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

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Background: Immunotherapy is a powerful tool in the fight against cancer. It uses the body s own immune system to fight the cancer. Unfortunately, cancer cells can find ways to escape from destruction by the body s immune system, even when immunotherapy is used. Natural killer (NK) cells are an important part of the body s immune system and can help fight cancer. In combination with immunotherapy, researchers are using engineered NK cells that recognize and kill cancer cells trying to escape destruction by the immune system. Objective: To test the effectiveness of irradiated PD-L1 CAR-NK cells, combined with pembrolizumab and N-803, in people with advanced forms of gastric or head and neck cancer. Eligibility: Adults ages 18 and older with advanced gastric or head and neck cancer who have already had standard cancer treatment. Design: Participants will be screened with a medical history and physical exam. Their symptoms and ability to do normal activities will be assessed. They will have blood and urine tests. They will have imaging scans of the chest, abdomen, and pelvis. Participants will get PD-L1 CAR-NK cells by intravenous (IV) infusion. They will get the cells once a week for 6 weeks. Then they will get the cells once every 2 weeks. Before each infusion, an IV catheter will be placed in a large arm vein for infusion of these treatments. Participants will get pembrolizumab by IV every 6 weeks. They will get N-803 under the skin every 4 weeks. Participants will get the study drugs for up to 2 years. They will have study visits every 1-2 weeks during treatment. They will have a safety visit 28 days after treatment ends. After treatment ends, participants will be contacted for follow-up every 2 months for a year. Then they will be contacted every 6 months. They will have tumor scans every 6-12 weeks until their cancer gets worse.

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 the immunotherapy combination treatment generally safe for humans?

Pembrolizumab, a part of the immunotherapy combination, has been associated with some side effects like pneumonitis (lung inflammation) in 1%-5% of patients and rare cases of type 1 diabetes (a condition where the body can't produce insulin). However, preclinical studies in nonhuman primates showed no significant toxic effects, suggesting it is generally safe, but monitoring for side effects is important. ^{1 2 3 4 5}

What makes the Immunotherapy Combination for Cancer treatment unique?

This treatment is unique because it combines N-803, an IL-15 superagonist that boosts immune cell activity, with PD-L1 t-haNK cells and pembrolizumab, which block proteins that prevent the immune system from attacking cancer cells. This combination aims to enhance the immune response against cancer more effectively than using these components individually. ^{1 6 7 8 9}

What data supports the effectiveness of this treatment for cancer?

Pembrolizumab (Keytruda) has shown clinical activity in various solid tumors, including non-small cell lung cancer and melanoma, by targeting the PD-1/PD-L1 pathway, which helps the immune system attack cancer cells. Additionally, combining immune-stimulating agents like IL-15 superagonists with PD-L1 inhibitors has been suggested to enhance immune responses against tumors. ^{1 5 6 8 9}

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

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]

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]

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, 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]

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]

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. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

4. United States pubmed.ncbi.nlm.nih.gov

Pegylated Engineered IL2 plus Anti-PD-1 Monoclonal Antibody: The Nectar Comes from the Combination. [2021]

5. England 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. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

8. United States 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. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Reverse Translation Identifies the Synergistic Role of Immune Checkpoint Blockade and IL15 to Enhance Immunotherapy of Ovarian Cancer. [2023]