lymphocytes] represents an encouraging strategy to enhance the activity of the adoptively transferred [cytotoxic T lymphocyte] and induce de novo antitumor responses,” the researchers wrote. “This strategy may hold broad promise for immune checkpoint blockade-resistant melanomas.”