NK Cells + Nivolumab + Relatlimab for Melanoma

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

Trial Summary

What is the purpose of this trial?

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 (ML NK) in combination with nivolumab and relatlimab in subjects with advanced and/or metastatic melanoma. There will be two arms to test the variables of ML NK cell source. ML NK cells from an autologous source will be used for Arm 1, and ML NK cells from an allogeneic source will be used for Arm 2. The investigators hypothesize that ML NK cells from either an autologous source or allogeneic source are safe and tolerable in subjects with advanced and/or metastatic melanoma.

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.

What data supports the idea that NK Cells + Nivolumab + Relatlimab for Melanoma is an effective treatment?

The available research shows that adding relatlimab to nivolumab more than doubled the time patients lived without their melanoma getting worse, compared to using nivolumab alone. This combination also had side effects that were relatively easy to manage. This suggests that NK Cells + Nivolumab + Relatlimab is an effective treatment for melanoma. ^{1 2 3 4 5}

What safety data exists for NK Cells + Nivolumab + Relatlimab treatment for melanoma?

Nivolumab, an immune checkpoint inhibitor, has been associated with immune-related adverse events (irAEs) in various cancers, including melanoma. The FDA approved nivolumab for melanoma based on its objective response rate and manageable safety profile, with immune-mediated adverse reactions being a key consideration. Nivolumab plus relatlimab (Opdualag) was approved in 2022 for unresectable or metastatic melanoma, with safety data indicating that the combination targets immune checkpoints and has a manageable adverse event profile. The safety of this combination therapy is supported by clinical trials and regulatory reviews. ^{1 6 7 8 9}

Is the drug combination of memory-like natural killer cells, Nivolumab, and Relatlimab promising for treating melanoma?

Yes, the combination of Nivolumab and Relatlimab, known as Opdualag, is a promising drug for treating melanoma. It has been approved for use in advanced melanoma and has shown better results than using Nivolumab alone. This combination targets specific proteins to help the immune system fight cancer more effectively. ^{1 3 9 10 11}

Research Team

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

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 (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]

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]

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]

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]

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 (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]

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]

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]

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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Relatlimab: First Approval. [2022]

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

Nivolumab and ipilimumab are associated with distinct immune landscape changes and response-associated immunophenotypes. [2021]

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

Nivolumab plus ipilimumab in advanced melanoma. [2022]

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

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

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

Anti-PD-1 therapy in melanoma. [2020]

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

Side effects of immune-checkpoint inhibitors: Can multiple side effects be seen in a patient? [2022]

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

U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab. [2023]

8. Greece pubmed.ncbi.nlm.nih.gov

Association Between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma. [2021]

9. New Zealand pubmed.ncbi.nlm.nih.gov

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

10. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. [2020]

11. England pubmed.ncbi.nlm.nih.gov

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab. [2023]