This is a single institution, Phase 1 study for patients with Stage III/IV unresectable Kirsten rat sarcoma (KRAS) mutated NSCLC to evaluate safety of the pooled mutant-KRAS peptide vaccine (KRAS peptide vaccine) with polyinosinic-polycytidylic acid (poly-ICLC) adjuvant in combination with chemoimmunotherapy, nivolumab and ipilimumab in the first line treatment setting. The primary objectives of this study are to determine the safety and feasibility of administering the KRAS peptide vaccine with poly-ICLC adjuvant with chemoimmunotherapy nivolumab and ipilimumab. The secondary objectives are to estimate the progression free survival (PFS) of pooled mutant-KRAS long peptide vaccine with poly-ICLC adjuvant in combination with chemoimmunotherapy, Nivolumab + Ipilimumab for the first line treatment of patients with unresectable Stage III/IV NSCLC whose tumors harbor selected KRAS mutations (KRAS glycine-to-cysteine substitution at codon 12 (G12C), KRAS glycine-to-valine substitution at codon 12 (G12V), KRAS glycine-to-aspartate substitution at codon 12 (G12D), KRAS glycine-to-arginine substitution at codon 12 (G12A), KRAS glycine-to-Aspartate "D" at codon 13 (G13D) or KRAS G12R) and to assess the impact of predicted KRAS mutations on mutant-KRAS specific T cell responses in the peripheral blood of these patients. Participants will receive two doses of chemoimmunotherapy followed by KRAS-targeted vaccine with ipilimumab and nivolumab. Exploratory objectives will assess the impact of predicted KRAS mutations on mutant-KRAS specific T cell responses in the peripheral blood, as well as changes in circulating tumor deoxyribonucleic acid (ctDNA). Approximately 15 subjects will be enrolled to have 12 evaluable subjects for T cell response assessment. Safety analysis will include all enrolled patients who receive at least one dose of vaccine. The evaluable population for T cell response will consist of all patients who receive at least one dose of vaccine and have baseline and post-treatment T cell measures in the peripheral blood at 12 weeks.

Inclusion Criteria:

• Histologically- or cytologically-proven non-small cell lung cancer deemed to be locally advanced/unresectable or metastatic as per AJCC version 9, who has not received prior therapy for this stage of disease.
• Must have tumor lesions amenable to repeated biopsy, and patient's acceptance to have a tumor biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the Principal Investigator).
• Measurable disease as defined by RECIST v1.1.
• Have one of the KRAS mutations (KRASG12C, KRASG12V, KRASG12D, KRASG12A, KRASG13D or KRASG12R) included in the vaccine at the time of vaccination expressed in tumor as defined by a CLIA-certified tumor or plasma based genomic testing platform performed either through a local laboratory or through our central laboratory.
• ECOG performance status 0 or 1.

Patients must have adequate organ and marrow function as defined below:

• Leukocytes ≥ 3,000/mcL

• Absolute neutrophil count ≥ 1,000/mcL

• Platelets ≥ 75 × 103/uL

• Hemoglobin ≥ 8.0 g/dL

• Total bilirubin ≤ 1.5 x ULN (< 2.0 x ULN for subjects with documented Gilbert's syndrome)

• AST(SGOT) and ALT(SGPT)≤ 2.5 × ULN (if liver metastases are present, £ 5 x ULN)

• Alkaline phosphatase ≤5.0 × ULN

• Creatinine ≤1.5 × ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

  o Female CrCl = (140 - age in years) x weight in kg x 0.85

• 72 x serum creatinine in mg/dL

  o Male CrCl = (140 - age in years) x weight in kg x 1.00

• 72 x serum creatinine in mg/dL

• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin (HCG)). WOCBP is defined in Section 4.6. NOTE: If a patient has a positive or indeterminate serum or urine pregnancy test, then an ultrasound must be done to rule out pregnancy to enroll on trial.

• WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 4 weeks (duration of ovulatory cycle) for a total of 5 months post treatment completion.

• Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for a total of 7 months post-treatment completion.

• At least one barrier method of contraception must be employed by all sexually active patients (male and female), regardless of other methods, to prevent the transfer of body fluids.

• Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

• Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study.
• Any of the following procedures or medications:
• Within 2 weeks prior to initiation of study treatment:
• Systemic or topical corticosteroids at immunosuppressive doses (> 10 mg/day of prednisone or equivalent). Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Palliative or adjuvant radiation or gamma knife radiosurgery.
• Chemotherapy
• Within 4 weeks prior to initiation of study treatment:
• Any investigational cytotoxic drug. Exposure to any cytotoxic drug within 4 weeks or 5 half-lives (whichever is shorter) is prohibited. If 5 half-lives are shorter than 4 weeks, agreement with IND Sponsor is mandatory.
• Any investigational device
• Non-oncology vaccines containing live virus. Examples include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid vaccine. Influenza, pneumonia vaccines (polysaccharide and conjugated forms) and COVID-19 vaccines will be allowed, however we recommend that subjects not receive any dose of vaccine within 7 days before or after their scheduled KRAS peptide vaccination.
• Allergen hyposensitization therapy.
• Growth factors, e.g. granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin
• Major surgery (excludes celiac plexus block, biliary stent placement, and other minor procedures such as dental work, skin biopsy, etc.).
• Patients with a history of prior treatment with immunotherapy agents (including, but not limited to: IL-2, interferon, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, anti-CTLA-4, or anti-LAG-3 antibodies).
• Patients who have received anti-PD(L)-1 therapy (i.e. durvalumab, atezolizumab, nivolumab) for early-stage disease with curative intent may be enrolled, so long as progressive disease occurred at least 6 months from the start of anti-PD(L)-1 therapy. Patients with a history of immune-related adverse events secondary to prior anti-PD(L)-1 therapy will not be permitted.
• History of severe hypersensitivity reaction to any monoclonal antibodies or related compounds or to any of their components (e.g., history of severe hypersensitivity reactions to drugs formulated with polysorbate 80). This includes any prior immunotherapy agents; patients having toxicity with prior anti-PD-L1 therapy requiring cessation of treatment must be excluded.
• Untreated or symptomatic brain metastases.
• Treated brain metastases allowed on study if asymptomatic and therapy was completed at least 2 weeks prior to treatment start, and steroid dosing outlined above.
• Has an active known autoimmune disease or which has required systemic therapy in the last 2 years. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Known history of interstitial lung disease or of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Has a pulse oximetry < 90% on room air.
• Requires the use of home oxygen.
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies), hepatitis B, or hepatitis C infection.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness that would limit compliance with study requirements.
• Patients who have been diagnosed with another cancer or myeloproliferative disorder in the past 5 years except for superficial bladder cancer, non-melanoma skin cancers, or a low-grade prostate cancer not requiring therapy.
• Has a diagnosis of immunodeficiency.
• Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Patients with a history of allogeneic hematopoietic stem cell transplant will be excluded.
• Any other sound medical or psychiatric reason as determined by the Investigator.
• Patient is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or other substance abuse (including alcohol) that could potentially interfere with adherence to study procedures or requirements.
• Patient is unwilling or unable to follow the study schedule for any reason.
• Patient is pregnant or breastfeeding.