Nivolumab in Combination with Lymphodepletion Chemotherapy, CD40L-Augmented Tumor Infiltrating Lymphocytes, and Interleukin-2 for the Treatment of Recurrent/Refractory Stage IV Non-small Cell Lung Cancer

Inclusion Criteria

• ENROLLMENT INCLUSION CRITERIA: Age greater than or equal to 18 years
• ENROLLMENT INCLUSION CRITERIA: Able to understand and give written informed consent
• ENROLLMENT INCLUSION CRITERIA: 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 * Tumors which were previously documented to harbor an eligible genomic alteration are acceptable, even if subsequent testing reported a secondary mutation or loss of original mutation. This is a recognized resistance mechanism in this population * Likewise, subsequent cell-free deoxyribonucleic acid (DNA) testing (e.g. Guardant360) failing to report a previously documented genomic alteration does not impact eligibility. This is because cell-free DNA has reduced sensitivity in this setting * Tumors which have mixed histology, or transformation into small cell or neuroendocrine histology are acceptable, since this is a well-established resistance mechanism in this population
• ENROLLMENT INCLUSION CRITERIA: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• ENROLLMENT INCLUSION CRITERIA: Expected survival >= 4 months
• ENROLLMENT INCLUSION CRITERIA: Patients 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
• ENROLLMENT INCLUSION CRITERIA: Measurable disease, not including any lesion that is used for TIL harvest, prior to initiation of nivolumab trial therapy, defined as >= 1 lesion that is >= 10 mm in one dimension by CT scan, MRI if >= 5 mm slice thickness is used, or >= 7 mm in one dimension if slice thickness between =< 3 mm is used
• ENROLLMENT INCLUSION CRITERIA: In accordance with the criteria above, safely accessible tumor for TIL harvest by excisional biopsy expected to yield 1.5 cm^3 of tissue, in aggregate
• ENROLLMENT INCLUSION CRITERIA: Patients 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 central nervous system (CNS)-specific treatment is not required prior to the first cycle of therapy. Note that the initial comparison scan may be from prior to informed consent. Please also refer to eligibility section on corticosteroids below
• ENROLLMENT INCLUSION CRITERIA: Hemoglobin >= 9.0 g/dL, with transfusions permissible (performed within 7 days [+ 3 day window] of enrollment)
• ENROLLMENT INCLUSION CRITERIA: Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (> 1000 per mm^3) (performed within 7 days [+ 3 day window] of enrollment)
• ENROLLMENT INCLUSION CRITERIA: Platelet count >= 75 x 10^9/L (> 75,000 per mm^3), without platelet transfusions for 7 days (performed within 7 days [+ 3 day window] of enrollment)
• ENROLLMENT INCLUSION CRITERIA: Prothrombin time =< 1.7 x the institutional upper limit of normal (ULN), unless participant is receiving intended anticoagulant therapy (performed within 7 days [+ 3 day window] of enrollment). This will not apply to subjects with confirmed Factor XII deficiency or suspected vitamin K deficiency
• ENROLLMENT INCLUSION CRITERIA: Serum bilirubin =< 2.0 x 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 principal investigator (PI) approval (performed within 7 days [+ 3 day window] of enrollment)
• ENROLLMENT INCLUSION CRITERIA: Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN unless liver metastases are present, in which case it must be =< 5 x ULN (performed within 7 days [+ 3 day window] of enrollment)
• ENROLLMENT INCLUSION CRITERIA: Serum creatinine of =< 1.5 x institutional ULN, or >= 30 mL/min for participant with creatinine levels >1.5 x institutional ULN (performed within 7 days [+ 3 day window] of enrollment)
• ENROLLMENT INCLUSION CRITERIA: Albumin >= 2.0 g/dl (performed within 7 days [+ 3 day window] of enrollment)
