CCL21-Gene Modified Dendritic Cell Vaccine and Pembrolizumab in Treating Patients With Stage IV Non-small Cell Lung Cancer

Inclusion Criteria:

* Participants with histologically confirmed diagnosis of NSCLC will be enrolled in this study.
* Stage IV pathologically proven NSCLC.
* The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
* Must have received prior systemic anti-cancer therapy for advanced disease that includes either:

  * A PD-1 and/or PD-L1 inhibitor in patients without a sensitizing EGFR mutation and/or ALK gene rearrangement or.
  * Have received prior tyrosine kinase inhibitor therapy in patients with a sensitizing EGFR mutation and/or ALK gene rearrangement. For patients with sensitizing EGFR mutations, prior therapy must include osimertinib if a T790M mutation in the EGFR gene has been documented, and for patients with ALK gene rearrangements, prior therapy must include a second generation ALK inhibitor (e.g. alectinib, brigatinib, ceritinib). Note: For this group, prior cytotoxic chemotherapy is permitted, but prior therapy with a PD-1 or PD-L1 inhibitor is not permitted.
* Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1.
* Absolute neutrophil count (ANC) \>= 1500/uL.
* Platelets \>= 100,000/uL.
* Hemoglobin \>= 9.0 g/dL or \>= 5.6 mmol/L.

  * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
* Creatinine =\< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) \>= 30mL/min for participant with creatinine levels \>1.5 x institutional ULN.

  * Creatinine clearance (CrCl) should be calculated per institutional standard.
* Total bilirubin =\< 1.5 x ULN OR direct bilirubin =\< ULN for participants with total bilirubin levels \> 1.5 x ULN.
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN (=\< 5 x ULN for participants with liver metastases).
* International normalized ratio (INR) OR prothrombin time (PT) =\< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial prothrombin time (aPTT) is within therapeutic range of intended use of anticoagulants.
* Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.
* A lesion that either:

  * Is intended to be accessed bronchoscopically OR.
  * Is intended to be accessed with computed tomography (CT) guided transthoracic injection and in the estimation of the radiologist performing the procedure will not require transversing a bullae that significantly increases the risk of pneumothorax.
* Male participants:

  * A male participant must agree to use a contraception of this protocol during the treatment period and for at least 4 months after the last dose of study treatment and refrain from donating sperm during this period.
* Female participants:

  * A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

    * Not a woman of childbearing potential (WOCBP). OR
    * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 4 months after the last dose of study treatment.

Exclusion Criteria:

* Comorbid disease or a medical or psychiatric condition that would impair the ability of the patient to receive or comply with the study protocol.
* Any use of systemic corticosteroids within 10 days of treatment initiation.
* Respiratory failure (defined as oxygen saturation \[SaO2\] \< 90% on room air; partial pressure of carbon dioxide \[PCO2\] \> 45 mmHg; or forced expiratory volume in one second \[FEV1\] \<1.0 liter).
* Acute viral, bacterial, or fungal infection, which requires specific therapy. Acute therapy must have been completed at least 7 days prior to study treatment.
* Human immunodeficiency virus (HIV) infected patients (defined as HIV-1/HIV-2 antibody positive).
* Patients with active hepatitis B or C. Active hepatitis B is defined as a known positive hepatitis B virus surface antigen (HBsAg) result. Active hepatitis C is defined by a known positive hepatitis (hep) C antibody (Ab) result and known quantitative hepatitis C virus (HCV) ribonucleic acid (RNA) results greater than the lower limits of detection of the assay.
* Hypersensitivity to any reagents used in the study.
* Pregnancy or inadequate contraception.
* Lactating females.
* Clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. In patients with brain metastases that have been treated with radiation therapy, treatment must end at least 14 days prior to starting study treatment. History of leptomeningeal disease is exclusionary regardless of prior therapy.
* Subjects with organ allografts.
* Previous or concurrent evidence of autoimmune disease requiring systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require inhaled steroid or local steroid injections will not be excluded from the study. Subjects with hypothyroidism who are managed by hormone replacement will not be excluded from the study.
* Patients with a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.