Clinical Trial of CD40L-Augmented TIL for Patients With EGFR, ALK, ROS1 or HER2-Driven NSCLC

Inclusion Criteria:

• Age greater than or equal to 18 years

• Diagnosis of stage IV or recurrent non-small cell lung cancer (NSCLC) with anactivating genomic alteration within either: EGFR, ALK, ROS1, or ERBB2 receptortyrosine 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 ofsystemic therapy for NSCLC, including appropriate prior targeted therapy for casesin 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 toinitiation of nivolumab trial therapy

• In accordance with the criteria above, safely accessible tumor for TIL harvest byexcisional biopsy expected to yield 1.5 cm3 of tissue, in aggregate

• Participants with known brain metastases are eligible for study enrollment if thebrain metastases have received appropriate central nervous system-directed therapyor are found to be clinically stable ≤ 10 mm when comparing scans obtained duringthe screening period with a scan obtained ≥28 days prior, or if the treatingphysician determines that immediate CNS-specific treatment is not required prior tothe first cycle of therapy. Please also refer to eligibility section oncorticosteroids 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), unlessparticipant is receiving intended anticoagulant therapy.

• e. Serum bilirubin ≤ 2.0x the institutional ULN, or ≤ 4.0x ULN if confirmedGilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantlyunconjugated in the absence of hemolysis or hepatic pathology) with PI approval.

• f. AST/ALT ≤ 2.5x institutional ULN unless liver metastases are present, in whichcase it must be ≤ 5x ULN

• g. Serum creatinine of ≤ 1.5x institutional ULN, or ≥30 mL/min for participant withcreatinine 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 oneffective antiretroviral therapy for past 6 months with undetectable viral load andnormal CD4 count

• Participants with history of chronic hepatitis B virus (HBV) infection must haveundetectable HBV viral load on suppressive therapy, if indicated, and no overtcirrhosis

• Participants with a history of hepatitis C virus (HCV) infection must have beentreated and cured. For participants with HCV infection who are currently ontreatment, they must have an undetectable HCV viral load and no overt cirrhosis

• Participants with a prior or concurrent malignancy must have a natural history whichdoes not have the potential to interfere with safety or efficacy assessment of theinvestigational 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 ofinhibitors 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 plaquepsoriasis not requiring systemic treatment (within the past 2 years), or otherautoimmune conditions which are not expected to recur, are allowed after approvalfrom 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 steroidtherapy or any other form of immunosuppressive therapy within 7 days prior toenrollment.

• a. Oral hydrocortisone, only for the purposes of a documented adrenal insufficiencydiagnosis, is permitted if ≤ 25 mg daily total dose

• b. Inhaled, intranasal, or topical corticosteroids are permitted

• Uncontrolled intercurrent illness including, but not limited to, symptomaticcongestive heart failure, unstable angina pectoris, cardiac arrhythmia (other thanatrial fibrillation or supraventricular tachycardia), and significant ≥85% carotidartery stenosis

• Unresolved toxicity (grade 2) from previous anti-cancer therapy. Participants withirreversible toxicity that is not reasonably expected to be exacerbated by theinvestigational product may be included (e.g., hearing loss, peripheral neuropathy)

• Mean QT interval corrected for heart rate (QTc) ≥480 ms calculated fromelectrocardiograms (EKGs) using Bazett's Correction

• Participants with active systemic infections requiring intravenous antibioticswithin 1 week prior to nivolumab. Prophylactic, empiric, or suppressive antibioticsare permitted with sponsor approval

• History of allogeneic organ transplant

• Participants with psychiatric illness/social situations that would limit compliancewith study requirements

• Participants with a history of anaphylaxis to beta-lactam antibiotics. Patients maybe evaluated for reported history by conducting a history and physical, and a skintest/challenge where appropriate under medical guidance