Phase I study of oncolytic virus (OV) MG1 maraba/MAGE-A3 (MG1MA3), with and without transgenic MAGE-A3 adenovirus vaccine (AdMA3) in incurable advanced/metastatic MAGE-A3-expressing solid tumours: CCTG IND.214.
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e14637 Background: OVs display oncolytic activity and boost adaptive cell immunity. MG1MA3 is a Maraba virus modified to express tumour antigen MAGE-A3. MG1MA3, both alone and after immune priming with a MAGE-A3 modified adenovirus (AdMA3) may trigger anti-tumour T-cell responses. Methods: N = 41 patients (pts) with MAGE-A3 expressing solid tumours were evaluated in 3 groups (A) Dose escalation of MG1MA3 iv d1+4, q8w (n = 9); (B) Single fixed dose AdMA3 1e10 pfu IM d1 (n = 6); (C) AdMA3 priming d(-14) followed by dose escalated MG1MA3 (d1+4, q8w) (n = 25). Arm A and C had a 3+3 design. Pre + post treatment blood and tissue biopsies were evaluated for viral and immune markers. Endpoints included MTD/MFD, RP2DL, safety, tolerability, pharmacokinetics, viral delivery and replication. Results: Dose limiting toxicities (hypoxia/dyspnea, vomiting, headache) occurred in 4 pts (2 each Arm A +C). RP2DL for arm C was AdMA3 1e10 pfu IM d(-14) then MG1MA3 1e11 pfu iv d1+4. Common treatment related toxicities on Arm C occurring hours to a few days after MG1MA3 included diarrhea, nausea, vomiting, anorexia, chills, fatigue, fever, flu-like symptoms, hypophosphatemia, headache, and hypotension. Preliminary tumour gene expression results reveal induction of pro-inflammatory genes, including chemokines (CCL2, CCL5, CX3CL1, CXCL10), acute phase response proteins (IL-6, TNF), antigen presenting cell (APC) activation markers (CD80, HLA-A, HLA-B), markers of APC and Natural Killer cell infiltration (CD56, CD68, TLR3), as well as a co-incident decrease in the suppressive cytokine TGF-β. MG1MA3 replication was observed in some pts, inferred by detection of circulating genomes on days 4, 8 and 15 after clearance of the input dose. Induction of anti-tumour immune responses (CD8 T cells and antibodies vs MAGE-A3) was demonstrated in 3 of 6 Arm C pts evaluated to date. In one patient, over 1% of circulating CD8 T cells were directed against MAGE-A3. Conclusions: AdMA3 prime followed by MG1MA3 OV boost is feasible with a defined RP2DL, and capable of inducing potent anti-tumour immune response. Alternate schedules will be evaluated. Clinical trial information: NCT02285816.
