(P 115) EFFICACY AND CORREALTIVE ANALYSIS OF USING NEOADJUVANT INTRATUMORAL HIGH DOSE TALIMOGENE LAHERPAREPVEC (TVEC) WITH CONCURRENT RADIATION IN HIGH-RISK EXTREMITY AND TRUNK SOFT-TISSUE SARCOMAS

Objective: Intratumoral oncolytic virus Talimogene Laherparepvec (TVEC) given concurrently with standard of care neoadjuvant external beam radiation (EBRT) has previously been shown to be safe for treatment of localized high risk soft tissue sarcoma (STS). TVEC probably enhances anti-tumor immune responses through both direct infection and GM-CSF. At a given time 4mL of 108 PFU/mL is the maximum volume of TVEC approved by FDA for injection of melanoma lesion. Given the large size of primary sarcomas, in this study we used 8mL of 108 PFU/mL of TVEC injection after initial seroconverting dose to achieve better pathological responses in this study. We report the efficacy and immune correlates of this single center phase IB/II study of TVEC 8 mL of 108 PFU/mL dosing, in addition to EBRT as neoadjuvant treatment for high-risk extremity and trunk STS.

Methods: A total of 8 patients with locally advanced high risk (size > 5 cm and Grade >/= 2) STS of the extremities and trunk were treated with intratumoral TVEC in addition to standard-of-care EBRT followed by surgical resection. EBRT doses of 50 Gy were delivered over 25 fractions, in addition to weekly TVEC dosed at 8 mL of 108 PFU/mL after the first seroconverting dose of 4mL of 106 PFU/mL. Resection of the tumor was performed 4-6 weeks after completion of EBRT. Tumor responses were assessed as per RECIST 1.1 from baseline to pre-operative imaging. Fresh tumor biopsies were obtained at the time of diagnosis prior to starting treatment and resected tumor tissue was obtained at the time of primary tumor resection. Peripheral blood specimens were obtained at baseline, at the end of radiation, and pre-operatively. Using flow cytometry immune cell studies were performed in disaggregated tissue specimens as well as peripheral blood samples. Trial accrual was stopped after 8 patients. Comparator tumor samples from patients undergoing only standard EBRT were taken as part of a separate study.

Results: Of the 6 patients treated in Phase 1, 0 out of 6 experienced a dose limiting toxicity. Adverse events (AEs) attributed to TVEC included grade 3 fatigue (12.5%) and dermatitis (12.5%). Treatment related grade 1-2 AEs included nausea (37.5%), chills (75.0%), anorexia (25.0%), fever (62.5%). Of the eight patients, four patient tumor specimens (50%) achieved >90% tumor necrosis. Three (37.5%) patient tumors achieved a partial response (undifferentiated sarcoma, dedifferentiated liposarcoma and myxoid round cell liposarcoma) and 5 patients had stable disease. Granzyme B producing CD8+ T cells in the blood were noted to increase between week 1 and week 8 (p < 0.05) of treatment. A strong positive correlation was noted between granzyme B+ CD8+ T cells in the blood at 8 and 12 weeks of treatment vis a vis in the resected tumor. CD8+ T cells were noted to be higher in TVEC+ EBRT treated tumors relative to EBRT alone treated comparator tumor samples (p < 0.05). In addition, an increase in CD8+ T cells was evidenced between the pre-treatment biopsy and the post treatment resected tumor among TVEC+ EBRT treated (p < 0.01). The CD4+ T cell population was significantly reduced in the surrounding tissue compared to the tumor (p < 0.05). Cytokine analysis in the blood revealed that higher pre-treatment Epidermal Growth Factor was associated with higher tumor necrosis (p < 0.05).

Conclusion: Neoadjuvant intratumoral TVEC at 8 mL of 108 PFU/mL dosing with concurrent EBRT increased pathological necrosis rate relative to EBRT alone for locally advanced STS. Intratumoral TVEC treatment in addition to EBRT increases cytotoxic CD8+ T cells in STS compared with EBRT alone treated and pre-treatment biopsy sarcoma tissue. Overall, no new safety signals were observed. Higher doses of TVEC with EBRT should be explored in STS.