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

Autor: Kokou D. Zamba, Maheen Rajput, David P. Kuehn, Jon Houtman, Chinemerem Abanonu, Steven Varga, Laura Stephens, Varun Monga, Sarah L. Mott, Weizhou Zhang, Lei Wang, Munir R. Tanas, Omar Jaber, Sudershan K. Bhatia, Catherine M. Metz, Sarag Boukhar, Bryan G. Allen, Jon Thomason, Benjamin J. Miller, Carryn M. Anderson, Stacey Hartwig, Mohammed M. Milhem
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
Cancer Research
medicine.medical_treatment
Herpesvirus 1
Human
0302 clinical medicine
Antineoplastic Agents
Immunological
Immunology and Allergy
Medicine
RC254-282
Tumor Biomarkers
Aged
80 and over
Oncolytic Virotherapy
medicine.diagnostic_test
Soft tissue sarcoma
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Sarcoma
Middle Aged
Oncology
030220 oncology & carcinogenesis
Preoperative Period
Molecular Medicine
Female
Radiology
Talimogene laherparepvec
Adult
medicine.medical_specialty
Immunology
03 medical and health sciences
Biopsy
Humans
Clinical Trials
Aged
Pharmacology
Myxoid liposarcoma
Biological Products
Radiotherapy
business.industry
Phase II as Topic
Extremities
medicine.disease
Oncolytic virus
Clinical trial
Radiation therapy
Oncolytic and Local Immunotherapy
030104 developmental biology
business
Zdroj: Journal for Immunotherapy of Cancer
Journal for ImmunoTherapy of Cancer, Vol 9, Iss 7 (2021)
ISSN: 2051-1426
Popis: BackgroundSoft-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.MethodsWe 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.ResultsNo 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.ConclusionPreoperative 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 numberNCT02453191.
Databáze: OpenAIRE
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