PD-L1 t-haNK + N-803 + Cetuximab for Head and Neck Cancer

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Glenn J. Hanna, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Glenn J. Hanna

Must be taking: Anti-PD-1/L1 therapy

Must not be taking: Corticosteroids, others

Disqualifiers: CNS metastases, Autoimmune disease, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to test the safety and efficacy of the combination of PD-L1 t-haNK (modified immune cells), N-803 (a manufactured protein that stimulates the immune system), and cetuximab (a targeted antibody) in treating advanced head and neck cancer. The names of the therapies involved in this study are: * PD-L1 t-haNK cell therapy (a NK cell therapy infusion) * N-803 (a type of recombinant human superagonist) * Cetuximab (a type of antibody)

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must wait at least 2 weeks after your last chemotherapy, biological agents, or investigational drugs before starting the trial.

What data supports the effectiveness of the drug combination PD-L1 t-haNK + N-803 + Cetuximab for head and neck cancer?

Research shows that combining cetuximab with an IL-15-based superagonist like N-803 can enhance the activity of natural killer (NK) cells, which are important for fighting cancer. In studies, this combination led to greater tumor reduction in head and neck cancer models compared to using cetuximab alone.

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Is the combination of PD-L1 t-haNK, N-803, and Cetuximab safe for humans?

Cetuximab has been used in humans for treating certain cancers and is known to activate immune cells, which can help fight tumors. N-803, an IL-15-based compound, has shown potential in enhancing immune cell activity in combination with Cetuximab, but specific safety data for the combination with PD-L1 t-haNK is not detailed in the provided research.

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What makes the PD-L1 t-haNK + N-803 + Cetuximab treatment unique for head and neck cancer?

This treatment is unique because it combines Cetuximab, which targets cancer cells overexpressing EGFR, with N-803, an IL-15 superagonist that boosts the activity of natural killer (NK) cells, and PD-L1 t-haNK cells, which are engineered NK cells that specifically target cancer cells expressing PD-L1. This combination aims to enhance the immune system's ability to attack cancer cells more effectively than standard treatments.

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Eligibility Criteria

This trial is for adults with advanced head and neck squamous cell carcinoma that has come back or spread. Participants should have tried other treatments without success. They must be in good physical condition, with no major organ dysfunction, and able to handle biopsies.

Inclusion Criteria

I am 18 years old or older.

I can provide records of my tumor's PD-L1 and HPV status.

I am not pregnant or will use contraception during and 6 months after the study.

Exclusion Criteria

I have received an organ transplant from another person.

I have hepatitis B or C, or I am HIV positive but undetectable with treatment.

Subjects who are pregnant, or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. Breastfeeding should be discontinued if the mother is treated on this protocol. Women who could potentially become pregnant while undergoing treatment on this protocol must be willing to use 2 methods of contraception.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive PD-L1 t-haNK, N-803, and Cetuximab every 2 weeks for at least 1 year

12 months

Visits every 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Follow-up every 3-4 months

Long-term follow-up

Participants are monitored for long-term safety and survival

15 years

Follow-up every 6-12 months

Participant Groups

The study tests a combination of three therapies: PD-L1 t-haNK (modified immune cells), N-803 (an immune system booster), and cetuximab (a targeted antibody). It aims to see if this mix can safely improve outcomes for patients with recurrent or metastatic head and neck cancer.

Group I: Dose Level 0: PD-L1 t-haNK + N-803 + Cetuximab Experimental Treatment 3 Interventions

Dose level modifications of PD-L1 t-haNK and N-803 due to toxicities will follow protocol specifications, starting at Dose Level 0 and de-escalating to Dose Level -1. Participants will complete: * Baseline visit. * Imaging scans every 8 weeks while on study. * Cycle 1 through End of Treatment: --Days 1 and 15 of 28 day cycle in the following order: Predetermined dose of PD-L1 t-haNK 1x daily, predetermined dose of N-803 1x daily, and predetermined dose of Cetuximab 1x daily. * End of Treatment visit with assessments. * Follow up: follow up every 3-4 months for up to 3 years after end of treatment. Longer-term follow-up every 6-12 months for up to 15 years.

Group II: Dose Level -1: PD-L1 t-haNK + N-803 + Cetuximab Experimental Treatment 3 Interventions

Dose level modifications of PD-L1 t-haNK and N-803 due to toxicities will follow protocol specifications. Participants will complete: * Baseline visit. * Imaging scans every 8 weeks while on study. * Cycle 1 through End of Treatment: --Days 1 and 15 of 28 day cycle in the following order: Predetermined dose of PD-L1 t-haNK 1x daily, predetermined dose of N-803 1x daily, and predetermined dose of Cetuximab 1x daily. * End of Treatment visit with assessments. * Follow up: follow up every 3-4 months for up to 3 years after end of treatment. Longer-term follow-up every 6-12 months for up to 15 years.

