Immunotherapy Combination for Cancer

Overseen By Jason M Redman, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Systemic steroids

Disqualifiers: Autoimmune disease, HIV, HBV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new cancer treatment that combines special immune cells with two drugs to help the immune system combat cancer. The treatment targets individuals with advanced gastric or head and neck cancer, particularly those who have already tried standard treatments. Participants receive engineered immune cells (natural killer cells) along with pembrolizumab and N-803 (an IL-15 superagonist complex) to determine if this combination can more effectively target and kill cancer cells. This trial may suit adults with advanced gastric or head and neck cancer who have previously undergone standard treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on other investigational drugs or certain systemic steroids. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

In a previous study, participants tolerated PD-L1 CAR-NK cells well, with no serious problems reported. No cases of cytokine release syndrome (CRS), a common side effect, occurred. Pembrolizumab, another part of the treatment, has undergone extensive study. Most patients experience some side effects, but the benefits often outweigh the risks. Research has shown that N-803 is safe when combined with other treatments. The FDA has approved it for bladder cancer, indicating its safety for use. Overall, these treatments appear well-tolerated, but side effects can vary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination because it offers a novel approach to fighting cancer by harnessing the power of the immune system. Unlike standard treatments like chemotherapy, this combination uses N-803 and PD-L1 t-haNK to stimulate and enhance the body's natural immune responses. N-803 is an IL-15 superagonist that boosts natural killer (NK) cell activity, while PD-L1 t-haNK targets and destroys cancer cells directly. When combined with Pembrolizumab, a well-known checkpoint inhibitor, this treatment has the potential to deliver a more comprehensive attack on cancer cells, potentially leading to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for advanced gastric or head and neck cancer?

Research has shown that specially designed natural killer (NK) cells, such as PD-L1 CAR-NK cells, hold promise in fighting cancer by targeting tumor cells that the immune system misses. In this trial, participants will first receive PD-L1 CAR-NK cell monotherapy, followed by a combination therapy of Pembrolizumab and N-803. Studies have found that using PD-L1 CAR-NK cells with pembrolizumab and N-803 better controls tumor growth. Pembrolizumab, a well-known cancer treatment, has demonstrated significant survival benefits in various cancers. N-803, which enhances NK cell activity, is approved for treating bladder cancer. Together, these treatments aim to strengthen the immune system's ability to fight gastric and head and neck cancers. ^{2 3 5 6 7}

Who Is on the Research Team?

Charalampos Floudas, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults over 18 with advanced gastric or head and neck cancer, who've had standard treatment. They must have measurable disease, be in good physical condition (ECOG <2), and have proper organ function. Those with treated brain metastases without progression are eligible. Participants must not be pregnant, agree to contraception during the trial, and sign consent.

Inclusion Criteria

My organs and bone marrow are functioning well.

leukocytes greater than or equal to 3,000/mcL

I can do most of my daily activities without help.

Exclusion Criteria

I have an autoimmune disease but it's not affecting my thyroid, diabetes type 1, or adrenal glands.

I haven't taken systemic steroids in the last 10 days, except for low-dose or local use.

I do not have HIV or HBV infections.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Lead-in

Participants receive 1 dose of PD-L1 CAR-NK cell monotherapy for PK/PD studies

1 week

1 visit (in-person)

Combination Treatment

Participants receive PD-L1 CAR-NK cells weekly for 6 weeks, then every 2 weeks, along with pembrolizumab every 6 weeks and N-803 every 4 weeks

Up to 2 years

Every 1-2 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Every 2 months, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• N-803
• PD-L1 t-haNK
• Pembrolizumab

Trial Overview The trial tests a combination of immunotherapies: irradiated PD-L1 CAR-NK cells plus pembrolizumab plus N-803 for their effectiveness against recurrent/metastatic gastric or head and neck cancers. Treatments involve IV infusions of NK cells, IV pembrolizumab every 6 weeks, and subcutaneous N-803 every 4 weeks for up to two years.

How Is the Trial Designed?

Group I: 1/Arm 1 Experimental Treatment 3 Interventions

1-week lead in for PD-L1 CAR NK cell monotherapy followed by combination therapy of Pembrolizumab plus N-803

N-803 is already approved in United States for the following indications:

Approved in United States as N-803 for:

• Non-muscle invasive bladder cancer (NMIBC) in combination with BCG

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a phase I trial with 38 patients suffering from advanced solid tumors, the combination of pegylated IL2 (bempegaldesleukin) and an anti-PD-1 monoclonal antibody was found to be safe and resulted in a high overall response rate of 59.5%.