• ENROLLMENT INCLUSION CRITERIA: Pulmonary function tests within past 4 months showing diffusing capacity of the lungs for carbon monoxide (DLCO) >= 45% of predicted. Adjusted DLCO based on hemoglobin concentration should be used, if available. If pulmonary function testing is not medically possible, then an equivalent six-minute walk test of >= 300 m is an acceptable alternative
• ENROLLMENT INCLUSION CRITERIA: 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
• ENROLLMENT INCLUSION CRITERIA: 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
• ENROLLMENT INCLUSION CRITERIA: 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
• ENROLLMENT INCLUSION CRITERIA: 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
• ENROLLMENT INCLUSION CRITERIA: Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. This is because alkylating agents used in this trial are known to be teratogenic. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study drug administration and refrain from donating sperm during this period
• PRE-LYMPHODEPLETION INCLUSION CRITERIA: ECOG performance status of 0 or 1
• PRE-LYMPHODEPLETION INCLUSION CRITERIA: Patients must have had disease progression after nivolumab, as manifested by tumor enlargement or new lesions of any kind
• PRE-LYMPHODEPLETION INCLUSION CRITERIA: Patients with known brain metastases are eligible for lymphodepletion if the brain metastases have received appropriate central nervous system-directed therapy or =< 20 mm, or if the treating physician determines that immediate CNS-specific treatment is not required and is unlikely to be required during the first cycle of therapy. Please also refer to eligibility section on corticosteroids below
• PRE-LYMPHODEPLETION INCLUSION CRITERIA: Hemoglobin >= 8.0 g/dL, with transfusions permissible (performed within 7 days [+ 3 day window] of first expected dose of lymphodepletion)
• PRE-LYMPHODEPLETION INCLUSION CRITERIA: Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (> 1000 per mm^3) (performed within 7 days [+ 3 day window] of first expected dose of lymphodepletion)
• PRE-LYMPHODEPLETION INCLUSION CRITERIA: Platelet count >= 75 x 10^9/L (>75,000 per mm^3), without platelet transfusions for 7 days (performed within 7 days [+ 3 day window] of first expected dose of lymphodepletion)
• PRE-LYMPHODEPLETION INCLUSION CRITERIA: Serum bilirubin =< 3.0 x the institutional ULN, or =< 5.0 x 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 (performed within 7 days [+ 3 day window] of first expected dose of lymphodepletion)
• PRE-LYMPHODEPLETION INCLUSION CRITERIA: AST (SGOT)/ALT (SGPT) =< 3.0 x institutional ULN unless liver metastases are present, in which case it must be =< 5 x ULN (performed within 7 days [+ 3 day window] of first expected dose of lymphodepletion)
• PRE-LYMPHODEPLETION INCLUSION CRITERIA: Serum creatinine of =< 2.0 x institutional ULN, or >= 30 mL/min for participant with creatinine levels > 2.0 x institutional ULN (performed within 7 days [+ 3 day window] of first expected dose of lymphodepletion)
• PRE-LYMPHODEPLETION INCLUSION CRITERIA: Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. This is because alkylating agents used in this trial are known to be teratogenic. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study drug administration and refrain from donating sperm during this period

Exclusion Criteria

• ENROLLMENT EXCLUSION CRITERIA: No more than six prior lines of systemic therapy for NSCLC
• ENROLLMENT EXCLUSION CRITERIA: No prior PD-1 or PD-L1 inhibitor treatment for metastatic NSCLC. Examples of inhibitors include: nivolumab, atezolizumab, pembrolizumab, avelumab, cemiplimab, spartalizumab, or durvalumab. Prior therapy for locally advanced, neoadjuvant, adjuvant, or otherwise definitive oligometastatic intent is acceptable if >= 120 days have elapsed since the last dose of PD-1 or PD-L1 inhibitor
• ENROLLMENT EXCLUSION CRITERIA: Patients who have a significant history of pulmonary disease that necessitates the use of supplemental oxygen, and patients with resting pulse oximetry < 92% on room air
