Vaccine Therapy in Treating Patients With Advanced Stage III-IV Melanoma

Inclusion Criteria:

* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Absolute neutrophil count (ANC) \> 1500/uL
* Platelets \>= 120,000/uL
* Total bilirubin =\< 1.5 mg/dL
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 1.5 x upper limit of normal (ULN)
* Serum creatinine =\< 1.5 mg/dL (if \> 1.5 mg/dL, then creatinine clearance should be \> 60 mL/min)
* Blood urea nitrogen (BUN) =\< 1.5 x ULN
* Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or physical exam
* An anticipated overall survival of at least 6 months
* Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment
* Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
* Patients must have undergone/undergo testing for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status
* Patients must have documented, clinically measurable 7th edition American Joint Committee on Cancer (AJCC) stage IIIB/C (bulky nodal and/or in transit disease) or stage IV (distant metastatic) melanoma; patients with brain metastases that have been appropriately treated with surgical resection and/or radiation are eligible for inclusion if they meet the performance status and life expectancy criteria; patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen)
* Stage IIIB/C patients must have refused, be ineligible for, or have failed at least one standard of care regional therapy (isolated limb perfusion or infusion) or one non-vaccine based systemic therapy (such as, high dose interleukin \[IL\]-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen)
* Stage IV patients must have refused, be ineligible for, or have failed at least one non-vaccine based systemic therapy (such as, high dose IL-2, dacarbazine/temozolomide, ipilimumab, or participation in a clinical trial); patients who are BRAF V600E mutation positive need to have failed, refused, or be ineligible for at least 2 lines of therapy (vemurafenib plus one other regimen)

Exclusion Criteria:

* Pregnant or nursing female patients
* Unwilling or unable to follow protocol requirements
* Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug
* Received an investigational agent within 30 days prior to enrollment
* Melanoma specific systemic therapy within 30 days of enrollment
* A history of AJCC stage IIIB/C or stage IV melanoma but no current clinical evidence of metastatic disease
* Known immunosuppressed conditions or active immunosuppressive therapy such as organ transplantation (including bone marrow transplant), high dose steroids, or human immunodeficiency virus (HIV); although a documented negative HIV test is not mandatory for enrollment, patients felt to have a high clinical suspicion for HIV will need to test negative prior to enrollment; use of topicals or eye drops containing steroids is acceptable; inhaled steroids are excluded
* Known autoimmune conditions including but not limited to rheumatoid arthritis, multiple sclerosis, lupus, scleroderma, sarcoidosis, vitiligo, inflammatory bowel disease, idiopathic thrombocytopenia purpura, Graves' disease, or Hashimoto's thyroiditis
* Previous history of splenectomy or whole spleen radiation
* Systemic immunoglobulin therapy within the last 30 days
* Previous history of anaphylaxis or severe allergic reaction to hsp110, gp100, other vaccines, or unknown allergens
* Previous or active non-melanoma malignancies (excluding non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed/treated within the last 5 years
* Active uncontrolled bacterial, viral, or fungal infection until these conditions are corrected or controlled