PD-L1.t-haNK / ImmunityBio - LARVOL DELTA

Phase II Trial of Neoadjuvant (NA) Pembrolizumab + N-803 alone or in combination with PD-L1 t-haNK Cells for Resectable Head and Neck Squamous Cell Carcinoma (HNSCC) (MHNCS 2026) - P2 | "TBD"

Clinical • Combination therapy • IO biomarker • P2 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • IL15 • IL2 • PD-L1

QUILT 3.064: QUILT-3.064: PD-L1 t-haNK In Subjects With Locally Advanced Or Metastatic Solid Cancers (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: ImmunityBio, Inc. | Trial completion date: Nov 2025 ➔ Mar 2026 | Trial primary completion date: Nov 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • PD-L1

The ATR inhibitor tuvusertib (M1774) sensitizes prostate carcinoma to natural killer cell-mediated cytotoxicity, which is further augmented by the IL-15 receptor superagonist N-803. (PubMed, Cancer Immunol Immunother) - "Enhanced avelumab-mediated antibody-dependent cell-mediated cytotoxicity and lysis by PD-L1 targeting high-affinity NK (PD-L1 t-haNK) cells were observed in tuvusertib-treated DU145. In vivo in the DU145 PCa xenograft model, tuvusertib and N-803 combination therapy demonstrated marked and significant antitumor efficacy relative to either monotherapy, eliciting superior tumor growth control and prolonging survival. Our findings support further investigation into the use of ATRi with immune checkpoint blockade and/or immune-stimulating agents in prostate cancer."

Journal • Ataxia • Genito-urinary Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Prostate Cancer • Solid Tumor • BCL2L1 • CDKN1A • IL15 • NKG2D • TNFRSF10B

QUILT-88: Combination Immunotherapy Plus Standard-of-Care Chemotherapy Versus Standard-of-Care Chemotherapy for the Treatment of Locally Advanced or Metastatic Pancreatic Cancer (clinicaltrials.gov) - P2 | N=328 | Active, not recruiting | Sponsor: ImmunityBio, Inc. | Trial completion date: Oct 2025 ➔ May 2026

Trial completion date • Oncology • Pancreatic Cancer • Solid Tumor

First-in-human immunotherapy targeting lymphopenia in recurrent Glioblastoma Multiform (GBM): NAI and PD-L1 t-haNK plus Bevacizumab with complete response (SNO 2025) - "Anktiva (nogapendekin alfa-inbakicept, NAI), an IL-15 receptor superagonist, is the first treatment to address lymphopenia by proliferating NK and T-cells. Administered in combination with PD-L1 targeted high-affinity CAR-NK cells (PD-L1 t-haNK) and bevacizumab, treating lymphopenia was hypothesized to elicit tumor response in recurrent GBMMETHODS : Phase I QUILT-3.078 trial of participants with GBM (IDH WT) who recurred after surgery and temozolomide/XRT...This is the first report of disease response in participants with refractory GBM who received orchestrated temporal immunotherapy with CAR-NK cells combined with an IL-15 receptor superagonist and bevacizumab to treat lymphopenia. Updated data to be presented."

Clinical • First-in-human • Lymphopenia • P1 data • Brain Cancer • Cardiovascular • Glioblastoma • Hematological Malignancies • Pulmonary Embolism • Respiratory Diseases • Solid Tumor • IL15 • PD-L1

First-in-human immunotherapy targeting lymphopenia in recurrent Glioblastoma Multiform (GBM): NAI and PD-L1 t-haNK plus Bevacizumab with complete response (WFNOS 2025) - "Anktiva (nogapendekin alfa-inbakicept, NAI), an IL-15 receptor superagonist, is the first treatment to address lymphopenia by proliferating NK and T-cells. Administered in combination with PD-L1 targeted high-affinity CAR-NK cells (PD-L1 t-haNK) and bevacizumab, treating lymphopenia was hypothesized to elicit tumor response in recurrent GBMMETHODS : Phase I QUILT-3.078 trial of participants with GBM (IDH WT) who recurred after surgery and temozolomide/XRT...This is the first report of disease response in participants with refractory GBM who received orchestrated temporal immunotherapy with CAR-NK cells combined with an IL-15 receptor superagonist and bevacizumab to treat lymphopenia. Updated data to be presented."

