P1/2, N=25, Suspended, Dushu Lake Hospital Affiliated to Soochow University | Recruiting --> Suspended

P1, N=36, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial primary completion date: Oct 2024 --> May 2030

P1, N=9, Not yet recruiting, Chulalongkorn University

XmAb808 as monotherapy and in combination with an anti-PD1 antibody is currently in clinical development in patients with advanced solid tumors. Our results suggest that XmAb808 may also combine with tumor antigen-targeted anti-CD3 (Signal 1) T-cell engagers.

Additionally, the B7-H3-CAR-Vδ1T cells exhibited a favorable safety profile. In conclusion, B7-H3-CAR-modified Vδ1T cells represent a promising strategy for treating solid tumors.

P1, N=27, Recruiting, UNC Lineberger Comprehensive Cancer Center | Not yet recruiting --> Recruiting

P1, N=27, Recruiting, UNC Lineberger Comprehensive Cancer Center | Not yet recruiting --> Recruiting

Our patient-based pipeline identified targets for chemokine receptor modification of CAR T cells targeting OS. CXCR2 and CXCR6 expression enhanced homing and anti-OS activity of B7-H3.CAR T cells. These findings support clinical evaluation of CXCR-modified CAR T cells to improve adoptive cell therapy for OS patients.

P1, N=42, Recruiting, UNC Lineberger Comprehensive Cancer Center | Not yet recruiting --> Recruiting

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

P1, N=39, Not yet recruiting, Tiantan Hospital, Beijing, China; Fuzhou Tcelltech Biological Science and Technology Inc.

We identify challenges to the success of CAR T cell therapy for solid tumors including localizing to and penetrating solid tumor sites, evading the hostile tumor microenvironment, supporting T cell expansion and persistence, and avoiding intrinsic tumor resistance. We highlight strategies to overcome these challenges and enhance the effect of B7-H3-CAR T cells, including advanced CAR T cell design and incorporation of combination therapies.

P1, N=52, Not yet recruiting, Tcelltech Inc.

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

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.