SBRT as a Vaccination for Metastatic Melanoma

Inclusion Criteria:

* Signed Written Informed Consent
* Willing and able to provide informed consent
* Age ≥ 18 years
* Target Population
* Histological confirmation of melanoma
* Advanced unresectable (AJCC Stage III or IV) disease (cutaneous, mucosal, acral or ocular)
* Stable disease or progression (RECIST 1.1) after anti-PD-1 monotherapy (≥ 16 weeks and ≥ 2 CT assessments). The maximum time period off anti-PD-1 monotherapy, prior to protocol therapy, cannot exceed 2 months.
* Prior systemic treatment regimen in the advanced/metastatic setting is allowed (BRAF inhibitor, chemotherapy, cytokine/biologic therapy or clinical trial)
* Prior treatment with anti-CTLA-4 checkpoint inhibitor is allowed
* Minimum of 2 or more measurable lesions by RECIST 1.1, with at least 1 lesion accessible for clinical, US, or CT-guided needle biopsy. If 2 lesions, then one of those must measure 4cm in maximum diameter and be amenable for biopsy; this lesion will be utilized for abscopal effect determination as well. Otherwise, if 3 or more lesions are present, one lesion will receive SBRT, 2nd lesion will be used for radiographic abscopal response assessment, and 3rd lesion will be used for pre- and post-treatment biopsies.
* ECOG Performance Status of 0-1

Exclusion Criteria:

* Target Disease Exceptions
* Prior radiation within 6 months of enrollment (excluding brain metastases), or at any time to one of the 3 lesions for treatment/assessment
* If patient has \>1 lesion which requires immediate/urgent management with RT due to present or impending clinical consequences (uncontrolled pain, risk of loss of function), such a patient will not be enrolled on this trial
* Medical History and Concurrent Diseases

  * Major toxicity from prior anti-PD-1 which precludes continuation of anti-PD-1 therapy.
  * Pregnancy or inability to use contraception (if childbearing age)
  * Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (\> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll. Patients with psoriasis not requiring active, systemic treatment are allowed.
  * Any condition requiring systemic treatment with corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses up to 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
  * Uncontrolled adrenal insufficiency
  * Requirement for anti-coagulation with Coumadin, low molecular weight heparin and anti-thrombin inhibitors will be accepted if anticoagulation has been stable for at least 4 weeks and no recent history of prior bleeding complications.
  * Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast or low risk Gleason 6 prostate cancer
  * Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS); Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection
  * Known medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results
  * Major surgery (i.e., nephrectomy) less than 28 days prior to the first dose of study drug
  * Anti-cancer therapy less than 14 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug
  * Presence of any toxicities attributed to prior immunotherapy, other than alopecia, that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study drug
* Physical and Laboratory Test Findings: Any of the following laboratory test findings:

  * WBC \< 2,000/mm3
  * Neutrophils \< 1,500/mm3
  * Platelets \< 100,000/mm3
  * AST or ALT \> 3 x ULN (\> 5 x ULN if liver metastases are present)
  * Total Bilirubin \> 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
  * Serum creatinine \> 1.5 x upper limit of normal (ULN) or creatinine clearance \< 40 mL/min (measured or calculated by Cockroft-Gault formula)
* Allergies and Adverse Drug Reaction: History of severe hypersensitivity reaction to any monoclonal antibody or study drug components
* Other Exclusion Criteria

  * Prisoners or subject who are involuntarily incarcerated
  * Not suitable for SBRT treatment
  * Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness