A Multiple Antigen Vaccine (STEMVAC) for the Treatment of Patients With Stage IV Non-Small Cell Lung Cancer

Inclusion Criteria:

* Histologically-confirmed diagnosis of stage IV non-squamous or squamous NSCLC.
* Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within one month of first vaccine. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
* Have completed 3-4 cycles of chemoimmunotherapy, without evidence of progressive disease. Pembrolizumab has to be included in at least 3 of these cycles.
* Have not received more than 2 cycles of maintenance pembrolizumab and/or pemetrexed and be a candidate for continuation of this therapy.
* At least 1 site of disease that could be biopsied during treatment. This site should not be a site that is used to determine measurable disease for efficacy purposes. Lesions that will be biopsied should not be on a previously irradiated area unless progression has been demonstrated in such lesions.
* Patients must be at least 28 days post systemic steroids prior to enrollment, unless this is a steroid administered concurrently with chemotherapy or used as part of prophylaxis to prevent intravenous (IV) contrast reactions.
* Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0 or 1.
* Patients must have recovered from major infections and/or surgical procedures, and in the opinion of a principle investigator (PI)/co-PI/study physician/physician extender, not have any significant active concurrent medical illnesses precluding protocol treatment.
* Willing to undergo up to two serial biopsies while on study.
* Estimated life expectancy of more than 6 months.
* White blood cells (WBC) \>= 3000/mm\^3 (within 60 days of first vaccination).
* Lymphocyte count \>= 800/mm\^3 (within 60 days of first vaccination).
* Platelet count \>= 75,000/mm\^3 (within 60 days of first vaccination).
* Hemoglobin (Hgb) \>= 9 g/dl (within 60 days of first vaccination).
* Serum creatinine =\< 1.2 mg/dl or creatinine clearance \> 50 ml/min (within 60 days of first vaccination).
* Total bilirubin =\< 1.5 mg/dl (within 60 days of first vaccination).
* Aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) =\< 2 times upper limit of normal (ULN) or SGOT =\< 5 times upper limit of normal (ULN) in the presence of liver metastasis (within 60 days of first vaccination).
* If female of childbearing potential has a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
* All patients who are having sex that can lead to pregnancy must agree to contraception for the duration of study.
* Patients must be at least 18 years of age.

Exclusion Criteria:

* Patients with any of the following cardiac conditions:

  * Symptomatic restrictive cardiomyopathy
  * Unstable angina within 4 months prior to enrollment
  * New York Heart Association functional class III-IV heart failure on active treatment
  * Symptomatic pericardial effusion
* Patients with central nervous system (CNS) metastasis that have not been treated. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks and, have no evidence of new or enlarging brain metastases and also are off steroids for 2 weeks prior to dosing with study medication.
* Patients with any contraindication to receiving recombinant human granulocyte-macrophage colony stimulating factor (rhuGM-CSF) based products.
* Patients with any clinically significant autoimmune disease that requires active treatment with immunosuppressants. Replacement therapy (e.g., thyroxine, insulin) is not considered a form of systemic treatment. Administration of systemic steroids (i.e., for allergic reactions, computed tomography (CT) scans, or the management of immune related adverse events \[irAEs\]) is allowed.
* Has a known history of another prior invasive malignancy within 2 years, except subjects with early stage cancer that has undergone potentially curative therapy with no evidence of that disease recurrence for 2 years since initiation of that therapy.
* Patients who are simultaneously enrolled in any other treatment study.
* Patients who are pregnant or breastfeeding.
* Patients with genetic driver alterations (e.g EGFR, ALK, ROS1, BRAF, MET ex 14, RET) for which targeted treatment exist and are Food and Drug Association (FDA) approved, except if the subject is not eligible or has progressed through those therapies.