NK Cells + Nivolumab + Relatlimab for Melanoma

Recruiting at 1 trial location

Overseen By Alice Y Zhou, M.D., Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Washington University School of Medicine

Must be taking: PD1/PDL1 therapy

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disorder, CNS metastases, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

33 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment option for individuals with advanced or metastatic melanoma that has not responded well to standard treatments. It combines memory-like natural killer cells with two drugs, nivolumab (Opdivo) and relatlimab (Opdualag when combined with nivolumab), to assess the combination's safety and effectiveness in fighting cancer. One group will receive natural killer cells from their own body, while another group will receive cells from a donor. Individuals with melanoma who have not succeeded with other treatments might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I have to stop taking my current medications to join the trial?

Yes, you will need to stop taking corticosteroids and any other immune suppressive medications for at least 14 days before apheresis or lymphodepletion and continue to avoid them until 30 days after the infusion of ML NK cells. However, small doses of corticosteroids (≤15mg prednisone or equivalent) are allowed if necessary.

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

Previous studies have tested treatments combining memory-like natural killer (ML NK) cells with nivolumab and relatlimab for safety. Nivolumab and relatlimab, already used in cancer treatments, are generally well-tolerated. However, using ML NK cells represents a newer approach. Early research on similar NK cell therapies has shown they are usually safe, with few serious side effects.

As a Phase 1 study, the main goal is to assess safety. This phase involves close monitoring to manage any side effects. While much remains to be learned, early findings suggest this combination could be safe for patients with advanced melanoma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine memory-like natural killer (ML NK) cells with nivolumab and relatlimab to tackle melanoma in a novel way. Unlike traditional treatments, such as chemotherapy or monotherapies like nivolumab alone, this approach leverages the power of the immune system by using ML NK cells. These cells are designed to remember and attack cancer cells more effectively. Additionally, the combination with nivolumab and relatlimab provides a dual checkpoint blockade, targeting different pathways to potentially enhance the anti-tumor response. This multi-faceted strategy could offer a more robust and targeted attack against melanoma cells compared to existing options.

What evidence suggests that this trial's treatments could be effective for melanoma?

This trial will study two different treatment arms involving memory-like natural killer (ML NK) cells combined with the drugs nivolumab and relatlimab for advanced melanoma. Research has shown that this combination may help treat advanced melanoma. Participants in Arm 1 will receive autologous ML NK cells, while those in Arm 2 will receive allogeneic ML NK cells. Studies have found that ML NK cells can be safe, tolerable, and possibly effective, especially for patients whose cancer has worsened after other treatments. Nivolumab and relatlimab strengthen the body's immune response against cancer. This combination aims to enhance the body's natural ability to fight cancer while also blocking the ways tumors avoid detection by the immune system. Early results suggest this method may help shrink tumors and slow the disease. ^{1 2 3 6 7}

Who Is on the Research Team?

Alice Y Zhou, M.D., Ph.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

Adults with advanced or metastatic melanoma that worsened after treatment with certain immunotherapies. Participants must be in good health, able to undergo cell harvesting, not have severe active infections like HIV or hepatitis, and cannot be pregnant. They should have stable organ function and agree to use effective contraception.

Inclusion Criteria

Your oxygen level is at least 90% when breathing normally.

Ability to understand and willingness to sign an IRB approved written informed consent document

Your total bilirubin level is less than 2 mg/dL.

Exclusion Criteria

I do not have any untreated infections like HIV or Hepatitis B/C.

I have new lung changes on a CT scan not checked with a scope, but stable after treatment if due to infection.

I have side effects from previous cancer immunotherapy that are not severe.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive memory-like natural killer cells with nivolumab and relatlimab. ML NK cells are infused on Day 0, and nivolumab and relatlimab are initiated at Day 29, continuing every 28 days for up to 11 cycles.

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including progression-free survival and overall survival.

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Memory-like natural killer cells
• Nivolumab
• Relatilmab

Trial Overview The trial is testing memory-like natural killer cells combined with nivolumab and relatlimab for treating melanoma. There are two groups: one receiving NK cells from their own body (autologous) and another from a donor (allogenic). The goal is to see if these treatments are safe and can shrink tumors.

How Is the Trial Designed?

Group I: Arm 2: Allogeneic: Memory-like natural killer cells + nivolumab + relatilimab Experimental Treatment 3 Interventions

* Subjects with a haploidentical donor will enroll into Arm 2 * Subjects will receive the IV infusion of ML NK cells on Day 0. * Relatlimab and nivolumab will be initiated at day 29 and continue every 28 days for 11 cycles, or until unacceptable toxicity, or progression, whichever is earlier.

Group II: Arm 1: Autologous: Memory-like natural killer cells + nivolumab + relatilimab Experimental Treatment 3 Interventions

* Subjects enrolled into arm 1 will receive autologous ML NK cells on Day 0. * Relatlimab and nivolumab will be initiated at day 29 and continue every 28 days for 11 cycles, or until unacceptable toxicity, or progression, whichever is earlier.

Group III: Allogeneic Donors Active Control 1 Intervention

Memory-like natural killer cells is already approved in United States, European Union for the following indications:

Approved in United States as Opdualag for:

• Advanced melanoma (unresectable or metastatic) in patients aged 12 years and older

Approved in European Union as Opdualag for:

• Advanced melanoma (unresectable or metastatic) in patients aged 12 years and older

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Melanoma Research Alliance

Collaborator

Trials

10

Recruited

580+

Rising Tide Foundation

Collaborator

Trials

17

Recruited

6,200+

Published Research Related to This Trial

In a study of 53 patients with metastatic renal cell carcinoma treated with nivolumab, those who experienced immune-related adverse events (irAEs) had significantly better overall survival compared to those without irAEs, indicating a potential link between irAEs and treatment efficacy.

The study found that a lower platelet-to-lymphocyte ratio before treatment was a risk factor associated with the development of irAEs, suggesting that this ratio could be a useful predictor for monitoring patient responses to nivolumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma. Kobayashi, K., Iikura, Y., Hiraide, M., et al.[2021]

In a study of 129 patients with advanced melanoma treated with nivolumab and relatlimab, those without diabetes had significantly better progression-free survival (PFS) and overall survival (OS) compared to patients with type 2 diabetes, indicating that diabetes negatively impacts treatment efficacy.

Interestingly, patients who developed immune checkpoint inhibitor-induced diabetes (ICI-DM) during treatment had the best outcomes, suggesting that this condition may enhance the effectiveness of the therapy, possibly due to changes in LAG3 expression in tumor tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab. Mallardo, D., Woodford, R., Menzies, AM., et al.[2023]

Nivolumab (NIVO) and ipilimumab (IPI) induce distinct changes in the immune system of metastatic melanoma patients, with specific immunophenotypes linked to treatment response and survival outcomes.

Patients receiving IPI before NIVO showed immunophenotypic changes that were associated with resistance to NIVO therapy, indicating that the order of treatment may significantly impact patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and ipilimumab are associated with distinct immune landscape changes and response-associated immunophenotypes. Woods, DM., Laino, AS., Winters, A., et al.[2021]

Nivolumab plus relatlimab is a combination immunotherapy that targets immune checkpoints, specifically PD-1 and LAG-3, and has been approved for treating unresectable or metastatic melanoma in adults and adolescents weighing at least 40 kg.

This combination therapy represents a significant advancement in cancer treatment, as it utilizes two different mechanisms to enhance the immune response against cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Relatlimab: First Approval. Paik, J.[2022]

Nivolumab, a monoclonal antibody used to treat recurrent renal cell carcinoma, can cause significant immune-related adverse events, such as hepatitis and adrenalitis, as seen in a case study of a 66-year-old male patient.