Clinical • First-in-human • Lymphopenia • P1 data • Brain Cancer • Cardiovascular • Glioblastoma • Hematological Malignancies • Pulmonary Embolism • Respiratory Diseases • Solid Tumor • IL15 • PD-L1

ATR inhibitor tuvusertib induces immunogenic modulation and sensitizes prostate carcinoma to natural killer cell-mediated cytotoxicity which is further enhanced by the IL-15 superagonist N-803 (SITC 2025) - "Impedance-based real-time cell analysis was used to assess the lysis of tuvusertib-treated PCa cells upon co-incubation with PBMC-derived NK cells in the presence or absence of anti-PD-L1 avelumab, PD-L1 targeting high-affinity NK cell line (PD-L1 t-hANK) cells, or TRAIL ligand. TRAIL signaling blockade mitigated the NK cell lysis of tuvusertib-treated cells. In vivo, tuvusertib and N-803 combination therapy resulted in the significant tumor growth control of the DU145 xenograft (p<0.0001) and the prolonged survival of the animals (p<0.05).Conclusions This study supports the combination of the ATR inhibitor tuvusertib with the anti-PD-L1 avelumab and/or IL-15 superagonist N-803 for prostate carcinoma.Acknowledgements This work was funded by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health and via Cooperative Research and Development Agreements (CRADAs) between the NCI and the..."

IO biomarker • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • BCL2L1 • CDKN1A • TNFRSF10B

N-803 and PD-L1 t-haNK Combined With Bevacizumab for Recurrent or Progressive Glioblastoma (clinicaltrials.gov) - P2 | N=34 | Recruiting | Sponsor: ImmunityBio, Inc. | Active, not recruiting ➔ Recruiting

Enrollment open • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • PD-L1

QUILT 3.064: QUILT-3.064: PD-L1 t-haNK In Subjects With Locally Advanced Or Metastatic Solid Cancers (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: ImmunityBio, Inc. | Trial completion date: Dec 2024 ➔ Nov 2025 | Trial primary completion date: Oct 2024 ➔ Nov 2025

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • PD-L1

QUILT-3.055: A Study of Combination Immunotherapies in Patients Who Have Previously Received Treatment With Immune Checkpoint Inhibitors (clinicaltrials.gov) - P2 | N=40 | Active, not recruiting | Sponsor: ImmunityBio, Inc. | Recruiting ➔ Active, not recruiting

Checkpoint inhibition • Enrollment closed • Cervical Cancer • Colorectal Cancer • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Genito-urinary Cancer • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Melanoma • Merkel Cell Carcinoma • Microsatellite Instability • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Skin Cancer • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer • ALK • BRAF • MSI

N-803 and PD-L1 t-haNK Combined With Bevacizumab for Recurrent or Progressive Glioblastoma (clinicaltrials.gov) - P2 | N=34 | Active, not recruiting | Sponsor: ImmunityBio, Inc. | Recruiting ➔ Active, not recruiting | N=20 ➔ 34

Enrollment change • Enrollment closed • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • PD-L1

Pembrolizumab + N-803 Alone or in Combination With PD-L1 t-haNK Cells for Resectable Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Trial completion date: Dec 2027 ➔ Dec 2028 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Enrollment open • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

QUILT-505: PD-L1 t-haNK, N-803 IL-15sa and Cetuximab for Recurrent, Metastatic HNSCC (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Glenn J. Hanna | Trial primary completion date: Jul 2025 ➔ Jul 2026

Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Immunotherapy Combination: Irradiated PD-L1 CAR-NK Cells Plus Pembrolizumab Plus N-803 for Subjects With Recurrent/Metastatic Gastric or Head and Neck Cancer (clinicaltrials.gov) - P2 | N=18 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting | N=55 ➔ 18

Enrollment change • Enrollment closed • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • PD-L1

