This phase II trial studies the side effects of talimogene laherparepvec and radiation therapy and to see how well they work in treating patients with newly diagnosed soft tissue sarcoma that can be removed by surgery (resectable). Biological therapies, such as talimogene laherparepvec, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Radiation therapy uses high energy x-rays, photons. electrons, or protons to kill tumor cells and shrink tumors. Giving talimogene laherparepvec and radiation therapy may work better in treating patients with soft tissue sarcoma.

PRIMARY OBJECTIVE:

I. To estimate the pathologic complete necrosis rate (the number of patients with >= 95% necrosis divided by the number of evaluable patients) following preoperative treatment with talimogene laherparepvec (T-VEC) in combination with radiation in patients with localized soft tissue sarcoma including a pre-planned interim safety analysis to assess post-surgical wound complications.

SECONDARY OBJECTIVES:

I. To estimate the toxicity of talimogene laherparepvec (T-VEC) in combination with radiation in localized soft tissue sarcomas, during neo-adjuvant treatment and post-surgical resection wound complications.

II. To estimate the rate of radiologic response, prior to surgery, and extent of surgical resection.

III. To estimate time to surgery, time to progression, time to recurrence, and death.

CORRELATIVE OBJECTIVES:

I. To characterize the clinical outcomes within three distinct histologic subtypes: liposarcoma (excluding myxoid liposarcoma), leiomyosarcoma and undifferentiated pleomorphic sarcoma.

II. To characterize the percentage of tumor necrosis in treated tumors. III. To assess if the combination of preoperative talimogene laherparepvec (T-VEC) with radiation will increase the expression of PD-L1 in soft tissue sarcomas.

IV. To assess the impact of preoperative talimogene laherparepvec (T-VEC) with radiation on the tumor infiltrating and circulating immune cells in patients with soft tissue sarcomas.

OUTLINE:

Patients receive talimogene laherparepvec intratumorally (IT) or via intralesional injection at weeks 1, 4, 6 and 8. Beginning 1 week after the start of talimogene laherparepvec, patients undergo radiation therapy on Monday-Friday of weeks 2-6. Patients undergo collection of blood and a tumor biopsy on study and undergo magnetic resonance imaging (MRI) throughout the trial.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every year for up to 5 years.

Inclusion Criteria:

• Age >= 18 years

  • Note: Because no dosing or adverse event data are currently available on the use of talimogene laherparepvec (T-VEC) in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials

• Newly diagnosed and a histopathologically confirmed potentially resectable soft tissue sarcoma of the extremity or trunk of the following subtypes:

  • Cohort 1: liposarcoma (excluding myxoid liposarcoma)

  • Cohort 2: leiomyosarcoma

  • Cohort 3: undifferentiated pleomorphic sarcoma (UPS) (malignant fibrous histiosarcoma [MFH])

  • NOTE: If local pathology report is suggestive of or suspicious for UPS, study chair and study pathologists may review for eligibility determination.

  • NOTE: Sites permissible for biopsy include

    • Extremities: upper (including shoulder) and lower (including hip)
    • Trunk: Body wall

• Patients must have a histologically determined grade 2 or 3 tumor by the French Federation of Cancer Centers Sarcoma Group (FNCLCC) sarcoma grading system

• Patients must have localized disease with a primary tumor > 5 cm by MRI or computed tomography (CT) scan

• Patients must have a primary tumor that is determined by multidisciplinary team (medical oncology, orthopedic/surgical oncology, and radiation oncology) to require radiation therapy for optimal management prior to surgical resection

• Patients must have a sarcoma in the extremity or trunk in location, which is accessible to direct or ultrasound guided injections

• Karnofsky performance score >= 70

• Absolute neutrophil count (ANC) >= 1500/uL

• Absolute lymphocyte count (ALC) >= 800/uL

• Platelets >= 100,000/uL

• Hemoglobin >= 9 g/dL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN

• Calculated creatinine clearance > 70 mL/min/1.73 m^2

• Patient must have a life expectancy of at least 3 months with appropriate therapy

• Patients must agree to use contraception during study treatment and for 4 months after the end of treatment

  • NOTE: Talimogene laherparepvec (T-VEC), as well as other therapeutic agents used in this trial, may cause fetal harm when administered to a pregnant woman; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• Ability to understand and the willingness to sign a written informed consent document

• Willingness to provide mandatory blood and tissue samples for correlative studies and central pathology confirmation of surgical specimens collected during study participation

• Willingness to provide a tissue sample that is mandatory at the time of surgery (if applicable) and the determination of the primary objective of the study

Exclusion Criteria:

• Patients with localized sarcomas that are not of the extremity or trunk wall (including head/neck, retroperitoneum, visceral organs, peritoneum, pelvis within the confines of the bony pelvis, and tumors arising in bone)

• Patients who have had prior treatment with anti-PD1 or anti-CTLA4 therapy

• Patients with grade 1 non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) tumors of any size are not eligible

• Patients with evidence of active bleeding or bleeding diathesis will be excluded (patients with excess of 2.5 mL of hemoptysis are not eligible)

• Patients requiring any therapeutic anticoagulation

• Patients must have had no prior radiotherapy to tumor-involved sites

• Patients with gross total resection of the primary tumor or who have developed tumor recurrence after gross total tumor resection prior to enrollment are not eligible

• History of serious or non-healing wound, ulcer, or bone fracture

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1)

• Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of talimogene laherparepvec (T-VEC) and during the study

• Previous treatment with talimogene laherparepvec (T-VEC) or any other oncolytic virus

• Patients with metastatic disease

• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to talimogene laherparepvec (T-VEC) or any of its components

• History or evidence of active autoimmune disease (e.g., pneumonitis, glomerulonephritis, vasculitis, or other); or history of active autoimmune disease that has required systemic treatment (i.e., use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) within 2 months of enrollment; (replacement therapy [e.g., thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency] is not considered a form of systemic treatment for autoimmune disease)

  • Evidence of clinically significant immunosuppression such as

    • Primary immunodeficiency state such as severe combined immunodeficiency disease
    • Concurrent opportunistic infection
    • Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 2 months prior to enrollment

• Active herpetic skin lesions or prior complications of herpetic infection (e.g., herpetic keratitis or encephalitis)

• Viral infections requiring intermittent or chronic systemic (intravenous or oral) treatment with an anti-herpetic drug, other than intermittent topical use (e.g., acyclovir)

• Other viral infections

  • Known to have acute or chronic active hepatitis B or hepatitis C infection
  • Known to have human immunodeficiency virus (HIV) infection
  • Prior therapy with viral-based tumor vaccine
  • Received live vaccine within 28 days prior to enrollment

• Patients who are unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for herpes simplex virus (HSV)-1 induced complications such as immunosuppressed individuals, individuals known to have HIV infection, pregnant women, or children under the age of 1 year, during talimogene laherparepvec (T-VEC) treatment and through 30 days after the last dose of talimogene laherparepvec (T-VEC)

• 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 who are pregnant, breastfeeding or plan to become pregnant

  • NOTE: Although no effects on embryo-fetal development have been observed in animal studies, adequate and well-controlled studies with talimogene laherparepvec (T-VEC) have not been conducted in pregnant women; therefore, sexually active patients and their partners must be willing to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of T-VEC