Evaluation of a Cancer Lysate Vaccine and Montanide (Registered Trademark) ISA-51 VG With or Without the IL-15 Super-Agonist N-803 as Adjuvant Therapy for PD-L1 Negative Non-Small Cell Lung Cancer

Background:

• Cancer-testis (CT) antigens (CTA), particularly those encoded by genes on the X chromosome (CT-X antigens) have emerged as attractive targets for cancer immunotherapy.
• Recent studies suggest that CT-X antigens which are up regulated by epigenetic mechanisms may be preferentially expressed in pluripotent stem/tumor initiating cells that mediate treatment resistance and metastasis of human cancers.
• Whereas pulmonary malignancies express a variety of CT-X antigens, immune responses to these proteins are uncommon in lung cancer patients due to low-level, heterogeneous antigen expression, epigenetic repression of genes regulating antigen processing/presentation, and local as well as systemic immunosuppression in these individuals.
• Conceivably, vaccination of lung cancer patients with tumor cells expressing high levels of CT-X antigens in combination with regimens that inhibit immunosuppressive functions of T regulatory cells and enhance activity of natural killer (NK) cells will induce broad immunity to these antigens.

Primary Objectives:

• Phase I Component: To determine the safety of H1299 lung cancer cell lysate vaccines administered with Montanide (Registered Trademark) ISA-51 VG adjuvant and N-803.
• Phase II Component: To assess the frequency of immunologic responses to purified CT-X and autosomal CT antigens in NSCLC participants following vaccinations with H1299 cancer cell lysate and Montanide (Registered Trademark) ISA-51 VG adjuvant in combination with N-803.

Eligibility:

• Participants with pathologically confirmed Stage IB-IIIA (T2a-T4/N0, T1-T3N1, T1-T2/N2) NSCLC per 8th edition TNM Staging System non-small cell lung cancer (NSCLC) who have no clinical evidence of active disease (NED) following standard therapy completed within the past 12 weeks.
• Participants must be 18 years or older with an ECOG performance status of 0-2.
• Participants must have adequate bone marrow, kidney, liver, lung, and cardiac function.
• Participants receiving systemic immunosuppressive medications will be excluded.
• Participants with HIV will be excluded.

Design:

• Following recovery from surgery, and adjuvant therapy if indicated, eligible participants will be vaccinated via deep subcutaneous (SQ) injection with H1299 cell lysate and Montanide (Registered Trademark) ISA-51 VG (Trademark) adjuvant with or without subcutaneous N-803 monthly until six vaccinations have been given.
• Imaging studies will be performed at baseline, one month following the 3rd and 6th vaccinations, and at post-treatment follow-up (every 3 months for 3 years and then every 6 months for another 2 years, for 5 years total follow-up).
• Leukapheresis will be performed at baseline and at treatment evaluation one month following completion of the six vaccinations.
• Systemic toxicities and immunologic responses to therapy will be recorded.
• Pre- and post-vaccination serologic and cell mediated responses to a panel of CT-X antigens will be assessed before and one month following completion of the six vaccinations.
• Individuals deemed to have responded to vaccine treatment and exhibit no evidence of disease recurrence or secondary malignancy will be eligible for 2 additional vaccinations at 3 months after receiving the sixth vaccine and 6 months after receiving the 6th vaccine with N-803.
• Numbers and percentages of immune subsets, soluble factors, and cytokines in peripheral blood will be assessed before and after the six vaccinations.
• Immunologic responses to autologous tumor cells (if available) as well as pooled lung cancer stem cell vs. normal lung-induced pluripotent stem cell (Lu-iPSC) lysates will be evaluated in an exploratory manner.
• Up to 28 participants may receive study intervention on this protocol.

• INCLUSION CRITERIA:
• Participant with histologically or cytologically proven Stage IB-IIIA (T2a-T4/N0, T1- T3N1, T1-T2/N2) NSCLC per 8th edition TNM Staging System with no clinical evidence of active disease (NED) or minimal residual disease (MRD) not readily accessible by non-invasive biopsy or resection/radiation following standard therapy. Initial diagnosis must be confirmed by the NIH Laboratory of Pathology.
• History of PD-L1 expression in cancer cells < 1% as determined by IHC analysis.
• Participant must be enrolled within 12 weeks following completion of prior SOC therapy.
• Participant must have an ECOG performance status of 0-2.
• Participant must be >=18 years of age.
• Participant must be willing to co-enroll on protocol 06C0014 (Prospective Analysis of Genetic and Epigenetic Alterations in Patients with Thoracic Malignancies) allowing for the collection of blood for correlative experiments pertaining to this protocol and related translational research efforts in the Thoracic Surgery Branch.
• Participant must have evidence of adequate bone marrow reserve, hepatic and renal function as evidenced by the following laboratory parameters (all eligibility assessment/enrollment bloodwork must be done at NIH no more than 2 weeks prior to enrollment):
• Absolute neutrophil count greater than 1500/mm3
• Absolute lymphocyte count greater than 800/mm3
• Platelet count greater than 75,000/mm3
• Hemoglobin greater than 8 g/dL (participant may receive transfusions to meet this parameter)
• INR< 1.5xULN
• Total bilirubin < 1.5 x upper limits of normal (except those with Gilberts disease)
• Serum creatinine less than or equal to 1.6 mg/mL or the eGFR must be greater than 60 mL/min/1.73m2
• Seronegative for HIV antibody by bloodwork performed at NIH no more than 4 weeks prior to enrollment.
• Seronegative for active hepatitis B, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RTPCR and be HCV RNA negative by bloodwork performed at NIH no more than 4 weeks

prior to enrollment.

• Participants who are breastfeeding or plan to breastfeed must agree to discontinue/postpone breastfeeding while receiving investigational treatment and for 120 days after the last dose of vaccine or N-803.
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) within 28 days prior initiation of study therapy, for the duration of study participation and up to 120 days after the last

dose of the drug.

-Participant must be able to understand and willing to sign an informed consent.

Exclusion criteria

• Participants receiving other investigational agents.
• Participants on any active treatment for their cancer upon study entry.
• Participant who is initially rendered NED or have MRD following standard therapy but exhibit disease progression prior to initiation of vaccination.
• Participant requiring chronic systemic treatment with steroids above physiologic doses.
• Participant receiving warfarin anticoagulation, who cannot be transitioned to other agents such as enoxaparin or dabigatran, and for whom anticoagulants cannot be held for up to 24 hours.
• Participant with uncontrolled hypertension (> 160/95), unstable coronary disease evidenced by uncontrolled arrhythmias, unstable angina, decompensated CHF (> NYHA Class II), or myocardial infarction within 6 months prior to initiation of study therapy.
• Participant with any of the following pulmonary function abnormalities: FEV, < 35% predicted; DLCO < 35% predicted (post-bronchodilator); oxygen saturation less than 92% on room air based on assessment at NIH or outside medical facility no more than 4 weeks prior to protocol enrollment.
• Active COVID infection
• Participant pregnancy
• Uncontrolled intercurrent illness occurring within 3 months prior to initiation of study therapy /social situations (as assessed by social services) that would limit compliance with study requirements.