N-803 + PD-L1 t-haNK + Bevacizumab for Glioblastoma
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: ImmunityBio, Inc.
Must not be taking: Bevacizumab, Corticosteroids, Anticoagulants, others
Disqualifiers: Uncontrolled disease, Autoimmune, Organ transplant, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This is a phase 2 open-label study to evaluate the safety and efficacy of N-803 and PD-L1 t-haNK when combined with Bevacizumab in subjects with recurrent or progressive GBM.
Participants will receive N-803 subcutaneously (SC), PD-L1 t-haNK intravenously (IV), and Bevacizumab IV combination therapy.
Treatment for all enrolled participants will consist of repeated cycles of 28 days for a maximum treatment period of 76 weeks (19 cycles). Treatment will be administered on days 1 and day 15 of each cycle. Treatment will be discontinued if the participant reports unacceptable toxicity (not corrected with dose reduction), withdraws consent, if the Investigator feels it is no longer in the participant's best interest to continue treatment, or the participant has confirmed progressive disease by iRANO, unless the participant is potentially deriving benefit per Investigator's assessment. Participants will be followed for collection of survival status every 12 weeks (± 2 weeks) for the first 2 years, then yearly thereafter.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are on chronic daily treatment with high-dose systemic corticosteroids or if you are receiving therapeutic anticoagulation. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the treatment N-803 + PD-L1 t-haNK + Bevacizumab for Glioblastoma?
Research shows that blocking PD-L1, a protein that helps tumors hide from the immune system, can lead to long-term survival in some glioblastoma models. Bevacizumab, another part of the treatment, has been shown to change the tumor environment in a way that might help the immune system fight the cancer more effectively.
12345Is the combination of N-803, PD-L1 t-haNK, and Bevacizumab safe for humans?
Bevacizumab (also known as Avastin) has been used in various treatments and is generally considered safe, though it can have side effects like high blood pressure and increased risk of bleeding. The safety of PD-L1 t-haNK and N-803 (IL-15 superagonist complex) in humans is still being studied, but early trials suggest they can be used safely, although more research is needed to fully understand their safety profiles.
12678What makes the N-803 + PD-L1 t-haNK + Bevacizumab treatment unique for glioblastoma?
This treatment is unique because it combines an immune system booster (N-803), engineered immune cells (PD-L1 t-haNK), and a drug that inhibits blood vessel growth (Bevacizumab) to target glioblastoma, a brain cancer with limited treatment options. The combination aims to enhance the immune response against the tumor, which is a novel approach compared to traditional therapies.
178910Eligibility Criteria
This trial is for adults over 18 with glioblastoma that's worsened after initial treatments. They should have a life expectancy of more than 12 weeks, be able to consent, and have had prior therapy including radiotherapy and temozolomide. Participants need a performance status score indicating they can carry out daily activities and must agree to use effective contraception.Inclusion Criteria
I've had radiotherapy and temozolomide as my first treatment and it's been at least 28 days since my last treatment.
I agree to use effective birth control during and up to 6 months after treatment.
Life expectancy > 12 weeks.
+7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive N-803 subcutaneously, PD-L1 t-haNK intravenously, and Bevacizumab intravenously in 28-day cycles for a maximum of 76 weeks
76 weeks
Visits on days 1 and 15 of each 28-day cycle
Follow-up
Participants are monitored for survival status every 12 weeks for the first 2 years, then yearly thereafter
2 years
Every 12 weeks (± 2 weeks) for the first 2 years, then yearly
Participant Groups
The study tests the combination of N-803 (given under the skin), PD-L1 t-haNK (given into the vein), and Bevacizumab (also IV) in patients with recurrent or progressive glioblastoma. Treatments are given in cycles every two weeks up to 76 weeks unless side effects become too severe or disease progresses.
1Treatment groups
Experimental Treatment
Group I: Pilot Combination TherapyExperimental Treatment3 Interventions
Participants will receive N-803 1 mg subcutaneously (SC), PD-L1 t-haNK (\~2 × 10\^9 cells/infusion) intravenously (IV), and Bevacizumab (10 mg/kg IV) combination therapy during 28-day cycles on days 1 and 15 of each cycle. Maximum treatment period is 76 weeks, 19 cycles.
Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:
🇪🇺 Approved in European Union as Avastin for:
- Colorectal cancer
- Breast cancer
- Non-small cell lung cancer
- Renal cell carcinoma
- Ovarian cancer
🇺🇸 Approved in United States as Avastin for:
- Colorectal cancer
- Non-small cell lung cancer
- Glioblastoma
- Renal cell carcinoma
- Cervical cancer
- Ovarian cancer
🇯🇵 Approved in Japan as Avastin for:
- Colorectal cancer
- Non-small cell lung cancer
- Breast cancer
- Renal cell carcinoma
- Ovarian cancer
🇨🇦 Approved in Canada as Avastin for:
- Colorectal cancer
- Non-small cell lung cancer
- Breast cancer
- Renal cell carcinoma
- Ovarian cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Providence Medical FoundationFullerton, CA
Hoag Memorial Hospital PresbyterianNewport Beach, CA
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Who Is Running the Clinical Trial?
ImmunityBio, Inc.Lead Sponsor
References
Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model. [2022]Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules, including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single-agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single-agent anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy in 50%, 20%, and 15% of treated animals, respectively. Combination therapy of anti-CTLA-4 plus anti-PD-1 cured 75% of the animals, even against advanced, later-stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor rechallenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8(+) and natural killer cells and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma.
Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab. [2021]Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post-Bev recurrent tumors from 9 patients were included. The expression of programmed cell death-1 (PD-1)/PD ligand-1 (PD-L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD-L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P
Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. [2023]PD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers.
Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma. [2019]Combination regimen with bevacizumab (BEV) and vorinostat is well tolerated in patients with recurrent glioblastoma.Treatment of recurrent glioblastoma remains challenging as this study and others attempt to improve progression-free survival and overall survival with BEV-containing regimens.
A Systematic Review of the Tumor-Infiltrating CD8+ T-Cells/PD-L1 Axis in High-Grade Glial Tumors: Toward Personalized Immuno-Oncology. [2021]Based on preclinical findings, programmed death-ligand 1 (PD-L1) can substantially attenuate CD8+ T-cell-mediated anti-tumoral immune responses. However, clinical studies have reported controversial results regarding the significance of the tumor-infiltrating CD8+ T-cells/PD-L1 axis on the clinical picture and the response rate of patients with high-grade glial tumors to anti-cancer therapies. Herein, we conducted a systematic review according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements to clarify the clinical significance of the tumor-infiltrating CD8+ T-cells/PD-L1 axis and elucidate the impact of this axis on the response rate of affected patients to anti-cancer therapies. Indeed, a better understanding of the impact of this axis on the response rate of affected patients to anti-cancer therapies can provide valuable insights to address the futile response rate of immune checkpoint inhibitors in patients with high-grade glial tumors. For this purpose, we systematically searched Scopus, Web of Science, Embase, and PubMed to obtain peer-reviewed studies published before 1 January 2021. We have observed that PD-L1 overexpression can be associated with the inferior prognosis of glioblastoma patients who have not been exposed to chemo-radiotherapy. Besides, exposure to anti-cancer therapies, e.g., chemo-radiotherapy, can up-regulate inhibitory immune checkpoint molecules in tumor-infiltrating CD8+ T-cells. Therefore, unlike unexposed patients, increased tumor-infiltrating CD8+ T-cells in anti-cancer therapy-exposed tumoral tissues can be associated with the inferior prognosis of affected patients. Because various inhibitory immune checkpoints can regulate anti-tumoral immune responses, the single-cell sequencing of the cells residing in the tumor microenvironment can provide valuable insights into the expression patterns of inhibitory immune checkpoints in the tumor micromovement. Thus, administrating immune checkpoint inhibitors based on the data from the single-cell sequencing of these cells can increase patients' response rates, decrease the risk of immune-related adverse events development, prevent immune-resistance development, and reduce the risk of tumor recurrence.
CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy. [2020]Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults and currently incurable. Despite multimodal treatment regimens, median survival in unselected patient cohorts is <1 year, and recurrence remains almost inevitable. Escape from immune surveillance is thought to contribute to the development and progression of GB. While GB tumors are frequently infiltrated by natural killer (NK) cells, these are actively suppressed by the GB cells and the GB tumor microenvironment. Nevertheless, ex vivo activation with cytokines can restore cytolytic activity of NK cells against GB, indicating that NK cells have potential for adoptive immunotherapy of GB if potent cytotoxicity can be maintained in vivo. NK cells contribute to cancer immune surveillance not only by their direct natural cytotoxicity which is triggered rapidly upon stimulation through germline-encoded cell surface receptors, but also by modulating T-cell mediated antitumor immune responses through maintaining the quality of dendritic cells and enhancing the presentation of tumor antigens. Furthermore, similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy. Here, we discuss effects of the GB tumor microenvironment on NK-cell functionality, summarize early treatment attempts with ex vivo activated NK cells, and describe relevant CAR target antigens validated with CAR-T cells. We then outline preclinical approaches that employ CAR-NK cells for GB immunotherapy, and give an overview on the ongoing clinical development of ErbB2 (HER2)-specific CAR-NK cells currently applied in a phase I clinical trial in glioblastoma patients.
KHYG-1 Cells With EGFRvIII-specific CAR Induced a Pseudoprogression-like Feature in Subcutaneous Tumours Derived from Glioblastoma-like Cells. [2020]We previously established a novel type of epidermal growth factor receptor variant III (EGFRvIII)-specific chimeric antigen receptor (CAR)-expressing natural killer (NK) cell line, designated EvCAR-KHYG-1, which inhibited the growth of glioblastoma (GBM) cells in vitro via apoptosis.
Intracranial injection of natural killer cells engineered with a HER2-targeted chimeric antigen receptor in patients with recurrent glioblastoma. [2023]Glioblastoma (GB) is incurable at present without established treatment options for recurrent disease. In this phase I first-in-human clinical trial we investigated safety and feasibility of adoptive transfer of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2, which is expressed at elevated levels by a subset of glioblastomas.
Investigating the Effects of Olaparib on the Susceptibility of Glioblastoma Multiforme Tumour Cells to Natural Killer Cell-Mediated Responses. [2023]Glioblastoma multiforme (GBM) is the most common adult primary brain malignancy, with dismal survival rates of ~14.6 months. The current standard-of-care consists of surgical resection and chemoradiotherapy, however the treatment response is limited by factors such as tumour heterogeneity, treatment resistance, the blood-brain barrier, and immunosuppression. Several immunotherapies have undergone clinical development for GBM but demonstrated inadequate efficacy, yet future combinatorial approaches are likely to hold more promise. Olaparib is FDA-approved for BRCA-mutated advanced ovarian and breast cancer, and clinical studies have revealed its utility as a safe and efficacious radio- and chemo-sensitiser in GBM. The ability of Olaparib to enhance natural killer (NK) cell-mediated responses has been reported in prostate, breast, and lung cancer. This study examined its potential combination with NK cell therapies in GBM by firstly investigating the susceptibility of the GBM cell line T98G to NK cells and, secondly, examining whether Olaparib can sensitise T98G cells to NK cell-mediated responses. Here, we characterise the NK receptor ligand profile of T98G cells and demonstrate that Olaparib does not dampen T98G susceptibility to NK cells or elicit immunomodulatory effects on the function of NK cells. This study provides novel insights into the potential combination of Olaparib with NK cell therapies for GBM.
The PD-1/B7-H1 pathway modulates the natural killer cells versus mouse glioma stem cells. [2023]Glioblastoma multiforme (GBM) is the most malignant primary type of brain tumor in adults. There has been increased focus on the immunotherapies to treat GBM patients, the therapeutic value of natural killer (NK) cells is still unknown. Programmed death-1 (PD-1) is a major immunological checkpoint that can negatively regulate the T-cell-mediated immune response. We tested the combination of the inhibiting the PD-1/B7H1 pathway with a NK-cell mediated immune response in an orthotopic mouse model of GBM.