RT Journal Article
SR Electronic
T1 Intratumoral talimogene laherparepvec injection with concurrent preoperative radiation in patients with locally advanced soft-tissue sarcoma of the trunk and extremities: phase IB/II trial
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e003119
DO 10.1136/jitc-2021-003119
VO 9
IS 7
A1 Varun Monga
A1 Benjamin J Miller
A1 Munir Tanas
A1 Sarag Boukhar
A1 Bryan Allen
A1 Carryn Anderson
A1 Laura Stephens
A1 Stacey Hartwig
A1 Steven Varga
A1 Jon Houtman
A1 Lei Wang
A1 Weizhou Zhang
A1 Omar Jaber
A1 Jon Thomason
A1 David Kuehn
A1 Maheen Rajput
A1 Catherine Metz
A1 K.D. Zamba
A1 Sarah Mott
A1 Chinemerem Abanonu
A1 Sudershan Bhatia
A1 Mohammed Milhem
YR 2021
UL http://jitc.bmj.com/content/9/7/e003119.abstract
AB Background Soft-tissue sarcomas (STS) in the extremities and trunk treated with standard-of-care preoperative external beam radiation therapy (EBRT) followed by surgical resection are associated with local and distant relapses. In preclinical studies, oncolytic virotherapy in sarcoma has demonstrated antitumor effects via direct intratumoral oncolysis and cytotoxic T-cell–mediated immune responses. Talimogene laherparepvec (TVEC) is a replication-competent, immune-enhanced, oncolytic herpes simplex virus type 1 engineered for intratumoral injection; it has been approved by the FDA for the treatment of locally advanced and metastatic melanoma.Methods We explored a novel combination of TVEC with standard-of-care EBRT administered preoperatively in patients with locally advanced STS of the extremities and trunk in a phase IB/II clinical trial. Thirty patients with primary STS >5 cm for which EBRT was indicated to achieve negative margins were enrolled. FDA-approved TVEC doses were used. Immune correlative studies in peripheral blood, biopsy and resected tumor tissues were performed.Results No dose-limiting toxicity was observed. Adverse events were similar to those reported in prior studies with TVEC. One patient with myxoid liposarcoma exhibited a partial response. Seven of the 29 (24%) evaluable patients achieved 95% pathological necrosis. None of the patients developed a herpes infection due to the treatment. Eight of the 29 (27%) patients developed postoperative wound complications, which is consistent with previous studies. None of the patients developed local recurrence after surgical resection of the primary sarcoma. 2-year progression-free and overall survival were 57% and 88%, respectively. Caspase-3 demonstrated increased expression of both in TVEC-treated tissue samples as compared with control samples treated with radiation alone.Conclusion Preoperative intratumoral TVEC with concurrent EBRT for locally advanced STS is safe and well-tolerated. This combination treatment may enhance immune responses in some cases but did not increase the proposed rate of pathological necrosis. The Caspase-3 biomarker may be associated with a positive effect of TVEC in sarcoma tumor tissue and should be explored in future studies.Trial registration number NCT02453191.Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. All of the individual participant data collected during the trial, the study protocol, statistical analysis plan, informed consent, and clinical study report after deidentification have been made available indefinitely at https://clinicaltrials.gov/ct2/show/NCT02453191?term=NCT02453191&draw=2&rank=1.