P1, N=11, Completed, Seattle Children's Hospital | Active, not recruiting --> Completed | Trial completion date: Mar 2040 --> Dec 2023 | Trial primary completion date: Mar 2025 --> Dec 2023

P1, N=50, Enrolling by invitation, Shanghai Simnova Biotechnology Co.,Ltd.

P1, N=30, Recruiting, Second Affiliated Hospital of Guangzhou Medical University | Trial completion date: Aug 2026 --> Aug 2036 | Trial primary completion date: Aug 2024 --> Aug 2026

P1, N=11, Recruiting, Second Affiliated Hospital of Guangzhou Medical University | Trial primary completion date: Nov 2024 --> Nov 2029

P1, N=30, Recruiting, Second Affiliated Hospital of Guangzhou Medical University | Trial completion date: May 2025 --> May 2035 | Trial primary completion date: May 2025 --> May 2030

P1, N=44, Recruiting, Seattle Children's Hospital | Trial completion date: Jun 2038 --> Jun 2040 | Trial primary completion date: Jun 2024 --> Jun 2025

P1, N=16, Recruiting, Shanghai Simnova Biotechnology Co.,Ltd. | Trial primary completion date: Aug 2023 --> May 2024

P1, N=44, Recruiting, Seattle Children's Hospital | Trial primary completion date: Jun 2023 --> Jun 2024

These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.

P1, N=72, Recruiting, Seattle Children's Hospital | Not yet recruiting --> Recruiting

In addition, the histopathological examination of mouse organs showed no obvious organic damage. Our findings confirmed that PD1 blocking and CCR6 can enhance the anti-tumor function of EGFR CAR-T cells in an NSCLC xenograft model, providing an effective treatment strategy to improve the efficacy of CAR-T in NSCLC.

Our data further support a role for metabolic reprogramming in immunomodulatory treatments and highlight the utility of genes like PGC-1α as attractive candidates to include in cargo along with chimeric receptors or TCRs for cell therapy of solid tumors.

P1, N=18, Recruiting, University of Pennsylvania | Not yet recruiting --> Recruiting

P1, N=30, Recruiting, Second Affiliated Hospital of Guangzhou Medical University | Trial completion date: Aug 2023 --> Aug 2026 | Trial primary completion date: Aug 2022 --> Aug 2024

P1, N=11, Active, not recruiting, Seattle Children's Hospital | Recruiting --> Active, not recruiting | N=36 --> 11

Our results demonstrates anti-tumor activity of EGFR806 CAR T cells against TNBC cells in vitro and in vivo. Given EGFR806 CAR T cells are currently undergoing clinical trials in primary brain tumor patients without obvious toxicity, our results are immediately actionable against the TNBC-BM patient population.

P1, N=18, Not yet recruiting, University of Pennsylvania | Initiation date: Jun 2022 --> Mar 2023

Hinge-modified EGFR-sdCAR cells showed clear functional attenuation in Jurkat-CAR-T cells and primary human CAR-T cells from multiple donors in vitro and in vivo. Overall, these results indicate that hinge length tuning provides a programmable strategy for throttling antigenic sensitivity in CARs targeting membrane-proximal epitopes, and could be employed for CAR-optimization and improved tumor selectivity.

Mechanistically, radiation significantly increased Icam1 expression on TNBC cells via activating NF-κB signaling, thereby promoting CAR-T cell infiltration and killing. These results suggest that CAR-T therapy combined with radiotherapy may be a promising strategy for TNBC treatment.

Overall, we demonstrated that 3D µCT/BLT is a valuable non-isotope-based technology for whole-body cell therapy monitoring and investigating CAR T cell pharmacokinetics. We also presented combining LSFM and MICS for ex vivo 3D- and 2D-microscopy tissue analysis to assess intratumoral therapeutic cell distribution and status.

Conclusion This work validates Cx43 as a double therapeutic target in TNBC, by (i) showcasing a tumour-suppressive role in both primary and metastatic scenarios and (ii) resensitizing primary tumour cells to NKs cytotoxicity. Notably, the aforementioned results have been confirmed in physiologically relevant homo- and hetero-spheroid models comprising breast CAFs.

P1, N=30, Recruiting, Second Affiliated Hospital of Guangzhou Medical University

We show that NG-347 changes the TME to a pro-inflammatory environment resulting in the recruitment and activation of both CAR T cells and mouse innate immune cells. We also show that the transgenes encoded by the virus are critical as synergy is lost in their absence.

P1, N=30, Recruiting, Chinese PLA General Hospital | Not yet recruiting --> Recruiting

Currently, there are no approved therapies for NSCLC patients with acquired resistance to the third-generation EGFR TKI osimertinib (OSI)...Blockade of the TGF-β pathway using galunisertib significantly enhanced the activity of EGFR CAR-NK cells against OSI-resistant NSCLC cells...DNTGFBRII-CAR-NK cells showed higher killing activity against OSI-resistant NSCLC cells and were resistant to TGF-β-mediated immunosuppression. In conclusion, EGFR CAR-NK cells show significant anti-tumor activity to EGFR TKI-resistant NSCLC cells, and the cytotoxicity is enhanced in combination with OSI treatment and blockade of the TGF-β pathway.

P1, N=18, Not yet recruiting, University of Pennsylvania | Initiation date: Dec 2021 --> Jun 2022

P1, N=30, Not yet recruiting, Chinese PLA General Hospital | Trial completion date: Jul 2023 --> Dec 2024 | Initiation date: Aug 2021 --> Dec 2021 | Trial primary completion date: Jul 2022 --> Dec 2023

P1, N=18, Not yet recruiting, University of Pennsylvania

The aim of our study was to investigate the use of TPs on the Idylla system to reduce TATs, such that results would be available with routine surgical pathology reports. Our approach of collecting TP samples directly from tissue and testing them via the Idylla system significantly reduced potential TATs. Samples processed with rapid intent often provided results the same day as or before the pathology report release.

Double-positive cells for PD1 and activation markers also displayed a positive correlation, suggesting PD1 highlights a population of activated CAR T cells. Further characterization of predictors of EGFRvIII-directed CART treatment efficacy may improve selection of patients and starting T cell populations for clinical expansion.

Importantly, intracranially-administered D2C7 CAR significantly prolonged survival of mice bearing orthotopic U87vIII or U87/U87vIII heterogeneous tumors compared to mock-treated controls. Altogether, these data provide evidence that D2C7 CAR T cells represent a viable therapeutic option for EGFRwt/EGFRvIII heterogeneous tumors.

Diffuse distribution of CLTX.Cy5.5 was also seen in fixed xenograft sections of PBT003-4, PBT1206, PBT030-2, PBT051 and PBT138 tumor cells, and not obviously associated with more discrete staining for IL13Rα2 and EGFR. Ongoing experiments are further examining association of CLTX with other putative components of CLTX receptor complexes, and their redistribution during binding by CLTX and CLTX-CAR T cells.

We found that combined inhibition of both EGFR and PDGFRA using FDA-approved EGFR-targeted agents (Erlotinib, Gefitinib, Dacomitinib, Neratinib, and Osimertinib) and Crenolanib, respectively, leads to synergistic cytotoxicity in vitro . These pathways are targetable with FDA-approved agents that could be used in patients with GBM with Chr. 7 gain.

Immunotherapy is considered a milestone in breast cancer treatments, including the engineered immune cells (CAR-T cell therapy) to better target the tumor cells, vaccines to stimulate the patient's immune system against tumor antigens, and checkpoint inhibitors (PD-1, PD-L1, and CTLA4) to block molecules that mediate immune inhibition. Targeted therapies and immunotherapy tested in breast cancer clinical trials are discussed here, with special emphasis on combinatorial approaches which are believed to maximize treatment efficacy and enhance patient survival.

HER3 is frequently overexpressed by RMS and can play a role in the residual myogenic differentiation ability and in resistance to signaling-directed therapy. HER family members could be exploited for therapeutic approaches in two ways: blocking the HER member (playing a driving role for tumor growth with antibodies or inhibitors) and targeting expressed HER members to vehiculate toxins or immune effectors.

The ICAM-1/LFA-1 interaction interference, through antibody or shRNA blockade, prevented CAR T-cell enrichment in tumor islets. The requirement for IFNγ and ICAM-1 to enable CAR T-cell entry into tumor islets is of significance for improving CAR T-cell therapy in solid tumors.

Trastuzumab is a monoclonal antibody against HER2 that prevents HER2-mediated signaling; it is administered mainly in HER2-positive cancers, such as breast, colorectal, biliary tract, and non-small-cell lung cancers...PD/PDL-1 inhibitors can cause myocarditis, rare but potentially fulminant and associated with a high fatality rate. CAR-T therapy is associated with several cardiac toxic effects, mainly in the context of a systemic adverse effect, the cytokines release syndrome.

7 gain, we found that combined inhibition of both EGFR and PDGFRA using a variety of FDA-approved EGFR-targeted agents (Erlotinib, Gefitinib, Dacomitinib, Neratinib, and Osimertinib) and Crenolanib, respectively, leads to synergistic cytotoxicity in vitro. We show that combined inhibition of EGFR and PDGFRA exerts synergistic cytotoxicity in GBM and prevents resistance pathways that emerge during single-agent targeted therapy against these receptor tyrosine kinases. These pathways are targetable with FDA-approved agents that could be used in patients with GBM with Chr. 7 gain.

Instead, in glioblastoma tumors, IFNγR signaling was required for sufficient adhesion of CAR T-cells to mediate productive cytotoxicity. Our work demonstrates that liquid and solid tumors differ in their interactions with CAR T-cells and suggests that enhancing T-cell/tumor interactions may yield improved responses in solid tumors.

We also outline promising new CAR T cells that are in pre-clinical development. Finally, we discuss strategies that are being used to overcome tumor-mediated immunosuppression in solid tumors; these strategies have the potential to improve clinical outcomes of CAR T cell therapy for children with sarcoma.

P1, N=11, Recruiting, Second Affiliated Hospital of Guangzhou Medical University

Amphiregulin did not help in distinguishing enchondromas from low-grade chondrosarcomas. The present study is the first to document the expression of this immunohistochemical marker in enchondromas. Furthermore, amphiregulin expression in enchondromas was localized in short bones, indicating a phenotypic distinction from that in long bones. This distinction may contribute to an improved understanding of the pathogenesis of these lesions.