• ENROLLMENT EXCLUSION CRITERIA: Patients with rapidly progressing tumors, as judged by the investigator
• ENROLLMENT EXCLUSION CRITERIA: 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
• ENROLLMENT EXCLUSION CRITERIA: Anti-cancer therapy within a specified period below prior to expected first dose of nivolumab trial drug: * Within 3 weeks of previous chemotherapy * Within 3 days of previous tyrosine kinase inhibitor (TKI) * Within 3 weeks of previous monoclonal antibody or antibody-drug conjugate * Within 4 weeks or 4 half-lives of any other investigational agents for cancer, whichever is lesser
• ENROLLMENT EXCLUSION CRITERIA: Active leptomeningeal or pachymeningeal metastases, or carcinomatous meningitis. This is due to prognostic implications and timeline for cell therapy
• ENROLLMENT EXCLUSION CRITERIA: 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 * Oral hydrocortisone, only for the purposes of a documented adrenal insufficiency diagnosis, is permitted if =< 25 mg daily total dose. * Inhaled, intranasal, or topical corticosteroids are permitted
• ENROLLMENT EXCLUSION CRITERIA: 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
• ENROLLMENT EXCLUSION CRITERIA: Has severe hypersensitivity (>= grade 3) to nivolumab, fludarabine, cyclophosphamide, dimethyl sulfoxide (DMSO) and/or any of its excipients
• ENROLLMENT EXCLUSION CRITERIA: Unresolved toxicity (> Common Terminology Criteria for Adverse Events [CTCAE] version [v]5 grade 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripheral neuropathy)
• ENROLLMENT EXCLUSION CRITERIA: Mean QT interval corrected for heart rate (QTc) >= 480 ms calculated from electrocardiograms (EKGs) using Bazett’s correction
• ENROLLMENT EXCLUSION CRITERIA: Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• ENROLLMENT EXCLUSION CRITERIA: Patients with active systemic infections requiring intravenous antibiotics within 1 week prior to nivolumab. Prophylactic, empiric, or suppressive antibiotics are permitted with sponsor approval
• ENROLLMENT EXCLUSION CRITERIA: Known history of previous tuberculosis
• ENROLLMENT EXCLUSION CRITERIA: History of allogeneic organ transplant
• ENROLLMENT EXCLUSION CRITERIA: History of primary immunodeficiency
• ENROLLMENT EXCLUSION CRITERIA: Participants with psychiatric illness/social situations that would limit compliance with study requirements
• ENROLLMENT EXCLUSION CRITERIA: Pregnant women are excluded from this study because cyclophosphamide/fludarabine is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cyclophosphamide/fludarabine, breastfeeding should be discontinued if the mother is treated
• ENROLLMENT EXCLUSION CRITERIA: 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
• ENROLLMENT EXCLUSION CRITERIA: Patients with a history of severe hypersensitivity syndromes to beta-lactam antibiotics, including Stevens-Johnson syndrome, toxic epidermal necrolysis, serum sickness, acute interstitial nephritis, hemolytic anemia, and drug rash with eosinophilia and systemic symptoms (DRESS). Skintest/ challenge is not appropriate for these conditions
• PRE-LYMPHODEPLETION EXCLUSION CRITERIA: Patients with resting pulse oximetry < 92% on room air
• PRE-LYMPHODEPLETION EXCLUSION CRITERIA: Receiving > 10 mg prednisone or equivalent chronic systemic steroid therapy prior to the first expected dose of lymphodepletion. Oral hydrocortisone, only for the purposes of a documented and confirmed adrenal insufficiency diagnosis, is permitted. Inhaled, intranasal, or topical corticosteroids are permitted
• PRE-LYMPHODEPLETION EXCLUSION CRITERIA: Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or ventricular cardiac arrhythmia
• PRE-LYMPHODEPLETION EXCLUSION CRITERIA: Anti-cancer bridging therapy within a specified period below prior to expected first dose of trial drug: * Within 3 days of previous tyrosine kinase inhibitor (TKI) * Within 14 days of previous monoclonal antibody, cytotoxic, or antibody-drug conjugate