A phase 1/2a study of T3011, an oncolytic HSV expressing IL-12 and PD-1 antibody, administered via intratumoral (IT) injection as monotherapy in advanced solid tumors

2520 Background: T3011, a replication-competent, genetically modified, next-generation oncolytic herpes simplex viruses (oHSV), deletes one copy of ICP34.5 and retains ICP47, thus maximizing replication activity and virulence attenuation of the virus. Moreover, T3011 was inserted with biologically active IL-12 and anti-PD-1 antibody genes. Therefore, while lysing tumor cells, T3011 can significantly improve the tumor microenvironment and elicit the body's specific anti-tumor immunity. Methods: An open-label, dose escalation and expansion study of T3011 administered via IT injection as a single agent in patients (pts) with advanced solid tumors. Pts who progressed on or were intolerable to the standard of care were eligible and received T3011 IT therapy Q2W in several dose cohorts (2.5×10 5 ~ 1×10 8 PFU/mL). The primary endpoints were safety and tolerability. Key secondary endpoints were PK/PD profile, efficacy endpoints including ORR, DCR, DOR, PFS by investigator per RECIST1.1 and OS. Results: As of 18 Jan. 2023, 90 Pts received T3011 monotherapy. Median follow-up time is 5.7(0.5-22.5) months. No DLT events were reported. Treatment-related adverse events (TRAEs) were observed in 66.7% pts (≥G3 TRAEs and treatment discontinuation both in 2.2% [2/90]), and treatment-related SAEs occurred in 2.2% (2/90) pts. The most frequently reported TRAEs (≥5%) were pyrexia (21.1%, 19/90), influenza like illness (8.9%, 8/90), TSH increased (6.7%, 6/90), proteinuria (6.7%, 6/90), facial edema, white blood cell count decreased, AST increased and anemia (5.6%, 5/90, each). MTD was not reached, RP2D was determined as 1x10 8 PFU/mL. Over 80% of pts had viral DNA un-detected in their blood, urine and saliva after injection. Moreover, almost all injection site and occlusive dressing samples that tested positive for viral DNA were confirmed to be free of viral activity. The confirmed ORR was 11% (6/55), DCR was 49% (27/55) in 55 pts (HNSCC, sarcoma, melanoma, breast cancer, etc.) treated under RP2D evaluable for tumor response.The median PFS was 2.8 mos (95%CI: 1.84, 4.60) in all 76 Pts received T3011(RP2D). 19 head and neck squamous-cell carcinoma (HNSCC) pts progressed on platinum-based chemotherapy and anti-PD-1/PD-L1 therapy treated with T3011(RP2D), median PFS was 3.9 mos (95%CI: 0.89, NA;1 pt failed from chemotherapy only for PFS analysis set). 12 HNSCC pts had at least one tumor evaluation post-dose, the confirmed ORR and DCR was 25% (3/12) and 50% (6/12) respectively. Conclusions: The safety profile and clinical compliance of T3011 IT therapy are excellent. T3011 injected locally will not spread to blood, urine and saliva, regional shedding doesn't raise the possibility of transmission to the local and systemic environment. The encouraging anti-tumor activity of T3011 monotherapy in advanced HNSCC pts supports further evaluation in phase II studies. Clinical trial information: NCT05602792 .