Sipuleucel-T (Sip-T) in Combination With N-803 in Metastatic Androgen Pathway Modulation Resistant (mAPMR) Prostate Cancer

Inclusion Criteria:

* Histologically or cytologically confirmed prostate adenocarcinoma.
* Imaging- or biopsy-proven metastatic disease. May have any type or location of metastases (bone, lymph node, visceral).
* Prior treatment must include either orchiectomy or luteinizing hormone-releasing agonist or antagonist treatment with documented testosterone ≤ 50 ng/dL.
* Eligible for standard of care Sipuleucel-T.
* Recovery to baseline or ≤ grade 1 from toxicities related to any prior treatments, unless AEs are clinically nonsignificant and/or stable on supportive therapy.
* At least 18 years of age.
* ECOG performance status ≤ 2
* Adequate bone marrow and organ function as defined below:

  * Absolute neutrophil count ≥ 1,500 K/cumm without granulocyte colony-stimulating factor support
  * Platelets ≥ 100,000 K/cumm without transfusion
  * Hemoglobin ≥ 10.0 g/dL
  * Total bilirubin ≤ 1.5 x IULN
  * AST(SGOT) and ALT(SGPT) ≤ 2.5 x IULN
  * Calculated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault
* PSA ≤ 200 ng/mL.
* Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Exclusion Criteria:

* Rapidly progressing disease or symptomatic prostate cancer as assessed by the investigator.
* Prior immunotherapy (e.g., anti-PD-1, anti-PD-L1, anti-CTLA4) within the 6 months prior to enrollment.
* Prior systemic radiotherapy (such as Ra-223, Lu177-PSMA) within the 6 months prior to enrollment. Prior palliative radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before first dose of study treatment is allowed. Prior definitive radiation therapy for localized prostate cancer is allowed.
* Prior exposure to Sipuleucel-T.
* Ongoing systemic immune suppression (oral steroids equivalent to 10 mg daily prednisone or less are allowed; topical, inhaled, and intra-articular steroids are allowed).
* Currently receiving any other investigational therapeutic or imaging agents.
* Patients with known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to first dose of study treatment after major surgery (e.g., removal or biopsy of brain metastasis). Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.
* A history of allergic reactions attributed to compounds of similar chemical or biologic composition to Sipuleucel-T or N-803 or other agents used in the study.
* Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. Patients with a known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Function Classification; to be eligible for this trial, patients should be a class 2B or better.
* HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.
* Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection.
* History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.
* Uncontrolled infection with hepatitis A.