Safety, Correlative Markers, and Clinical Results of Adjuvant Nivolumab in Combination with Vaccine in Resected High-Risk Metastatic Melanoma

Abstract

Purpose The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. Experimental Design HLA-A*0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies. Results Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4+/CD4+, CD25+Treg/CD4+, and tetramer specific CD8+ T-cell populations were observed with treatment (P < 0.05). Trends for lower baseline myeloid-derived suppressor cell and CD25+Treg/CD4+ populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS. Conclusions Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study.

The importance of correctly timing cancer immunotherapy

“…Indeed, treatment with a multi-peptide tumor-epitope vaccine and PD-1 antibody (nivolumab) was well tolerated in patients with resected high-risk metastatic melanoma. Furthermore, immunological activity, such as increased antigen-specific CD8 + T-cells but also increased frequencies of CD25 + or CTLA-4 + CD4 + T-cells, was associated with promising survival results [82]. Preclinical evidence has shown that TEGVAX vaccine, which is an IFNγ-inducing cancer vaccine combined with GM-CSF and TLR agonists, is associated with DC activation and an increase in the number of tumor-specific IFNγ-producing tumor-infiltrating T-cells [83].…”

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

“…[13][14][15] It is well documented that Th cells are key orchestrators of immunity and that their activity is necessary for effective antitumor responses. Th cells promote survival of CD8…”

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

“…21-23 We have recently reported that patients receiving dacarbazine (DTIC) one day before peptide (Melan-A and gp100)-vaccination plus interferon (IFN)-α show a progressive enhancement of the TCR repertoire diversity of Melan-A-specific CD8 + T cells, accompanied by the maintenance of highly-avid and beneficial anti-tumor activity, as compared with cells isolated from patients receiving vaccination alone. 18 These highly anti-tumor reactive and multifunctional CD8 + T cells were not impaired by the presence of a high level of PD-1 and showed an AKT activation pathway sustained by the inducible co-stimulator (ICOS) molecule.…”