Prompt recognition and management of these side effects are crucial; in this case, the patient's hepatitis improved with methylprednisolone, and adrenalitis was treated with fludrocortisone, leading to normalization of symptoms and electrolyte levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side effects of immune-checkpoint inhibitors: Can multiple side effects be seen in a patient? Özyurt, E., Özçelik, S., Sürmeli, H., et al.[2022]

Nivolumab, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

In a phase 1 trial involving 53 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 40% objective response rate, with 65% of patients showing clinical activity, indicating significant effectiveness in tumor reduction.

The concurrent treatment had a manageable safety profile, with 53% of patients experiencing grade 3 or 4 adverse events, which were similar to those seen with monotherapy and generally reversible, suggesting that this combination therapy is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in advanced melanoma. Wolchok, JD., Kluger, H., Callahan, MK., et al.[2022]

The combination of nivolumab and ipilimumab, two immune checkpoint inhibitors, is a promising treatment for advanced melanoma, enhancing the body's immune response against the cancer.

Adding denosumab to this treatment may further improve anti-tumor effects by counteracting the immunosuppressive environment created by CD8+ T cells, as suggested by recent reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. Yoshida, S., Fujimura, T., Kambayashi, Y., et al.[2020]

Anti-PD-1 antibodies, such as nivolumab and pembrolizumab, have shown high clinical benefit rates and tolerability in treating melanoma by blocking immune-regulatory mechanisms that allow cancer to evade the immune system.

Combining anti-PD-1 therapies with other anti-cancer agents may enhance treatment effectiveness, and there are already reports of long-term survivors benefiting from these immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-1 therapy in melanoma. Homet Moreno, B., Parisi, G., Robert, L., et al.[2020]

In a phase III trial, the combination of the LAG3 immune checkpoint inhibitor relatlimab with the PD-1 inhibitor nivolumab significantly improved progression-free survival for melanoma patients, more than doubling the time without disease progression.

The combination therapy was associated with relatively manageable side effects, suggesting it could be a safe and effective addition to current melanoma treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LAG3-PD-1 Combo Impresses in Melanoma. [2021]

Nivolumab (OPDIVO) received accelerated FDA approval for treating unresectable or metastatic melanoma based on a 31.7% objective response rate in a study of 120 patients, showing promising efficacy after prior treatments.

The treatment demonstrated durable responses, with 87% of responding patients maintaining their response for at least 6 months, although it carries risks of immune-mediated adverse reactions that were monitored in a safety assessment of 268 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab. Hazarika, M., Chuk, MK., Theoret, MR., et al.[2023]

Citations

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Study Details | NCT05629546 | Memory-Like Natural Killer ... This is a Phase 1 open-label, study designed to characterize the safety, tolerability, and preliminary anti-tumor activity of memory-like natural killer cells ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-04954

Memory-Like Natural Killer Cell Therapy with Interlekin-2, ... Giving ML NK cells may be safe, tolerable and effective in treating patients with advanced or metastatic melanoma after progression on checkpoint inhibitors.

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Memory-Like Natural Killer Cells With Nivolumab and ... This is a Phase 1 open-label, study designed to characterize the safety, tolerability, and preliminary anti-tumor activity of memory-like ...

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NK Cells + Nivolumab + Relatlimab for Melanoma This is a Phase 1 open-label, study designed to characterize the safety, tolerability, and preliminary anti-tumor activity of memory-like natural killer ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12083276/

Effect of prior and first-line immunotherapy on baseline ... We report results from exploratory biomarker analyses to characterize the responses of patients with advanced melanoma to treatment with nivolumab.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12154414/

Power of Memory: A Natural Killer Cell Perspective - PMC NK cell memory is a recently discovered phenomenon and is among one of the first instances of immunological memory identified within the innate immune system.

7. cell.com cell.com/cancer-cell/abstract/S1535-6108(25)00405-2

Engineered natural killer cells for cancer therapy Early-phase clinical trials have demonstrated remarkable safety and encouraging therapeutic efficacy of chimeric antigen receptor (CAR)-NK cells ...