NeoVax Plus Ipilimumab in Renal Cell Carcinoma

Inclusion Criteria for Initial Registration: * Ability to understand and the willingness to sign a written informed consent document. * Patients should have suspected stage III or stage IV clear cell renal cell carcinoma (ccRCC), with anticipation that all disease can be surgically resected. Confirmation of clear cell histology, final stage (III or IV), and removal of all disease will be done after the surgery, and will be required for further participation of the trial. * Patient is agreeable to allow tumor and normal tissue samples to be submitted for complete exome and transcription sequencing. * Patients undergoing a potentially curative metastatectomy are eligible if the tumor tissue from the surgery is enough to make a vaccine. * ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1. * Age ≥ 18 years. * Participants must have normal organ and marrow function as defined below: * leukocytes ≥3,000/mcL (microliter) * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/mcL * AST (SGOT) /ALT (SGPT) ≤2.5 × institutional upper limit of normal * creatinine clearance ≥40 mL/min/(calculated using the Cockroft-Gault equation) * Women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent of HCG) before entry onto the trial and within 7 days prior to start of study medication, because the effects NeoVax on the developing human fetus are unknown. It is the investigators' responsibility to repeat the pregnancy test should start of treatment be delayed. * Female patients enrolled in the study, who are not free from menses for \>2 years, post hysterectomy / oophorectomy, or surgically sterilized, must be willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from sexual activity for the duration of treatment with ipilimumab plus 5 half-lives of ipilimumab (75 days) plus 30 days (duration of ovulatory cycle) for a total of 105 days post-treatment completion. Approved contraceptive methods include for example: intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception. * Male patients must agree to use an adequate method of contraception for the duration of treatment with study drugs plus 5 half-lives of the study drug (75 days) plus 90 days (duration of sperm turnover) for a total of 165 days post-treatment. Eligibility Criteria for Secondary Registration * ECOG performance status ≤1. * Participants must have normal organ and marrow function as defined below: * leukocytes ≥3,000/mcL * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/mcL * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal * creatinine ≥40 mL/min/(calculated using the Cockroft-Gault equation) * Patients must have histologically confirmed clear cell renal cell carcinoma (ccRCC), stage III or fully resected stage IV (no evidence of disease), before starting study drugs per AJCC 8th edition. * No evidence of disease (NED) at secondary registration. * Women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent of HCG) within 7 days prior to start of study medication, because the effects NeoVax on the developing human fetus are unknown. It is the investigators' responsibility to repeat the pregnancy test should start of treatment be delayed. * Female patients enrolled in the study, who are not free from menses for \>2 years, post hysterectomy / oophorectomy, or surgically sterilized, must be willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from sexual activity throughout the study, starting with visit 1 through 4 weeks after the last dose of study therapy. Approved contraceptive methods include for example; intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception. * Male patients must agree to use an adequate method of contraception for the duration of treatment with study drugs plus 5 half-lives of the study drug (75 days) plus 90 days (duration of sperm turnover) for a total of 165 days post-treatment. Exclusion Criteria: * Prior treatment with immune-modulatory agents including, but not limited to: IL-2, CTLA-4 blockade, PD-1/PD-L1 blockade, CD40 stimulation, or CD137 stimulation. * Prior investigational ccRCC-directed cancer vaccine therapy. * Patients with active brain metastases or leptomeningeal disease. * Prior systemic therapy, including targeted therapy such as VEGF or mTOR inhibitors unless it is \>6 months between last dose of drug and first vaccination with NeoVax. Systemic therapy is allowed only if prior therapy was not immune therapy (i.e. VEGF TKI), and it was \>6 months ago. * Treatment with other investigational products within the last 2 months prior to entry into this study. * Previous bone marrow or stem cell transplant. * Concomitant therapy with any anti-cancer agents for ACTIVE cancer treatment, other investigational anti-cancer therapies, or immunosuppressive agents; chronic use of systemic corticosteroids with prednisone \>10 mg/day. * Use of a non-oncology vaccine therapy for prevention of infectious diseases (with the exception of vaccination against the SARS-CoV-2 virus for the prevention of COVID-19 disease) is not allowed for 4 weeks prior to day 1, until 8 weeks after last study dose. Given the severity of the COVID-19 pandemic, vaccination specifically against the SARS-CoV-2 virus for the prevention of COVID-19 is ALLOWED in this study. * History of severe allergic reactions attributed to any vaccine therapy for the prevention of infectious diseases. * History of or current active autoimmune diseases, \[e.g. including but not limited to inflammatory bowel diseases \[IBD\], rheumatoid arthritis, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis (scleroderma and variants), systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies (such as Guillain-Barre syndrome). Vitiligo and adequately controlled endocrine deficiencies such as hypothyroidism are not exclusionary.\]. * Patients who have had a history of acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation. * Concomitant treatment with corticosteroids greater than physiologic doses (used in the management of cancer or non-cancer-related illnesses). Topical (if not including the proposed vaccination sites) or inhalational steroids are allowed. * Known chronic infections with HIV, hepatitis B or C. * Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia. * History of current immunodeficiency disease \[e.g., splenectomy or splenic irradiation\]. * Any underlying medical condition, psychiatric condition or social situation that in the opinion of the investigator would compromise study administration as per protocol or compromise the assessment of AEs. * Pregnant women are excluded from this study because personalized neoantigen peptides and poly-ICLC are agents with unknown risks to the developing fetus. Because there is an unknown but potential risk of adverse events in nursing enfants secondary to treatment of the mother with personalized neoantigen peptides and poly-ICLC, nursing women are excluded from this study. * Individuals with a history of another invasive malignancy are ineligible except for the following circumstances: a) individuals with a history of invasive malignancy are eligible if they have been disease-free for at least 2 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; b) individuals with any of the following cancers are eligible if diagnosed and treated: carcinoma in situ of the breast, oral cavity or cervix and basal cell or squamous cell carcinoma of the skin.