Association of lymphopenia rescue and CA19-9 levels with overall survival following IL-15 superagonist N-803 and PD-L1 t-haNK chemo-immunotherapy for 3rd line or greater metastatic pancreatic cancer. (ASCO 2025) - P2 | "The multimodal chemo-immunotherapy protocol to induce immunogenic cell death resulted in OS that exceeded 6 months for both 3rd and ≥ 5th line patients, exceeding OS achieved by other therapies in this setting by ~2 months. It is notable that both favorable baseline ALC/CA19-9 and on-study higher ALC was associated with prolonged survival, given N-803's ability to increase both NK and CD8+/CD4+ T cells, the first FDA approved agent that proliferates lymphocytes in the face of lymphopenia. These findings support further investigation of this novel therapeutic regimen that includes PD-L1 t-haNK, and N-803 that, as an IL-15 superagonist, may be able to overcome lymphopenia and improve prognosis."

Clinical • Lymphopenia • Metastases • Hematological Malignancies • Oncology • Pancreatic Cancer • Solid Tumor • CA 19-9 • CD4 • CD8

Generation of cytokine-induced memory-like PD-L1 t-haNK (NK-92®) cells (AACR 2025) - "We show here that the Natural Killer cell line NK-92®, or 'activated' NK (aNKTM), can acquire a memory-like phenotype upon overnight induction with IL-12, IL-18, and the IL-15 superagonist N-803, as evidenced by increased steady-state IFNγ secretion (>50-fold increase) and up-regulation of CD25. This increase would then drive upregulation of PD-L1 expression on neighboring tumor cells, creating an expanding wave of targets sensitized to killing by PD-L1 t-haNK cells. A next generation, memory-like PD-L1 t-haNK cell line equipped with inducible safety switch features to remove the need for irradiation and extend their half-life in patients is being developed and would constitute a promising "off-the-shelf" cellular therapy against immunologically cold cancers."

IO biomarker • Oncology • IFNG • IL12A • IL18 • IL2RA • PD-L1

Immunogenic modulation with the ATR inhibitor tuvusertib enhances NK-mediated killing of prostate cancer [WITHDRAWN] (AACR 2025) - "Furthermore, tuvusertib treatment increased PD-L1 expression on the DU145 cells, which is associated with enhanced donor NK killing in the presence of avelumab and augmented sensitivity to PD-L1 t-haNK cells.Next, the anti-tumor effect of combining tuvusertib with N-803 (provided by ImmunityBio, Culver City, CA, USA) was investigated. Furthermore, tuvusertib synergized with N-803, resulting in a superior anticancer response. This provides a rationale for further investigation of this combination therapy."

IO biomarker • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • TNFRSF10B

Immunotherapy Combination: Irradiated PD-L1 CAR-NK Cells Plus Pembrolizumab Plus N-803 for Subjects With Recurrent/Metastatic Gastric or Head and Neck Cancer (clinicaltrials.gov) - P2 | N=55 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Dec 2027 | Trial primary completion date: Jan 2025 ➔ Jan 2027

Trial completion date • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • PD-L1

ImmunityBio Receives FDA RMAT Designation for ANKTIVA and CAR-NK for the Reversal of Lymphopenia in Patients Receiving Standard-of-Care Chemotherapy/Radiotherapy and in Treatment of Multiply Relapsed Locally Advanced or Metastatic Pancreatic Cancer (Businesswire) - "...RMAT designation follows clinical data of Absolute Lymphocyte Count (ALC) and significant Overall Survival (OS) correlations in QUILT trials across multiple tumor types....Company intends to submit...BLA for the indication of reversal of lymphopenia in patients receiving standard-of-care chemotherapy and/or radiation and for the treatment of locally advanced or metastatic pancreatic cancer, which includes the first-in-class CAR-NK (PD-L1 t-haNK). ImmunityBio to provide data from fully enrolled clinical trials in metastatic pancreatic cancer (QUILT-88) and in checkpoint relapsed NSCLC (QUILT-3.055, NSCLC Cohort) patients, as well as lymphopenia reversal across multiple tumor types (QUILT-3.055, All Cohorts), with supportive data of lymphocyte proliferation in healthy volunteers (QUILT-1.004). In addition, ImmunityBio intends to file an Expanded Access Policy (EAP) for ANKTIVA and PD-L1 t-haNK in combination with standard of care chemotherapy/radiotherapy within 15 days..."

