To determine the effect of a special preparation of cells, called tumor-infiltrating lymphocytes (TIL) stimulated with CD40L, when given with the drug nivolumab, for patients with EGFR, ALK, ROS1, or HER2-genomically altered lung cancer.

Inclusion Criteria:

• Age greater than or equal to 18 years
• Diagnosis of stage IV or recurrent non-small cell lung cancer (NSCLC) with an activating genomic alteration within either: EGFR, ALK, ROS1, or ERBB2 receptor tyrosine kinase domains
• ECOG performance status of 0 or 1
• Expected survival ≥ 4 months
• Participants must have had disease progression after at least one prior line of systemic therapy for NSCLC, including appropriate prior targeted therapy for cases in which a targeted therapy is conventionally used for this genomic alteration, prior to initiating nivolumab trial therapy
• Measurable disease, not including any lesion that is used for TIL harvest, prior to initiation of nivolumab trial therapy
• In accordance with the criteria above, safely accessible tumor for TIL harvest by excisional biopsy expected to yield 1.5 cm3 of tissue, in aggregate
• Participants with known brain metastases are eligible for study enrollment if the brain metastases have received appropriate central nervous system-directed therapy or are found to be clinically stable ≤ 10 mm when comparing scans obtained during the screening period with a scan obtained ≥28 days prior, or if the treating physician determines that immediate CNS-specific treatment is not required prior to the first cycle of therapy. Please also refer to eligibility section on corticosteroids below.
• Adequate normal organ and marrow function as defined below:
• a. Hemoglobin ≥ 9.0 g/dL, with transfusions permissible;
• b. Absolute neutrophil count (ANC) ≥ 1000 per mm3);
• c. Platelet count ≥ 75,000 per mm3, without platelet transfusions for 7 days;
• d. Prothrombin Time ≤ 1.7x the institutional upper limit of normal (ULN), unless participant is receiving intended anticoagulant therapy.
• e. Serum bilirubin ≤ 2.0x the institutional ULN, or ≤ 4.0x ULN if confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology) with PI approval.
• f. AST/ALT ≤ 2.5x institutional ULN unless liver metastases are present, in which case it must be ≤ 5x ULN
• g. Serum creatinine of ≤ 1.5x institutional ULN, or ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
• h. Albumin ≥ 2.0 g/dl
• Pulmonary function tests within past 4 months showing DLCO ≥45% of predicted. Adjusted DLCO based on hemoglobin concentration should be used, if available.
• Human immunodeficiency virus (HIV)-infected participants must be receiving on effective antiretroviral therapy for past 6 months with undetectable viral load and normal CD4 count
• Participants with history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy, if indicated, and no overt cirrhosis
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they must have an undetectable HCV viral load and no overt cirrhosis
• Participants with a prior or concurrent malignancy must have a natural history which does not have the potential to interfere with safety or efficacy assessment of the investigational regimen

Exclusion Criteria:

• No more than six prior lines of systemic therapy for NSCLC
• No prior PD-1 or PD-L1 inhibitor treatment for metastatic NSCLC. Examples of inhibitors include: nivolumab, atezolizumab, pembrolizumab, avelumab, cemplimumab, spartalizumab, or durvalumab.
• Participants with rapidly progressing tumors, as judged by the investigator
• Active or prior documented autoimmune disease within the past 2 years. NOTE: Subjects with vitiligo, Grave's disease, limited site eczema, or limited site plaque psoriasis not requiring systemic treatment (within the past 2 years), or other autoimmune conditions which are not expected to recur, are allowed after approval from the medical monitor or PI
• Active leptomeningeal or pachymeningeal metastases, or carcinomatous meningitis. This is due to prognostic implications and timeline for cell therapy
• Has a diagnosis of primary immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to enrollment.
• a. Oral hydrocortisone, only for the purposes of a documented adrenal insufficiency diagnosis, is permitted if ≤ 25 mg daily total dose
• b. Inhaled, intranasal, or topical corticosteroids are permitted
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (other than atrial fibrillation or supraventricular tachycardia), and significant ≥85% carotid artery stenosis
• Unresolved toxicity (grade 2) from previous anti-cancer therapy. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripheral neuropathy)
• Mean QT interval corrected for heart rate (QTc) ≥480 ms calculated from electrocardiograms (EKGs) using Bazett's Correction
• Participants with active systemic infections requiring intravenous antibiotics within 1 week prior to nivolumab. Prophylactic, empiric, or suppressive antibiotics are permitted with sponsor approval
• History of allogeneic organ transplant
• Participants with psychiatric illness/social situations that would limit compliance with study requirements
• Participants with a history of anaphylaxis to beta-lactam antibiotics. Patients may be evaluated for reported history by conducting a history and physical, and a skin test/challenge where appropriate under medical guidance