The treatment led to significant immune activation, evidenced by a greater than four-fold increase in the ratio of CD8 T cells to regulatory T cells in tumors, indicating a robust immune response regardless of the initial PD-L1 expression levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegylated Engineered IL2 plus Anti-PD-1 Monoclonal Antibody: The Nectar Comes from the Combination. Rouanne, M., Zitvogel, L., Marabelle, A.[2021]

In a phase Ib trial (KEYNOTE-028) involving 43 patients with advanced anal carcinoma, pembrolizumab showed a manageable safety profile, with 64% experiencing treatment-related adverse events, but no treatment-related deaths or discontinuations.

Among patients with PD-L1-positive tumors, pembrolizumab achieved a 17% overall response rate and a 58% disease control rate, indicating promising antitumor activity and supporting further research in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ott, PA., Piha-Paul, SA., Munster, P., et al.[2021]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

N-809, a novel bifunctional agent, effectively blocks PD-L1 and enhances immune responses by promoting the activation and trafficking of CD8+ T cells and natural killer (NK) cells to the tumor microenvironment, leading to reduced tumor burden and increased survival in murine models.

In contrast to the combination of N-803 and αPD-L1, N-809 not only improved immune cell activation but also decreased the presence of immunosuppressive cells like regulatory T cells and M2-like macrophages, suggesting a unique mechanism that could enhance the efficacy of cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist. Knudson, KM., Hicks, KC., Ozawa, Y., et al.[2021]

The combination of IL15 'superagonist' N-803 and immune checkpoint blockade (ICB) shows promise in enhancing natural killer (NK) cell function and antitumor activity in ovarian cancer, as demonstrated in both patient samples and preclinical models.

While N-803 initially stimulated NK cell expansion, its effects were not sustained beyond two weeks; however, combining N-803 with ICB significantly improved NK cell persistence and expansion, suggesting a potential strategy to overcome resistance to cytokine therapy in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reverse Translation Identifies the Synergistic Role of Immune Checkpoint Blockade and IL15 to Enhance Immunotherapy of Ovarian Cancer. Felices, M., Wesley, E., Bendzick, LE., et al.[2023]

Citations

1. jhoonline.biomedcentral.com jhoonline.biomedcentral.com/articles/10.1186/s13045-025-01664-8

IL-15: from discovery to FDA approval In April 2024, the FDA approved the interleukin (IL)−15 superagonist, N-803 (Anktiva, nogapendekin alfa inbakicept-pmln), for the treatment of bladder cancer.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10297013/

Exploiting an Interleukin-15 Heterodimeric Agonist (N803) for ... In addition, multiple clinical studies have demonstrated N803 to be safe for the treatment of cancer patients. The combination of N803 with the ...

3. immunitybio.com immunitybio.com/immunitybio-announces-publication-of-preclinical-data-demonstrating-il-15-superagonist-n-803-improves-natural-killer-mediated-tumor-cell-killing/

ImmunityBio Announces Publication of Preclinical Data ... ImmunityBio Announces Publication of Preclinical Data Demonstrating IL-15 Superagonist N-803 Improves Natural Killer-Mediated Tumor Cell Killing.

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.4508

Final clinical results of pivotal trial of IL-15RαFc ... In 160 patients with BCG-unresponsive NMIBC, there is a 99% bladder cancer specific overall survival at 2 years. In CIS patients 71% CR rate with 24.1 months ...

5. astctjournal.org astctjournal.org/article/S2666-6367(24)00691-2/fulltext

N-803, an IL-15 Superagonist Complex as Maintenance ... A Phase 2 trial of N-803 as maintenance after allogeneic transplant for AML/MDS showed that relapse decreased with more than 3 doses of N-803.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6089612/

ALT-803, an IL-15 superagonist, in combination with ... The ability of ALT-803 to safely re-induce objective responses to immunotherapy in patients whose disease has relapsed after previous single-agent PD-1 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8096327/

Safety, Tolerability, and Long-Term Clinical Outcomes of an IL ... This phase 1b trial found the combination of intravesical N-803 and BCG to be associated with modest toxic effects, low immunogenicity, and substantial ...