Cetuximab is already approved in United States, European Union for the following indications:

🇺🇸 Approved in United States as Erbitux for:

• Locally or regionally advanced squamous cell carcinoma of the head and neck
• Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer
• BRAF V600E mutation-positive metastatic colorectal cancer

🇪🇺 Approved in European Union as Erbitux for:

• Squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Brigham and Women's Hospital Boston, MA

Dana Farber Cancer Institute Boston, MA

Who Is Running the Clinical Trial?

Glenn J. Hanna Lead Sponsor

ImmunityBio, Inc. Industry Sponsor

References

1. Germany pubmed.ncbi.nlm.nih.gov

An IL-15-based superagonist ALT-803 enhances the NK cell response to cetuximab-treated squamous cell carcinoma of the head and neck. [2020] Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide and epidermal growth factor receptor (EGFR) is overexpressed in greater than 90% of patient tumors. Cetuximab is a monoclonal antibody that binds to EGFR and can activate immune cells, such as natural killer (NK) cells, that express receptors for the Fc (constant region) of immunoglobulin G. IL-15 (interleukin-15) is a critical factor for the development, proliferation and activation of effector NK cells. A novel IL-15 compound known as ALT-803 that consists of genetically modified IL-15 plus the IL-15 receptor alpha protein (IL15Rα) fused to the Fc portion of IgG1 has recently been developed. We hypothesized that treatment with ALT-803 would increase NK cell-mediated cytotoxicity of cetuximab-coated head and neck squamous cells. CD56+ NK cells from normal healthy donors were treated overnight with ALT-803 and tested for their ability to lyse cetuximab-coated tumor cells. Cytotoxicity was greater following NK cell ALT-803 activation, as compared to controls. ALT-803-treated NK cells secreted significantly higher levels of IFN-γ than control conditions. Additionally, NK cells showed increased levels of phospho-ERK and phospho-STAT5 when co-cultured with cetuximab-coated tumors and ALT-803. Administration of both cetuximab and ALT-803 to mice harboring Cal27 SCCHN tumors resulted in significantly decreased tumor volume when compared to controls and compared to single-agent treatment alone. Overall, the present data suggest that cetuximab treatment in combination with ALT-803 in patients with EGFR-positive SCCHN may result in significant NK cell activation and have important anti-tumor activity.

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

CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer. [2022] Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell-based immunity.

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

Cetuximab therapy in head and neck cancer: immune modulation with interleukin-12 and other natural killer cell-activating cytokines. [2021] Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide. Greater than 90% of SCCHN of the oropharynx overexpress the epidermal growth factor receptor (EGFR or HER1). Cetuximab (Erbitux-TM) is a humanized anti-HER1 monoclonal antibody (mAb) that binds to HER1 overexpressing tumor cells. Cetuximab has a direct effect on HER1-positive cancer cells, but it also can activate immune cells that bear receptors for the Fc (constant portion) of IgG such as natural killer (NK) cells. NK cells have an activating Fc receptor for IgG (FcγRIIIa), which mediates Ab dependent cellular cytotoxicity (ADCC) and enhances production of interferon-γ (IFN-γ) in response to Ab-coated targets. Interleukin-12 (IL-12) is a cytokine produced by antigen-presenting cells that stimulates IFN-γ production from NK cells. We hypothesized that IL-12 would enhance the anti-tumor activity of cetuximab by activating the FcR effector mechanisms of NK cells.

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

Phase I Trial of Cetuximab, Radiotherapy, and Ipilimumab in Locally Advanced Head and Neck Cancer. [2023] Concurrent radiotherapy with cetuximab, an anti-EGFR mAb, is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). Cytotoxic T lymphocyte antigen-4-positive (CTLA-4+) regulatory T cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added ipilimumab, an anti-CTLA-4 mAb, to cetuximab-radiotherapy.

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

Cetuximab: a review of its use in squamous cell carcinoma of the head and neck. [2021] Cetuximab (Erbitux®) is a chimeric monoclonal antibody directed against the human epidermal growth factor receptor (EGFR). EGFR is overexpressed and/or upregulated in most squamous cell carcinomas of the head and neck (SCCHN); this overexpression is associated with more aggressive disease and poorer prognosis. In the EU, cetuximab is approved in combination with radiation therapy for the treatment of locally advanced SCCHN and in combination with platinum-based chemotherapy for the treatment of recurrent and/or metastatic SCCHN. In randomized, open-label, multinational, phase III clinical trials, cetuximab plus radiotherapy significantly improved the duration of locoregional control (primary endpoint) compared with radiotherapy alone in patients with locally advanced SCCHN, while cetuximab plus first-line platinum-based chemotherapy significantly improved overall survival (primary endpoint) compared with first-line platinum-based chemotherapy alone in patients with recurrent and/or metastatic SCCHN. The efficacy benefits of cetuximab-based combination therapy were achieved without an adverse impact on patients' health-related quality of life. In addition, cetuximab had an acceptable tolerability profile when added to radiotherapy or platinum-based chemotherapy; in particular, it did not exacerbate the toxicities commonly associated with these other treatment modalities. Cetuximab-related adverse events, which include skin rash, hypomagnesaemia and infusion-related reactions, are mostly mild to moderate in severity and manageable. Thus, cetuximab-based combination therapy is a valuable treatment option in patients with SCCHN. In the setting of locally advanced, unresectable disease, cetuximab plus radiotherapy offers an alternative approach to the current standard of care, namely platinum-based chemotherapy plus radiotherapy (chemoradiotherapy). Based on informal comparisons, cetuximab plus radiotherapy appears to be at least as effective as chemoradiotherapy and, moreover, less toxic; however, formal comparisons of these regimens are required before their relative efficacy and tolerability can be conclusively determined. In the setting of recurrent and/or metastatic SCCHN, cetuximab plus platinum-based chemotherapy provides a first-line treatment of choice for fit patients in whom palliative chemotherapy is indicated.

