In animal models, compared with conventional CAR-T cells, B7H3-IL7R-S CAR-T cells suppressed tumor growth and prolonged overall survival. Our study demonstrated the therapeutic potential of IL7Rα-incorporating CAR-T cells for glioblastoma treatment, suggesting a promising strategy for augmenting the effectiveness of CAR-T cell therapy.

P1, N=9, Recruiting, Chulalongkorn University | Not yet recruiting --> Recruiting

P1, N=27, Not yet recruiting, UNC Lineberger Comprehensive Cancer Center | Initiation date: Mar 2024 --> Jul 2024

The iPS CD276-targeted CAR-NK cells, comparing with the iPS NK cells and the NK-free medium, exhibited specific and significant cytotoxic activity against CD276-positive ESCC PSO rather than CD276-negative NC PSO, and exhibited significant cytotoxicity against CD276-expressing cultured ESCC cells, as well as against CD276-expressing KYSE-150 in vitro and in BNDG mouse xenograft. The efficacy of the iPSC CD276-targeted CAR-NK cells demonstrated by their successful treatment of CD276-expressing ESCC in a multitude of pre-clinical models implied that they hold tremendous therapeutic potential for treating patients with CD276-expressing ESCC.

This study demonstrates a novel high-content and high-throughput screen can identify drugs to enhance CAR T cell activity. This and other high-content technologies will pave the way to develop clinical trials implementing rational drug plus CAR T cell combinatorial therapies. Importantly, the technique could also be repurposed for an array of basic and translational research applications where drugs are needed to modulate cell surface protein expression.

Our study highlights the power of CRISPR-based genetic screening in investigating tumor-CAR T interaction and identifies potential druggable targets in tumor cells that confer resistance to CAR T cell killing. Furthermore, we devised targeted strategies that synergize with CAR T therapy against GBM. These findings shed light on the development of novel combinatorial strategies for effective immunotherapy of GBM and other solid tumors.

P1, N=42, Not yet recruiting, UNC Lineberger Comprehensive Cancer Center

P1, N=27, Not yet recruiting, UNC Lineberger Comprehensive Cancer Center

Protein structure prediction suggests that linker length and compactness influence the functionality of the generated bispecific CARs. Thus, we present a bispecific CAR design strategy to prevent immune escape in AML that can be extended to other peptide-scFv combinations.

P1, N=27, Not yet recruiting, UNC Lineberger Comprehensive Cancer Center

Using an immunocompetent glioma model, we evaluated a panel of seven fully murine B7-H3 CARs with variations in transmembrane, costimulatory, and activation domains...Indeed, complete brain macrophage depletion using a CSF1R inhibitor abrogated CAR T-cell anti-tumor activity. In sum, our study highlights the critical role of CAR design and its modulation of the TIME in mediating the efficacy of adoptive immunotherapy for high-grade glioma.

We have developed a simple thaw/wash procedure to prepare B7-H3-CAR T cells for their locoregional delivery to the neural axis. While we focus here on CAR T cells, the methods could be readily adapted to other cryopreserved immune effector cell products.

Vγ9Vδ2 T cells demonstrate a robust anti-tumor effect in some glioma cases, while weaker in others. Elevated BTN2A1 and BTN3A1 expression correlates with improved response. WAT group tumors can be sensitized using a BTN3A1 agonistic antibody or bisphosphonates. Genetically engineered Vγ9Vδ2 T cells, i.e.,  Car-B7H3, show promising efficacy. These results together highlight the versatility of Vγ9Vδ2 T cells for GBM treatment.

P1/2, N=25, Recruiting, Dushu Lake Hospital Affiliated to Soochow University

P1, N=32, Recruiting, St. Jude Children's Research Hospital | Trial completion date: Feb 2026 --> Mar 2027 | Trial primary completion date: Mar 2025 --> Mar 2026

Multiple mechanisms, including reduced cancer cell proliferation, upregulation of the targeted antigen, modulation of apoptotic molecules may contribute to this signal. The information in the literature and the results we describesupport the ability of radiotherapy to improve the efficacy of CAR T cell therapy in solid tumors.

P1, N=68, Active, not recruiting, Seattle Children's Hospital | Recruiting --> Active, not recruiting

P1, N=36, Recruiting, St. Jude Children's Research Hospital | Not yet recruiting --> Recruiting

P1, N=36, Not yet recruiting, St. Jude Children's Research Hospital

In patients with rHGGs, B7H3 UCAR-T cells was not associated with any toxic effects of grade 3 or higher. B7H3 UCAR-T cells resulted in a significantly longer overall survival and a higher objective response rate than history data. B7H3 UCAR-T cells persist well in patients.

Patient-based determination of chemokines secreted by pediatric OS identifies robust targets for chemokine receptor modification of CAR T cells. CXCR2 and CXCR6 both enhance homing of B7-H3.CAR T cells, with improved antitumor activity and evidence of reduced non-specific expansion in vivo. Optimization of these receptors with additional CARs active in OS is warranted.

Further work will utilize our novel AML models to study how both cellular interactions and secreted factors produced within the TME impact CAR T cell functionality. These findings will inform strategies to improve CAR T cell design and bypass potential challenges faced when generating effective CAR T cells for pediatric AML.

B7-H3-CAR-T cells may serve as a novel therapeutic method for the targeted treatment of AML.

Stereotactic placement of the guide cannula can be adjusted to deliver CAR T cells directly into the lateral ventricle or other locations in the brain. This platform offers a reliable mechanism for the preclinical testing of repeated intracranial infusions of CAR T cells and other novel therapeutics for these devastating pediatric tumors.

Abstract is embargoed at this time.

Moreover, biochemical characterization revealed that the combined use of both CD28 and 4-1BB ICDs in the BiCisCAR resulted in the activation of three TCR downstream signaling pathways including AKT, Erk1/2 and p65.Conclusions and Future DirectionsThus, we have developed a potent BiCisCAR with dual targeting of FGFR4 and CD276 that shows optimal biochemical activity, persistence, and limited exhaustion, and addresses heterogenous expression of target antigens. This BiCisCAR will be further developed for future clinical trials in patients with high-risk RMS.

In summary, we have established an immune-competent OS model to evaluate the effector function of B7-H3-CAR T cells and have demonstrated the advantage given by 2nd genetic modifications to enhance their antitumor activity. We are currently using this model to define mechanisms of immune resistance with the goal of further enhancing OS-redirected CAR T-cell therapy.

These findings provide a strong rationale for clinically evaluating B7-H3-CAR T for pediatric patients with chemotherapy-resistant ACC. Additionally, the newly established pediatric ACC PDX models provide a valuable resource for investigating different aspects of this rare and aggressive disease.

Moreover, we derive conditions in the CAR T-cell expansion rate that determines treatment success or failure. Finally, we show that our model captures distinct CAR T-cell killing dynamics from low to high antigen receptor densities in patient-derived brain tumor cells.

P=N/A, N=12, Recruiting, Second Affiliated Hospital of Soochow University

P1, N=24, Recruiting, PersonGen BioTherapeutics (Suzhou) Co., Ltd. | Not yet recruiting --> Recruiting

Given the importance of NK cells in tumor development and metastatic defence, NK cell-based immunotherapies, including adoptive transfer of NK cells, have garnered a lot of interest. With the advancement of improved cellular manufacturing methods, novel cellular engineering strategies, precision genome editing technologies, and combination therapy approaches, we firmly believe that CAR-T cells will soon become an off-the-shelf, cost-effective, and potentially curative therapy for oncogenesis.

P1, N=18, Recruiting, PersonGen BioTherapeutics (Suzhou) Co., Ltd.

P1, N=10, Recruiting, PersonGen BioTherapeutics (Suzhou) Co., Ltd.

P1, N=32, Recruiting, St. Jude Children's Research Hospital | Trial completion date: Mar 2027 --> Feb 2026 | Trial primary completion date: Mar 2026 --> Mar 2025

These data show that JK184 may be a potential adjutant in combination with CAR T cells or ICB therapy.

We identified a GBM-specific mAb and its antigen. More mAbs against various GBM samples and novel target antigens are expected to be identified using this strategy.

P1/2, N=40, Recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University | Trial completion date: Jul 2024 --> Aug 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P1, N=12, Recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University | Trial completion date: Jul 2022 --> May 2024 | Trial primary completion date: May 2022 --> Mar 2024

We further discuss the current state of preclinical models in advancing this field of study. Finally, examples of clinical trials of immunomodulating strategies such as monoclonal antibodies and chimeric antigen receptor T (CAR-T) cells for relapsed/refractory/progressive pediatric renal tumors are described.

These data provide further proof of concept for ALK as a neuroblastoma CAR T-cell target.

To overcome this potent immune suppression, we demonstrated that co-transducing NK cells with a B7H3 CAR and a TGF-β dominant negative receptor (DNR) preserves cytolytic function in the presence of exogenous TGF-β. This study demonstrates that a novel DNR and CAR co-expression strategy may be a promising therapeutic for recalcitrant CNS tumors like GBM.