Abstract
BackgroundHDIL-2 is approved for advanced melanoma based on its durable antitumor activity. MAGE-A3 cancer immunotherapeutic (MAGE-A3 CI) is a recombinant MAGE-A3 protein combined with an immunostimulant adjuvant system and has shown antitumor activity in melanoma. We assessed the safety and anti-tumor activity of HDIL-2 combined with MAGE-A3 CI in advanced melanoma.MethodsPatients with unresectable Stage III or Stage IV MAGE-A3-positive melanoma were enrolled in this phase II study. Treatment included an induction phase of MAGE-A3 CI plus HDIL-2 for 8 cycles followed by a maintenance phase of MAGE-A3 CI monotherapy. The primary endpoints were safety and objective response assessed per RECIST v1.1. Immune biomarker and correlative studies on tumor and peripheral blood were performed.ResultsEighteen patients were enrolled. Seventeen patients were evaluable for safety and sixteen for response. Responses occurred in 4/16 (25%) patients with 3 complete responses, and stable disease in 6/16 (38%) patients with a disease control rate of 63%. The median duration of response was not reached at median follow-up of 36.8 months. Induction therapy of HDIL-2 + MAGE-A3 CI had similar toxicities to those reported with HDIL-2 alone. Maintenance MAGE-A3 monotherapy was well-tolerated. Increased immune checkpoint receptor expression by circulating T regulatory cells was associated with poor clinical outcomes; and responders tended to have increased tumor infiltrating T cells in the baseline tumor samples.ConclusionsThe safety profile of HDIL-2 + MAGE-A3 CI was similar to HDIL-2 monotherapy. Maintenance MAGE-A3 CI provides robust anti-tumor activity in patients who achieved disease control with induction therapy. Immune monitoring data suggest that MAGE-A3 CI plus checkpoint inhibitors could be a promising treatment for MAGE-A3-positive melanoma.Trial registrationClinicalTrials.gov, NCT01266603. Registered 12/24/2010, https://clinicaltrials.gov/ct2/show/NCT01266603
Highlights
High-dose interleukin-2 (HDIL-2) is approved for advanced melanoma based on its durable antitumor activity
Seventeen patients were evaluable for safety and sixteen for response because one patient received one cycle of HDIL-2 without ever receiving the MAGE-A3 MAGE-A3 cancer immunotherapeutic (CI)
Our study showed that the combination of MAGE-A3 CI with HDIL-2 has an acceptable safety profile
Summary
HDIL-2 is approved for advanced melanoma based on its durable antitumor activity. MAGE-A3 cancer immunotherapeutic (MAGE-A3 CI) is a recombinant MAGE-A3 protein combined with an immunostimulant adjuvant system and has shown antitumor activity in melanoma. We assessed the safety and anti-tumor activity of HDIL-2 combined with MAGE-A3 CI in advanced melanoma. A prior study has demonstrated that combining a peptide tumor vaccine (gp100) with HDIL-2 can improve the response rates and prolong overall survival (OS) compared to HDIL-2 monotherapy by priming the immune system to tumor-specific antigens [11]. Antitumor activity of MAGE-A3 CI was demonstrated in phase II studies in multiple malignancies, including metastatic melanoma, and MAGE-A3 CI has been shown to induce both humoral and cellular immune responses against the MAGE-A3 antigen [13,14,15]
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