FDA event • Non Small Cell Lung Cancer • Pancreatic Cancer

Case report: PD-L1-targeted high-affinity natural killer cells and IL-15 superagonist N-803-based therapy extend overall survival of advanced metastatic pancreatic cancer patients. (PubMed, Front Oncol) - "From late 2019 to 2021, single-patient Investigational New Drug (spIND) protocols for five mPC patients were designed and approved that generally comprised combined Abraxane (nab-paclitaxel) and gemcitabine therapy with experimental therapeutics N-803, PD-L1-targeted high-affinity natural killer (PD-L1 t-haNK) cells, and aldoxorubicin, a serum albumin-binding doxorubicin prodrug. Some patients also received stereotactic body radiation therapy (SBRT), cyclophosphamide, pembrolizumab, nivolumab, and/or experimental ETBX-051 (brachyury) and/or ETBX-061 (MUC1) vaccines...The OS of 13, 26.9, and 23.2 months for three patients is particularly notable. The findings here support the ongoing clinical investigations of N-803 and PD-L1 t-haNK cells in combination therapy."

Journal • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CA 19-9 • MUC1 • PD-L1

QUILT-3.055: a Study of Combination Immunotherapies in Patients Who Have Previously Received Treatment with Immune Checkpoint Inhibitors (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: ImmunityBio, Inc. | Active, not recruiting ➔ Recruiting | N=147 ➔ 40

Checkpoint inhibition • Enrollment change • Enrollment open • Cervical Cancer • Colorectal Cancer • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Genito-urinary Cancer • Head and Neck Cancer • Hepatocellular Cancer • Hepatology • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Melanoma • Merkel Cell Carcinoma • Microsatellite Instability • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Skin Cancer • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer • ALK • BRAF • MSI

QUILT-88: Combination Immunotherapy Plus Standard-of-Care Chemotherapy Versus Standard-of-Care Chemotherapy for the Treatment of Locally Advanced or Metastatic Pancreatic Cancer (clinicaltrials.gov) - P2 | N=328 | Active, not recruiting | Sponsor: ImmunityBio, Inc. | Trial completion date: Oct 2024 ➔ Oct 2025 | Trial primary completion date: Oct 2024 ➔ Oct 2025

Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

Recurrent pancreatic cancer treated with N-803 and PD-L1 t-haNK followed by an EGFR-targeted nanocell drug conjugate. (PubMed, Oncologist) - "The epidermal growth factor receptor-targeted antibody-nanocell conjugate E-EDV-D682 provides tumor-targeted chemotherapy in the form of its anthracycline metabolite PNU159682 (nemorubicin) cargo and is currently being studied in combination with immunomodulatory EDVs delivering the adjuvant α-galactosyl ceramide (GC)...Under the initial single-patient Investigational New Drug (spIND) protocol, the patient received N-803, PD-L1 t-haNK cells, and the albumin doxorubicin conjugate aldoxorubicin for ~27 months...Due to progression, a second spIND protocol was designed whereby the patient received E-EDV-D682 plus EDV-GC for more than 24 months, which resulted in stable disease and the patient's continued survival at the time this report was written. The patient's extended survival despite the dire prognosis associated with recurrent mPC points to the merits of this temporal combination regimen in overcoming immuno-chemo resistance with enhanced immune activity..."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD4 • CD8 • EGFR • IL15 • PD-L1

QUILT 3.064: QUILT-3.064: PD-L1 t-haNK In Subjects With Locally Advanced Or Metastatic Solid Cancers (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: ImmunityBio, Inc. | Trial primary completion date: Jun 2024 ➔ Oct 2024

Metastases • Trial primary completion date • Oncology • Solid Tumor • PD-L1

QUILT-88: Combination Immunotherapy Plus Standard-of-Care Chemotherapy Versus Standard-of-Care Chemotherapy for the Treatment of Locally Advanced or Metastatic Pancreatic Cancer (clinicaltrials.gov) - P2 | N=328 | Active, not recruiting | Sponsor: ImmunityBio, Inc. | Trial primary completion date: Jun 2024 ➔ Oct 2024

Metastases • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor