Nivolumab and BO-112 Before Surgery for the Treatment of Resectable Soft Tissue Sarcoma

Inclusion Criteria:

* Written informed consent, and assent where appropriate, must be obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
* Biopsy proven soft tissue sarcoma of the extremity, trunk or retroperitoneum including undifferentiated pleomorphic sarcoma, myxofibrosarcoma, leiomyosarcoma, dedifferentiated liposarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, or pleomorphic rhabdomyosarcoma. Undifferentiated pleomorphic sarcoma encompasses any of the following histologies:

  * Pleomorphic undifferentiated sarcoma
  * Unclassified spindle cell sarcoma
  * Spindle cell sarcoma not otherwise specified
  * Pleomorphic spindle cell sarcoma
  * Pleomorphic fibroblastic sarcoma
  * Undifferentiated high-grade pleomorphic sarcoma
  * Pleomorphic sarcoma with prominent inflammation
  * Pleomorphic sarcoma with giant cells
  * Malignant fibrous histiocytoma (including storiform-pleomorphic and inflammatory subtypes)
  * Fibrosarcoma
* Tumor that is injectable
* Hemoglobin \>= 9 g/dL
* Absolute neutrophil count \>= 1,000/mm\^3
* Platelet count \>= 100,000/mm\^3 and transfusion independent
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x institutional upper limit of normal (ULN)
* Serum creatinine \< 1.5 x ULN or creatinine clearance \> 60 mL/min for patients with creatinine levels above ULN (as determined by Cockcroft-Gault equation)
* Bilirubin =\< 1.5 x ULN; for subjects with documented/suspected Gilbert's disease, bilirubin =\< 3 x ULN
* Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =\< 1.5 x institutional upper limit of normal unless the patient is on anticoagulant therapy within 28 days prior to enrollment (if the patient is receiving anticoagulant therapy, PT, and a PTT must be within therapeutic range of intended use of anticoagulants)
* Patients must be willing to submit blood and tissue specimens for translational medicine studies
* Patients must be offered the opportunity to participate in specimen banking for future research
* Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) within 24 hours prior to the start of study drug
* Women must not be breastfeeding
* Women of childbearing potential (WOCBP) must be willing to use either two adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy, or to abstain from heterosexual activity (complete abstinence) throughout the study, starting with visit 1 through 5 months after the last dose of study therapy. Approved contraceptive methods include intrauterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, female condoms with spermicide, or oral contraceptives. Spermicides alone are not an acceptable method of contraception. 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
* Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to highly effective contraception during active participation in study treatment and for a period of 7 months after the last dose of nivolumab
* HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

Highly effective methods of contraception have a failure rate of \< 1% when used consistently and correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to use one of the highly effective methods of contraception listed below. Male subjects must inform their female partners who are WOCBP of the contraceptive requirements of the protocol and are expected to adhere to using contraception with their partner. Contraception methods are as follows:

* Progestogen only hormonal contraception associated with inhibition of ovulation
* Hormonal methods of contraception including oral contraceptive pills containing combined estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena
* Nonhormonal IUDs, such as ParaGard
* Bilateral tubal occlusion
* Vasectomized partner with documented azoospermia 90 days after procedure

  * Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success
* Intrauterine hormone-releasing system (IUS)
* Complete abstinence

  * Complete abstinence is defined as the complete avoidance of heterosexual intercourse
  * Complete abstinence is an acceptable form of contraception for all study drugs and must be used throughout the duration of the study treatment (plus 5 half-lives of the investigational drug plus 30 days)
  * It is not necessary to use any other method of contraception when complete abstinence is elected
  * Subjects who choose complete abstinence must continue to have pregnancy tests, as specified
  * Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence
  * The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject

    * LESS EFFECTIVE METHODS OF CONTRACEPTION
* Diaphragm with spermicide
* Cervical cap with spermicide
* Vaginal sponge with spermicide
* Male or female condom with or without spermicide

  * A male and a female condom must not be used together
* Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action

  * UNACCEPTABLE METHODS OF CONTRACEPTION
* Periodic abstinence (calendar, symptothermal, post-ovulation methods)
* Withdrawal (coitus interruptus)
* Spermicide only
* Lactation amenorrhea method (LAM)

Exclusion Criteria:

* Contraindications to tumor biopsy and injections (coagulopathy, known history of keloid formation, etc.)
* Women who are pregnant or breastfeeding
* Inability to give informed consent
* History of other malignancy that can interfere with interpretation of the results
* Prior irradiation in the area to be treated with preoperative radiation such that the risk of re-irradiation outweighs its benefit, according to the treating radiation oncologist
* Any condition that might interfere with the subject's participation in the study, safety, or in the evaluation of the study results
* Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study
* Patients must not have received any live vaccine within 30 days prior to registration. Seasonal flu vaccines and other vaccines that do not contain live virus are permitted
* Any concurrent chemotherapy, immunotherapy, or biologic therapy for cancer treatment. Concurrent use of hormones is acceptable
* Patient must not have evidence of any clinically significant immunosuppression such as the following: primary immunodeficiency state such as severe combined immunodeficiency disease; concurrent opportunistic infection; receiving systemic immunosuppressive therapy within 28 days before enrollment with the exceptions of intranasal, topical, and inhaled corticosteroids or oral corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
* Active or prior documented autoimmune disease within the past 3 years

  * NOTE: Subjects with active, known or suspected autoimmune disease such as vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
* Active or prior documented inflammatory bowel disease
* History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids or has current ILD/pneumonitis or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
* Current or history of fibromyalgia, myositis, myocarditis or myasthenia gravis
* Exposure to any investigational drug within 7 days prior to screening visit or for which 5 half-lives have not elapsed
* Prisoners or subjects who are involuntarily incarcerated

  * Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a subject
* Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness