HER2 t-haNK / ImmunityBio - LARVOL DELTA

Local CAR-NK cell therapy in combination with systemic checkpoint inhibition induces anti-tumor responses even in distant tumor locations in an immunocompetent glioblastoma mouse model (SNO 2025) - "We showed previously that a combination of local injection of HER2-specific NK-92/5.28.z CAR-NK cells and systemic anti-PD-1 checkpoint inhibition modulates the immunosuppressive TME to a more inflammatory phenotype... The induction of an endogenous immune response by local therapy with HER2-specific CAR-NK cells in combination with systemic checkpoint inhibition is an essential step to achieve therapeutic efficacy. Thereby, tumor control can also be attained in areas not directly accessible for locally injected CAR-NK cells. Ongoing work aims to elucidate the underlying immunological mechanisms and further increase efficacy of this approach."

Checkpoint inhibition • Combination therapy • IO biomarker • Preclinical • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • HER-2 • PD-L1

Local CAR-NK cell therapy in combination with systemic checkpoint inhibition induces anti-tumor responses even in distant tumor locations in an immunocompetent glioblastoma mouse model (WFNOS 2025) - "We showed previously that a combination of local injection of HER2-specific NK-92/5.28.z CAR-NK cells and systemic anti-PD-1 checkpoint inhibition modulates the immunosuppressive TME to a more inflammatory phenotype... The induction of an endogenous immune response by local therapy with HER2-specific CAR-NK cells in combination with systemic checkpoint inhibition is an essential step to achieve therapeutic efficacy. Thereby, tumor control can also be attained in areas not directly accessible for locally injected CAR-NK cells. Ongoing work aims to elucidate the underlying immunological mechanisms and further increase efficacy of this approach."

Checkpoint inhibition • Combination therapy • IO biomarker • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Solid Tumor • HER-2 • PD-L1

CAR-NK cell therapy combined with checkpoint inhibition induces a distant anti-tumor response in an immunocompetent glioblastoma mouse model (EANO 2025) - "We have previously shown that combination of NK-92/5.28.z CAR-NK cells and anti-PD-1 checkpoint inhibition modulates the immunosuppressive TME to a more anti-tumorigenic phenotype... The activation of an endogenous immune response by HER2-specific CAR-NK cells in combination with checkpoint inhibition is important for therapeutic efficacy, providing tumor control in areas not accessible for CAR-NK cells. Ongoing work aims at elucidating the underlying immunological mechanisms and further increasing efficiency of this approach."

Checkpoint inhibition • IO biomarker • Preclinical • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • HER-2 • PD-L1

ErbB2/HER2-targeted CAR-NK cells eliminate breast cancer cells in an organoid model that recapitulates tumor progression. (PubMed, Mol Ther) - "Importantly, NK-92/5.28.z cells retained high and specific cytotoxicity against these breast cancer cells in vitro and in an aggressive organoid-based in vivo mouse model that reflects advanced-stage disease. Our data highlight the therapeutic potential of NK-92/5.28.z cells against ErbB2-positive breast cancer, supporting their further development toward clinical application."

IO biomarker • Journal • Brain Cancer • Breast Cancer • CNS Tumor • Glioblastoma • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • TP53

CAR-NK cell therapy combined with checkpoint inhibition induces an NKT cell response in glioblastoma. (PubMed, Br J Cancer) - "The combination therapy reverted the immunosuppressive tumor microenvironment with increased T and NKT cell infiltration. This resulted in successful treatment of advanced orthotopic tumors refractory to CAR-NK cell monotherapy."

Checkpoint inhibition • IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CD4 • HER-2

Modulation of the intratumoral immune microenvironment by local therapy with natural killer cells engineered with a HER2-targeted chimeric antigen receptor in combination with systemic anti-PD-1 checkpoint inhibition in patients with recurrent glioblastoma (SNO 2024) - "In the multicenter CAR2BRAIN phase I first-in-human clinical trial, we investigated the modulation of the tumor microenvironment by repetitive local injection of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2 alone and in combination with systemic anti-PD-1 checkpoint inhibitor therapy in patients with recurrent HER2-positive GB. Local immunotherapy with HER2-targeted CAR-NK cells is feasible and safe both as monotherapy and in combination with the systemic checkpoint inhibitor ezabenlimab and induces local immune reactions in CSF and tumor tissue. Given the signal for possible clinical benefit provided by the increase in PFS in the patients of the biopsy-treat-resect-treat cohort, further trials are warranted."

Checkpoint inhibition • Clinical • Combination therapy • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CD4 • CD8 • FOXP3 • HER-2

Repetitive intracranial injection of natural killer cells engineered with a HER2-targeted chimeric antigen receptor alone and in combination with systemic anti-PD-1 checkpoint inhibition in patients with recurrent glioblastoma (EANO 2024) - "In the multicenter CAR2BRAIN phase I first-in-human clinical trial, we investigated repetitive local adoptive transfer of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2 alone and in combination with the anti-PD-1 checkpoint inhibitor ezabenlimab in patients with recurrent HER2-positive GB. Immunotherapy with repetitive intracranial injection of HER2-targeted CAR-NK cells is feasible and safe both as monotherapy and in combination with the systemic checkpoint inhibitor ezabenlimab, and favorably modulates the intratumoral immune microenvironment. Given the highly promising results obtained so far, further trials are warranted to confirm the potential clinical benefit of this strategy."

Checkpoint inhibition • Clinical • Combination therapy • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CD4 • CD8 • FOXP3 • HER-2

Bortezomib promotes the TRAIL-mediated killing of resistant rhabdomyosarcoma by ErbB2/Her2-targeted CAR-NK-92 cells via DR5 upregulation. (PubMed, Mol Ther Oncol) - "Western blot analyses indicated that the combination treatment with bortezomib and NK-92/5.28.z cells increased apoptosis by interacting with the nuclear factor κB, JNK, and caspase pathways. Overall, bortezomib pretreatment can sensitize r/r RMS tumors to CAR- and, by upregulating DR5, TRAIL-mediated cytotoxicity of NK-92/5.28.z cells."

IO biomarker • Journal • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • HER-2

CAR2BRAIN: Intracranial Injection of NK-92/5.28.z Cells in Combination With Intravenous Ezabenlimab in Patients With Recurrent HER2-positive Glioblastoma (clinicaltrials.gov) - P1 | N=42 | Active, not recruiting | Sponsor: Johann Wolfgang Goethe University Hospital | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2023 ➔ Jun 2026 | Trial primary completion date: Oct 2023 ➔ Dec 2025

Combination therapy • Enrollment closed • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • HER-2

CAR-mediated targeting of NK cells overcomes tumor immune escape caused by ICAM-1 downregulation. (PubMed, J Immunother Cancer) - "Downregulation of ICAM-1 on breast cancer cells is a critical escape mechanism from trastuzumab-triggered ADCC. In contrast, CAR-NK cells are able to overcome cancer cell resistance caused by ICAM-1 reduction, highlighting the potential of CAR-NK cells in cancer immunotherapy."

IO biomarker • Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ICAM1 • KLRC1

ErbB2 (HER2)-CAR-NK-92 cells for enhanced immunotherapy of metastatic fusion-driven alveolar rhabdomyosarcoma. (PubMed, Front Immunol) - "The persistence of NK-92/5.28.z cells at tumor sites demonstrates efficient antitumor response, which could help overcome current obstacles in the treatment of solid tumors. These findings encourage further development of NK-92/5.28.z cells as off-the-shelf immunotherapy for the treatment of metastatic RMS."

Journal • Metastases • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • HER-2

Intracranial injection of NK cells engineered with a HER2-targeted chimeric antigen receptor in patients with recurrent glioblastoma. (PubMed, Neuro Oncol) - "Intracranial injection of HER2-targeted CAR-NK cells is feasible and safe in patients with recurrent GB. 1 x 10 8 NK-92/5.28.z cells was determined as the maximum feasible dose for a subsequent expansion cohort with repetitive local injections of CAR-NK cells."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CD8 • HER-2

[VIRTUAL] Combination therapy of CAR-NK-cells and anti-PD-1 results in high efficacy against advanced-stage glioblastoma in a syngeneic mouse model and induces protective anti-tumor immunity in vivo (EANO 2021) - P1 | "Our data demonstrate that efficacy of NK-92/5.28.z cells can be enhanced by combination with checkpoint blockade, resulting in successful treatment of advanced tumors refractory to NK-92/5.28.z monotherapy. Furthermore, the combination therapy induced a cytotoxic rather than immunosuppressive TME, leading to a primed immune system. To translate the concept of CAR-NK-cell therapy plus checkpoint inhibition to a clinical setting, we are adding a combination therapy cohort to our ongoing phase I clinical study (CAR2BRAIN; NCT03383978)."

Combination therapy • IO biomarker • Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • FOXP3 • LAG3 • PD-L1

AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastoma. (PubMed, Oncoimmunology) - "Here, we evaluated tumor-cell specific delivery of an anti-PD-1 immunoadhesin (aPD-1) via a targeted adeno-associated viral vector (AAV) as well as HER2-specific NK-92/5.28.z (anti-HER2.CAR/NK-92) cells as components for a combination immunotherapy...In subcutaneous GL261-HER2 and Tu2449-HER2 immunocompetent mouse models, administration of the combination therapy significantly prolonged survival, including complete tumor control in several animals in the GL261-HER2 model. In summary, local therapy with aPD-1 encoding HER2-AAVs in combination with anti-HER2.CAR/NK-92 cells may be a promising novel strategy for GB immunotherapy with the potential to enhance efficacy and reduce systemic side effects of immune-checkpoint inhibitors."

Checkpoint inhibition • Combination therapy • IO biomarker • Journal • Brain Cancer • CNS Tumor • Gene Therapies • Glioblastoma • Immune Modulation • Inflammation • Oncology • Solid Tumor • HER-2

CAR2BRAIN: Intracranial Injection of NK-92/5.28.z Cells in Combination With Intravenous Ezabenlimab in Patients With Recurrent HER2-positive Glioblastoma (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: Johann Wolfgang Goethe University Hospital | N=30 ➔ 42 | Trial completion date: Dec 2022 ➔ Dec 2023 | Trial primary completion date: Sep 2022 ➔ Oct 2023

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Immunology • Oncology • Solid Tumor • HER-2

[VIRTUAL] Local immunotherapy of glioblastoma via AAV-mediated gene transfer of checkpoint inhibitors in combination with CAR-NK cells (EANO 2021) - "Local therapy with aPD-1 encoding HER2-AAVs in combination with NK-92/5.28.z cells is a promising novel strategy for GB immunotherapy with the potential to enhance efficacy and reduce side effects."

Checkpoint inhibition • Combination therapy • IO biomarker • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • HER-2 • PD-L1