Sponsor decision

The goal of this Phase 1 clinical study is test tumor infiltrating lymphocytes (known as C-TIL051) with NKTR-255 and anti-PD1 therapy for subjects with refractory non-small cell lung cancer.

The purpose of this study is to:

1. Test the safety and ability for subjects to tolerate the TIL therapy
2. Measure to see how the NSCLC responds to the TIL therapy

Participants will be asked to:

• Provide a tumor sample prior to the start of any treatment which will be used to make the C-TIL051.
• Receive standard of care treatment until their lung cancer no longer responds
• When necessary, the C-TIL051 will be manufactured by the sponsor and sent back to the site
• Subject will then receive chemotherapy (called lymphodepletion) for 3 days followed by 2 days of rest
• C-TIL051 will then be infused on day 0 followed by NKTR-255 (IL-15) about 12 to 24 hours later
• Pembrolizumab will be administered every 3 weeks for up to 2 years

NKTR-255 is a novel polymer-conjugated human IL-15 receptor agonist molecule designed to increase the proliferation and survival of memory CD8+ T cells and enhance the formation of long-term immunological memory which may lead to sustained anti-cancer immune response. The combination of NKTR 255 and TIL's could improve proliferation and persistence of cellular therapies leading to enhanced anti-tumor activity.

Inclusion Criteria:

• Able to understand and give written informed consent
• Histologically and cytologically confirmed diagnosis of stage IV or recurrent non-small cell lung cancer (NSCLC) with adenocarcinoma or squamous histology
• Planned for treatment with an anti-PD1 agent
• Tumor accessible by surgery, previously not irradiated and ≥ 1.5 cm in diameter
• Measurable disease after resection of tumor by RECIST 1.1
• ECOG ≤ 1
• Expected survival > 6 months
• Adequate organ and marrow function
• ECHO, MUGA or cardiac stress test within past 6 months showing LVEF >50% and without evidence of reversible ischemia
• Pulmonary function tests within past 6 months showing DLCO >50% of predicted

Exclusion Criteria:

• Previous treatment with PD1/PDL1 inhibitor for metastatic disease, Immune checkpoint blockade (ICB) given as part of definitive therapy for stage Ib-III disease with surgery or after chemo/radiation is acceptable if last dose of ICB is at least 6 months prior to enrollment in this study.
• Known driver mutations such as EGFR, ALK, ROS1, RET, METex14, and NTRK alterations.
• Current or prior use of any immunosuppressive medications within 14 days before tumor harvest
• Known active CNS metastases which are symptomatic
• History of leptomeningeal metastases
• Uncontrolled intercurrent illness
• Known history of HIV+ or AIDS, hepatitis C, acute or chronic active hepatitis B or other serious chronic infection
• Live vaccine within 30 days of tumor harvest
• History of allogeneic organ transplant
• History of primary immunodeficiency
• Hypersensitivity to anti-PD1 agent, cyclophosphamide, fludarabine, interleukin-2, gentamicin, or any excipient
• Any condition that may interfere with evaluation of study treatment, safety or study results
• Active infection that requires IV antibiotics within 7 days of tumor harvest
• Unresolved greater than grade 1 toxicity (CTCAE v5.0) from previous therapy
• History of interstitial pneumonitis of autoimmune etiology that is symptomatic or requires treatment
• Pulmonary disease history requiring escalating amounts of oxygen > 2L
• Known autoimmune conditions requiring systemic immune suppression therapy other than low dose prednisone or equivalent.
• Other malignancy, other than cutaneous localized) that required active treatment in the last 2 years.
• Women who are pregnant or lactating
• Women of childbearing potential or fertile men who are unwilling to use effective contraception during study and 6 months after treatment