A study of tolododekin alfa (also known as ANK-101) administered in combination with an anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody in participants with advanced or metastatic non-small cell lung cancer (NSCLC). Cohort A will enroll participants who have progressed on prior standard of care treatment with an anti-PD-1/PD-L1 antibody and a platinum-based chemotherapy regimen. Cohort B will enroll participants who are treatment-naïve for locally advanced or metastatic NSCLC.

Inclusion Criteria:

1. Have confirmed locally advanced or metastatic NSCLC
2. Thyroid-stimulating hormone (TSH) within normal limits
3. Have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
4. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 1
5. Have a life expectancy > 12 weeks
6. Have baseline electrocardiogram (ECG) without evidence of acute ischemia or prolonged QT interval
7. Heterosexually active women of childbearing potential (WOCBP) must agree to use at least 2 forms of highly effective methods of contraception
8. All male participants who are not sterile must commit to the use of a reliable method of birth control or abstinence
9. Human immunodeficiency virus (HIV)-infected participants must be on anti-retroviral therapy (ART) and have well-controlled HIV infection/disease
10. Resolution of all prior anticancer therapy toxicities to ≤ Grade 1 prior to C1D1.
11. Willingness to provide fresh tumor biopsy specimens
12. Capable of understanding and complying with protocol requirements
13. Provides written informed consent for the study

Exclusion Criteria:

1. Cohort A only: Participants with Grade 3 or higher toxic effects to manage adverse events from previous treatment with immunotherapy
2. Cohort B only: Prior therapy with an immune checkpoint inhibitor.
3. Have known EGFR or ALK mutations
4. Have had prior treatment with recombinant interleukin-12 (IL-12)
5. Have received short-term systemic therapy with immunosuppressive agents prior to C1D1
6. Have active autoimmune disease or medical conditions requiring chronic steroid or other immunosuppressive therapy prior toC1D1
7. Have received live vaccines within 28 days prior to C1D1
8. Have primary or acquired immunodeficient states
9. Women of childbearing potential who has a positive serum pregnancy test prior to C1D1 or female participant who is breastfeeding
10. Have a history of allogeneic tissue/solid organ transplant
11. Has known active uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV).
12. HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease
13. Have known active central nervous system metastases
14. Have congestive heart failure, active coronary artery disease, unevaluated new onset angina, unstable angina, or clinically significant cardiac arrhythmias.
15. Have uncontrolled bleeding disorders prior to C1D1
16. Participants on coumadin (warfarin), due to potential for increased bleeding risk associated with surgery
17. History of noninfectious pneumonitis within the previous 5 years
18. Cohort A only: History of allergy to protein-based therapies, history of any significant drug allergy, or known allergies, hypersensitivity, or intolerance to cetrelimab excipients OR Cohort B only: Hypersensitivity to any component of the anti-PD-1/PD-L1 antibody selected as standard of care
19. Have other systemic conditions or organ abnormalities that may interfere with the conduct of the study
20. Have any acute or chronic psychiatric problems or substance abuse disorder that make the participant unsuitable for participation