6. Switzerland pubmed.ncbi.nlm.nih.gov

TTCC-2019-02: real-world evidence of first-line cetuximab plus paclitaxel in recurrent or metastatic squamous cell carcinoma of the head and neck. [2023] Label="Objectives" NlmCategory="UNASSIGNED">The aim of this study was to confirm the efficacy of the ERBITAX scheme (paclitaxel 80 mg/m2 weekly and cetuximab 400 mg/m2 loading dose, and then 250 mg/m2 weekly) as first-line treatment for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) who are medically unfit for cisplatin-based (PT) chemotherapy.

7. England pubmed.ncbi.nlm.nih.gov

Cetuximab. [2020] Cetuximab (Erbitux; ImClone Systems/Bristol-Myers Squibb) is a monoclonal antibody that binds to the epidermal growth factor receptor, which is important in the growth of many cancers. In February 2004, it was granted accelerated approval by the US FDA for the treatment of metastatic colorectal cancer on the basis of tumour response rates in Phase II trials.

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

PD-L1 Mediates Dysfunction in Activated PD-1+ NK Cells in Head and Neck Cancer Patients. [2020] Inhibitory immune-checkpoint receptors (ICRs), including programmed death 1 (PD-1), have been characterized as exhaustion markers on T cells that infiltrate the tumor microenvironment (TME) of many cancer types, including head and neck cancer (HNC). However, expression and function of ICRs, including PD-1, on natural killer (NK) cells remains less defined. NK cells are innate immune effector cells that lyse epidermal growth factor receptor-overexpressing HNC cells via cetuximab-mediated antibody-dependent cytotoxicity. Cetuximab is clinically effective but only in 10% to 15% of patients. Therefore, it is necessary to investigate how immunomodulation with cetuximab or PD-1 blockade might enhance NK cell responses in the TME and improve monoclonal antibody therapeutic efficacy. We observed that expression of PD-1 on NK cells marks an activated phenotype, which was suppressed only after binding programmed death ligand-1 (PD-L1). HNC patients who exhibit higher circulating PD-1+ NK cells associate with better clinical outcome, and these cells are enriched in the TME. Cetuximab-mediated NK cell activation increased PD-1 expression on NK cells in vitro, which was confirmed in vivo in a prospective neoadjuvant cetuximab trial. In contrast, PD-L1 ligation of PD-1+ NK cells diminished their activation status, whereas PD-1 blockade increased cetuximab-mediated NK cell activation and cytotoxicity, but only against HNC targets with high PD-L1 expression. Therefore, blocking the PD-1-PD-L1 axis may be a useful strategy to reverse immune evasion of HNC tumors with high PD-L1 expression during cetuximab therapy by reversing NK cell dysfunction.

9. England pubmed.ncbi.nlm.nih.gov

Direct and antibody-dependent cell-mediated cytotoxicity of head and neck squamous cell carcinoma cells by high-affinity natural killer cells. [2021] High affinity natural killer cells (haNKs) are a cell therapy product capable of mediating both direct and antibody-dependent cell-mediated cytotoxicity (ADCC). These cells may be particularly useful in tumors that escape T-cell anti-tumor immunity by harboring antigen processing and presentation defects. Here, we demonstrated that haNKs directly kill both HPV-positive and negative head and neck squamous cell carcinoma cells. Variable tumor cell sensitivity to haNK direct cytotoxicity did not correlated with MHC class I chain-related protein A or B (MICA or MICB) expression. Importantly, haNK killing was significantly enhanced via ADCC mediated by cetuximab or avelumab in cells with higher baseline EGFR or PD-L1 expression, respectively. The ability of IFNγ to induce tumor cell PD-L1 expression correlated with enhanced PD-L1-specific ADCC. IFNγ induced neither tumor cell EGFR expression nor EGFR-specific ADCC. Although a single dose of 8 Gy IR did not appear to directly enhance susceptibility to haNK killing alone, enhanced PD-L1- and EGFR-mediated ADCC after IR correlated with increased PD-L1 and EGFR expression in one of four models. This pre-clinical evidence supports the investigation of haNK cellular therapy in combination with ADCC-mediating mAbs, with or without IR, in the clinical trial setting for patients with advanced HNSCCs. Given the MHC-unrestricted nature of this treatment, it may represent an opportunity to treat patients with non-T-cell inflamed tumors.

10. England pubmed.ncbi.nlm.nih.gov

Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells. [2021] Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here, we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1-dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted.

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

Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial. [2022] Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial.