Updated results from an ongoing phase 1/2a study of T3011, an oncolytic HSV expressing IL-12 and PD-1 antibody, administered via IT injection as monotherapy or combined with pembrolizumab in advanced solid tumors.
Authors: Niu Jiaxin , Kaufman Howard L. , Kichenadasse Ganessan , Haydon Andrew Mark , Barve Minal A. , Ganju Vinod , Buchbinder Elizabeth Iannotti , Spira Alexander I. , Pang Weijia , Fu Wenmin , Zhao Min , Kirkwood John M. M. 
Published: June 2023

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Background: T3011 is a recombinant HSV-1 oncolytic virus expressing both IL-12 and anti-human PD-1 antibody. Upon injection, locally produced IL-12 induces IFN-γ production, enhances the oncolytic activity of NK cells and cytotoxic T lymphocytes, promotes anti-angiogenesis and inhibits tumor growth. PD-1 antibodies act as immune checkpoint inhibitors to augment tumor-killing activity of T-cells. Here we report the updated results from an open-label, dose escalation and expansion study of T3011 administered via intratumoral injection as monotherapy or in combination with intravenous pembrolizumab. Methods: Pts with pathologically confirmed recurrent or metastatic malignancy after failure of SOC were enrolled and received T3011 monotherapy (1*106-5*107 PFU/mL Q2W) or in combination with pembrolizumab (Lead-in T3011 1*106 PFU/mL Q2W monotherapy for 2 cycles followed by combination therapy Q3W). Pts with documented progression on T3011 monotherapy may cross over to receive combination therapy at the discretion of the investigator. The primary endpoints were safety and tolerability. Key secondary endpoints included confirmed ORR, DCR, DOR, PFS by investigator per RECIST1.1; OS; PD and PK. Results: As of 17 Jan 2023, 29 pts received T3011 alone or in combination with pembrolizumab, the median follow-up was 14.1 (1.2-27.6) months. No DLTs were reported. Any treatment-related adverse events (TRAEs) occurred in 75.9% (22/29) of pts (≥G3 in 10.3%). Treatment-related SAEs occurred in 3.4% (1/29). Most frequent TRAEs (≥10%) were pyrexia (27.6%), fatigue (20.7%) and chills, injection site pain, arthralgia, nausea, headache (10.3% each). No additional safety signals were observed with combination therapy. 12 advanced melanoma pts failing prior PD-1 or PD-1/CTLA-4 combination treatment received 5*107 PFU/mL of T3011 monotherapy. The confirmed ORR and DCR were 25.0% (3/12) and 33.3% (4/12), respectively. 12-month PFS rate was 36.4%. 6 of these pts were re-challenged with immunotherapy with T3011 (5*107 PFU/mL) combined with pembrolizumab after progressing on T3011 monotherapy, 1 pt achieved PR after 4 months lasting > 8 months at data cutoff. 15 pts had tumor tissues for PD analysis. Increased CD8+ cells were observed in 46.7% (7/15) of all pts and 50% (5/10) of melanoma pts. It appeared to be more pronounced in pts with PR and SD, 66.7% (6/9) in all pts and 80% (4/5) in melanoma pts, respectively. Notably, the increment of CT8+ cells in 2 melanoma pts with PR was over 15 folds. Conclusions: Both T3011 IT monotherapy and combination therapy with pembrolizumab were safe and tolerable. The efficacy of T3011 in immune-resistant melanoma was encouraging. Our data suggest T3011 may modify the tumor microenvironment and overcome immune resistance. Clinical trial information: NCT04370587 .