Inclusion Criteria:
* Subject has provided informed consent.
* Histologically confirmed diagnosis of locally advanced STS that is unresectable with clear wide margins, for which preoperative radiotherapy is considered appropriate.
EXAMPLES:
* Resectable stage IIB, III, and IV disease that are not suitable for surgically resection alone due to inability to achieve clear margins.
* Including metastatic (stage IV) disease for which radiotherapy and surgical resection are indicated.
* Except certain histologic subtypes: GIST, Desmoid, Ewing sarcoma, Kaposi sarcoma, bone sarcomas and myxoid liposarcomas (Grade 1).
* Previous treatment: prior systemic anti-cancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy are allowed provided therapy completed at least 1 year prior to enrollment.
* No prior Talimogene laherparepvec or tumor vaccines allowed.
* No prior radiation to the same tumor bed allowed.
* Age ≥18 years.
* Both men and women of all races and ethnic groups are eligible for this trial.
* ECOG performance status ≤1.
* Patient must have measurable disease:
* Tumor size at least ≥ 5 cm in the longest diameter as measured by CT scan or MRI for which radiation is feasible.
* Patient must have injectable disease (direct injection or ultrasound guided).
Exclusion Criteria:
* Certain histologic subtypes: GIST, Desmoid, Ewing sarcoma, Kaposi sarcoma bone sarcomas and low grade myxoid liposarcomas ( Grade 1).
* History or evidence of sarcoma associated with immunodeficiency states (e.g.: Hereditary immune deficiency, HIV, organ transplant or leukemia).
* Subjects with retroperitoneal and visceral sarcoma.
* History or evidence of gastrointestinal inflammatory bowel disease (ulcerative colitis or Crohn's disease) or other symptomatic autoimmune disease including, inflammatory bowel disease, or history of any poorly controlled or severe systemic autoimmune disease (i.e., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, type I diabetes, or autoimmune vasculitis).
* History of other malignancy within the past 3 years except treated with curative intent and no known active disease present and has not received chemotherapy for ≥ 1 year before enrollment/randomization and low risk for recurrence.
* History of prior or current autoimmune disease.
* History of prior or current splenectomy or splenic irradiation.
* Active herpetic skin lesions
* Require intermittent or chronic treatment with an anti-herpetic drug (e.g., acyclovir), other than intermittent topical use.
* Any non-oncology vaccine therapies used for the prevention of infectious disease within 28 days prior to enrollment and during treatment period.
* Concomitant treatment with therapeutic anticoagulants such as warfarin. Patients on therapeutic low molecular weight heparin may be allowed provided the dose can be safely held as per the treating investigator on the morning of scheduled intratumoral injection and can be resumed 12 hours after the procedure
* Known human immunodeficiency virus (HIV) disease (requires negative test for clinically suspected HIV infection).
* Acute or chronic hepatitis B or hepatitis C infection (requires negative test for clinically suspected hepatitis B or hepatitis C infection).
* Evidence of hepatitis B -
1. Positive HBV surface antigen (indicative for chronic hepatitis B or recent acute hepatitis B).
2. Negative HBV surface antigen but positive HBV total core antibody (indicative for resolved hepatitis B infection or occult hepatitis B) and detectable copies of HBV DNA by PCR (detectable HBV DNA copies suggest occult hepatitis B).
* Evidence of hepatitis C -
1\. Positive HCV antibody and positive HCV RNA by PCR (undetectable RNA copies suggest past and resolved hepatitis C infection).
* Female subjects who are pregnant or breast-feeding, or planning to become pregnant during study treatment and through 3 months after the last dose of study treatment.
* Female subjects of childbearing potential or male subjects who are unwilling to use 2 highly effective methods of contraception during study treatment and through 3 months after the last dose of study treatment. See Section 7.5 for more details.
* Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(s).
* Other investigational procedures while participating in this study that could affect the primary objective of the study as determined by the PI are excluded.
* Subject previously has entered this study.
* Patients who are receiving any other investigational agents.
* Evidence of CNS metastases.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to talimogene laherparepvec.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Patients on or requiring immunosuppressive therapies.
* Any of the following laboratory abnormalities:
* Hemoglobin \< 9.0 g/dL
* Absolute neutrophil count (ANC) \< 1500 per mm3
* Platelet count \< 100,000 per mm3
* Total bilirubin \> 1.5 × ULN
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.5 × ULN
* Alkaline phosphatase \> 2.5 × ULN
* PT (or INR) and PTT (or aPTT) \> 1.5 × ULN
* Creatinine \> 2.0 × ULN
