A Phase II Study Evaluating T-Cell Clonality After Stereotactic Body Radiation Therapy Alone and in Combination With the Immunocytokine PDS01ADC in Localized High and Intermediate Risk Prostate Cancer Treated With Androgen Deprivation Therapy

Background: * Patients with intermediate and high risk localized prostate cancer often receive radiotherapy with androgen deprivation therapy as a potentially curative treatment. With any local treatment for prostate cancer (radiation or surgery), as many as 20-30% of these intermediate and high risk patients will eventually develop biochemical recurrence within 5 years of treatment. * There is a growing body of evidence suggesting that stereotactic body radiation therapy (SBRT), which delivers highly conformal high-dose radiation, can promote anti-tumor immune responses both locally and systemically as well as synergize with immune checkpoint inhibitors and other forms of immunotherapy. SBRT is now considered a reasonable alternative to conventional fractionated external beam radiation therapy (EBRT) by the National Comprehensive Cancer Network (NCCN) guidelines and has rapidly proliferated in clinical use. * PDS01ADC (NHS-IL12) is an immunocytokine composed of two IL-12 heterodimers, each fused to the H-chain of the NHS76 antibody. The NHS76 IgG1 antibody has affinity for both single- and double-stranded DNA (dsDNA) allowing for targeted delivery of proinflammatory cytokine, IL-12, to necrotic portions of tumor at sites of DNA exposure to promote local immunomodulation. * SBRT-induced dsDNA breaks are tumoricidal and may promote immunogenicity. SBRT also upregulates PD-L1 expression and leads to activation of TGF- \<=. SBRT may enhance intratumoral binding of DNA-damage localizing agent, PDS01ADC. Preclinical models have demonstrated impressive synergy with radiation plus PDS01ADC. * This study will evaluate the proof of concept that immunocytokines can synergize with standard radiation + ADT in prostate cancer with a focus on T-cell clonality. Objectives: * Safety Lead-In: To determine the safety and tolerated doses of the immunocytokine PDS01ADC and Stereotactic Body Radiation Therapy (SBRT) in participants with localized high and intermediate risk prostate cancer receiving standard of care Androgen Deprivation Therapy (ADT) * To evaluate T-cell clonality, as a measure of immunologic activity, after treatment with SBRT alone or in combination with immunotherapy agent PDS01ADC in participants with prostate cancer receiving standard of care ADT Eligibility: * Participants with intermediate or high risk localized prostate cancer * Participants with no history of prior radiation to the prostate or prior prostatectomy * Participants without autoimmune disease or history of bleeding disorder * Participants with adequate organ and bone marrow function Design: * This is an open label, randomized, Phase II trial evaluating T-cell clonality after treatment with SBRT alone or in combination with immunotherapy agent PDS01ADCin participants with localized intermediate or high risk prostate cancer receiving standard of care ADT. SBRT will be performed as standard of care and it is not an investigational activity under this protocol. * The trial will begin with a safety lead-in cohort with de-escalating doses of PDS01ADC (starting dose 16.8 mcg/kg, and de-escalated if needed to 12 mcg/kg, or 8 mcg/kg) only if needed, to evaluate safety and tolerability of the combination of treatments. * ADT will be administered to all participants on the study as standard care. * Those participants receiving immunotherapy agents will receive PDS01ADC by subcutaneous injection (sc) at a dose determined during the safety lead-in, every 4 weeks for 3 doses. * To account for 3 inevaluable participants and 10 screen failures, the accrual ceiling has been set at 65 participants (18 participants during the safety lead-in phase, 34 during the randomized phase II portion).