Universal Immunization to Fortify Immunotherapy Efficacy and Response (UNIFIER)

Universal Immunization to Fortify Immunotherapy Efficacy and Response (UNIFIER)

Although immune checkpoint inhibitors (ICIs) have substantially extended survival in many patients, most patients do not achieve durable responses on these treatments. There is a substantial unmet need for methods to sensitize more patients to ICIs. Studies have shown that personalized mRNA lipid nanoparticle vaccines enhance antitumor immunity in combination with PD1 inhibition, under the assumption that these vaccines generate T cells reactive against the targets encoded by the mRNA in the vaccines. However, it was recently found that mRNA vaccines targeting non-tumor antigens are also powerful adjuvants to immune checkpoint blockade.

Retrospective clinical data strongly suggests that receipt of COVID mRNA vaccines with ICIs is responsible for significant improvements in three-year overall survival in multiple large cohorts of patients with non-small cell lung cancer (NSCLC) and metastatic melanoma. Patients treated with these vaccines also have increased expression of programmed death ligand 1 (PD-L1) on their tumors.

This trial is designed to evaluate whether the Pfizer-BioNTech COVID mRNA vaccine improves responses to immune checkpoint inhibitors in patients with stage IV melanoma and stage IV non-small cell lung cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Melanoma (Skin) Stage IV; Stage 4 NSCLC
• Intervention / Treatment: Biological: Pfizer-BioNTech mRNA COVID-19 vaccine

• Study Type: Interventional
• Enrollment (Estimated): 1200
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults ≥ 18 years of age.
• Histologically or cytologically confirmed stage IV non-small cell lung cancer (NSCLC) or stage IV melanoma, with clinical disposition to immunotherapy
• ECOG Performance Status of 0 to 2.
• Dispositioned to immune checkpoint inhibitor (ICI) therapy alone or with concurrent chemotherapy.
• May be receiving subsequent-line therapy after targeted mutation therapy.
• Willing to receive Pfizer-BioNTech mRNA COVID-19 vaccine (for vaccine arms).
• Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures.
• Subjects must not have more than one active malignancy at the time of enrollment (Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen or primary endpoint [as determined by the treating physician or approved by the PI] are eligible for this trial).
• Subjects of childbearing potential (SOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 5 months after the last dose of study treatment to minimize the risk of pregnancy. Prior to study enrollment, subjects of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy.

SOCBP includes any subject who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as:

• Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or

• For subjects with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.

  • Subjects with partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 5 months following the last dose of study treatment.

Exclusion Criteria:

• Dispositioned to targeted therapy (e.g., EGFR, ALK, ROS1).
• Determination by the treating physician that immune checkpoint inhibitor (ICI) therapy is not an appropriate intervention for the participant.
• Known hypersensitivity or allergy to any component of the mRNA COVID-19 vaccines (Pfizer-BioNTech or Moderna), including polyethylene glycol (PEG) or polysorbate
• Administration of a vaccine containing live virus within 30 days prior to the first dose of trial treatment. Note: Most flu vaccines are killed viruses, with the exception of the intra-nasal vainer (Flu-Mist) which is an attenuated live virus and therefore prohibited for 30 days prior to first dose.
• Receipt of any other COVID-19 vaccine or investigational vaccine within 30 days prior to enrollment.
• Uncontrolled or unstable comorbid conditions (e.g., active infection, unstable cardiovascular disease, history of vaccine-related myocarditis, or uncontrolled autoimmune disease) that, in the opinion of the investigator, could interfere with study participation or pose additional risk.
• History of any other disease, metabolic dysfunction, clinical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician.
• Subjects who are confirmed to be pregnant or breastfeeding.
• Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1 : Intervention	Biological: Pfizer-BioNTech mRNA COVID-19 vaccine; Participants will receive a Pfizer-BioNTech COVID-19 mRNA vaccine within 7 days before initiating their immune checkpoint inhibitor therapy. Participants will receive the mRNA COVID-19 vaccine at their local pharmacy and this vaccine will not be provided by the study site. The vaccine is expected to change during the study. Participants will obtain the most up-to-date Pfizer COVID-19 mRNA vaccine available for which they qualify under standard of care.
No Intervention: Arm 2: No Intervention (Control Arm); Participants on this arm will not receive the Pfizer COVID-19 mRNA vaccine before beginning their planned immune checkpoint inhibitor therapy. They will begin their planned immune checkpoint inhibitor therapy within a week of randomization.
No Intervention: Patient-Preference Cohort; In both Phase II and Phase III, eligible participants who provide consent but decline randomization will be enrolled in this patient-preference cohort and the reasons for declining randomization will be documented. Participants in this cohort may choose whether to receive a COVID-19 mRNA vaccine before or after beginning their planned immune checkpoint inhibitor therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of immune-related adverse events requiring hospitalization	Determine the incidence of immune response adverse events requiring hospitalization within 60 days of starting immune checkpoint inhibitor therapy among subjects in the Phase II portion of the study.	60 days after the start of immune checkpoint inhibitor therapy
Overall survival	Determine the overall survival among subjects with stage IV non small cell lung cancer on the Phase III portion of the study. Overall survival is defined as the time from randomization to death from any cause.	5 years
Overall survival	Determine the overall survival among subjects with stage IV non small cell lung cancer receiving first-line of immune checkpoint inhibitor therapy without brain metastases on the Phase III portion of the study. Overall survival is defined as the time from randomization to death from any cause.	5 years
Overall survival	Determine the overall survival among subjects with stage IV melanoma on the Phase III portion of the study. Overall survival is defined as the time from randomization to death from any cause.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Determine the overall survival among subjects with melanoma receiving ipilumumab and nivolumab on the Phase II portion of the study. Overall survival is defined as the time from randomization to death from any cause.	5 years
Progression-free survival	Determine the progression-free survival among subjects with stage IV non-small cell lung cancer on the Phase II portion of the study. Progression-free survival is defined as the time from randomization to documented disease progression or death from any cause, whichever occurs first.	5 years
Progression-free survival	Determine the progression-free survival among subjects with stage IV melanoma on the Phase II portion of the study. Progression-free survival is defined as the time from randomization to documented disease progression or death from any cause, whichever occurs first.	5 years
Progression-free survival	Determine the progression-free survival among subjects with stage IV non-small cell lung cancer receiving first line of immune checkpoint inhibitor therapy without brain metastases on the Phase II portion of the study. Progression-free survival is defined as the time from randomization to documented disease progression or death from any cause, whichever occurs first.	5 years
Progression-free survival	Determine the progression-free survival among subjects receiving combination PD-1 and CTLA-4 directed immune checkpoint inhibitor therapy on the Phase II portion of the study. Progression-free survival is defined as the time from randomization to documented disease progression or death from any cause, whichever occurs first.	5 years
Change in tumor proportion score	Determine the change in tumor proportion score within 100 days of receiving Pfizer-BioNTech COVID mRNA vaccine among patients with biopsy obtained as standard of care on the Phase II portion of the study.	100 days after receipt of Pfizer-BioNTech COVID mRNA vaccine
Feasibility of administering COVID-19 mRNA vaccine within 7 days prior to initiating immune checkpoint inhibitor therapy	Determine the percentage of subjects who experience a delay related to vaccine in starting immune checkpoint inhibitor therapy after receiving COVID-19 mRNA vaccine on the Phase II portion of the study. A subject is considered to experienced a delay if immune checkpoint inhibitor therapy is started 14 days or more after randomization.	14 days after randomization
Overall survival	Determine the overall survival among subjects with stage IV melanoma receiving ipilumumab and nivolumab on the Phase III portion of the study. Overall survival is defined as the time from randomization to death from any cause.	5 years
Progression-free survival	Determine the progression-free survival among subjects with stage IV non-small cell lung cancer on the Phase III portion of the study. Progression-free survival is defined as the time from randomization to documented disease progression or death from any cause, whichever occurs first.	5 years
Progression-free survival	Determine the progression-free survival among subjects with stage IV melanoma on the Phase III portion of the study. Progression-free survival is defined as the time from randomization to documented disease progression or death from any cause, whichever occurs first.	5 years
Progression-free survival	Determine the progression-free survival among subjects with stage IV non-small cell lung cancer receiving first line of immune checkpoint inhibitor therapy without brain metastases on the Phase III portion of the study. Progression-free survival is defined as the time from randomization to documented disease progression or death from any cause, whichever occurs first.	5 years
Progression-free survival	Determine the progression-free survival among subjects receiving combination PD-1 and CTLA-4 directed immune checkpoint inhibitor therapy on the Phase III portion of the study. Progression-free survival is defined as the time from randomization to documented disease progression or death from any cause, whichever occurs first.	5 years
Change in tumor proportion score	Determine the change in tumor proportion score within 100 days of receiving Pfizer-BioNTech COVID mRNA vaccine among non-small cell lung cancer patients with biopsy obtained as standard of care on the Phase III portion of the study.	100 days after receipt of Pfizer-BioNTech COVID mRNA vaccine

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: M.D. Anderson Cancer Center
• Investigators: Principal Investigator: Elias Sayour, MD, PhD, University of Florida; Principal Investigator: Steven Lin, MD, PhD, M.D. Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): March 1, 2035
• Study Completion (Estimated): March 1, 2035

Study Registration Dates

• First Submitted: May 12, 2026
• First Submitted That Met QC Criteria: May 12, 2026
• First Posted (Actual): May 19, 2026

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: non-small cell lung cancer; COVID; melanoma; mRNA vaccine; immune checkpoint inhibitor; stage 4
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Carcinoma, Non-Small-Cell Lung; Melanoma
• Other Study ID Numbers: UF-THO-008

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No