Smarter™ Sonogenetic CAR-T Development Service

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Background

The therapeutic landscape for solid tumors remains challenging, with many patients experiencing relapse or refractory disease despite multimodal treatments. While CAR T-cells have demonstrated unprecedented efficacy in blood cancers, their application in solid tumors encounters several significant obstacles, such as on-target, off-tumor toxicity (OTOT), antigen heterogeneity, immunosuppressive tumor microenvironment (TME), T-cell exhaustion and limited persistence. Addressing these multifaceted challenges requires innovative CAR T-cell designs that incorporate sophisticated control mechanisms and enhanced functional attributes. Creative Biolabs is committed to offering an advanced Smarter™ Sonogenetic CART development solution to address these hurdles.

Fig.1 On-target, off-tumor toxicities. (OA Literature) Fig.1 The on-target, off-tumor toxicities of CAR-T cell therapy.¹

One-Stop Smarter™ Sonogenetic CART Development Services at Creative Biolabs

Creative Biolabs offers an integrated, end-to-end service platform for the Smarter™ Sonogenetic CART development, a cutting-edge therapeutic approach designed to overcome the limitations of conventional CAR T-cell therapy in solid tumors. This technology leverage focused ultrasound for precise spatiotemporal control of CAR expression and incorporates a novel positive feedback mechanism to sustain anti-tumor activity.

Highlights of Our Smarter™ Sonogenetic CART Technology

Sonogenetic Control

Smarter™ Sonogenetic CAR T-cells are engineered with an ultrasensitive heat-shock promoter for optimal focused ultrasound inducibility. This promoter drives CAR expression only when locally stimulated by non-invasive focused ultrasound. This "on-demand" activation ensures that the potent cytotoxic activity of the CAR T-cells is confined to the tumor site, significantly minimizing the risk of on-target, off-tumor toxicity to healthy tissues.

Positive Feedback Loop

A key innovation is the integration of a positive feedback loop within the CAR signaling pathway. Upon initial focused ultrasound triggered CAR expression and subsequent engagement with the tumor antigen, the CAR signaling cascade itself further upregulates CAR production. This self-sustaining mechanism ensures robust and prolonged CAR expression and effector function specifically within the tumor microenvironment, even after the initial focused ultrasound stimulus is removed. This leads to enhanced cytotoxicity and persistence.

What We Can Offer

The Smarter Sonogenetic CAR-T Development Service is a comprehensive platform designed to create next-generation, precision-guided CAR-T cells, primarily for solid tumors. The core innovation is using non-invasive focused ultrasound to remotely and locally activate the CAR T-cells. Here is a breakdown of the services and the analyses provided:

Analysis and testing of sonogenetic CART. (Creative Biolabs Original)

Workflow

Workflow of sonogenetic CART. (Creative Biolabs Original)

Kindly reach out to us to schedule a private consultation and obtain a detailed technical proposal.

Related Services

Creative Biolabs provides a tailored suite of services specifically designed to support the unique requirements of Smarter™ Sonogenetic CAR T-cell development. Our comprehensive offerings span the entire preclinical development pipeline:

01 Target Validation and Advanced Smarter™ Sonogenetic CAR Design
- Strategic Biomarker Assessment: We assist in validating tumor-associated antigens suitable for the Smarter™ Sonogenetic CAR T-cell development, considering expression profiles and amenability to focused ultrasound targeted therapy.
- Ultrasensitive Sonogenetic Promoter Integration & Optimization: Leveraging our expertise, we guide the selection and integration of highly responsive focused ultrasound inducible promoters, ensuring efficient and localized CAR expression.
- Positive Feedback Loop Engineering: Our team provides expert consultation and services for the design and molecular construction of the feedback amplification system, ensuring robust CAR signaling-dependent upregulation of CAR expression.
- Custom scFv Generation and Affinity Engineering: We develop high-affinity single-chain variable fragments (scFvs) tailored to your target antigen. For the Smarter™ Sonogenetic CAR Design, affinity tuning can be crucial to optimize the interaction dynamics post focused ultrasound activation, ensuring potent tumor engagement without premature exhaustion.
- Sophisticated Vector Design and High-Titer Viral Packaging: We design and produce lentiviral or retroviral vectors encoding the complete sonogenetic Smarter™ Sonogenetic CAR cassette, including the focused ultrasound inducible promoter, CAR construct, and feedback loop components, ensuring efficient and stable transduction of T-cells.
02 Rigorous Preclinical Proof-of-Concept & Validation
- In Vitro Sonogenetic Activation, Cytotoxicity, and Persistence Assays: We conduct comprehensive in vitro studies to validate focused ultrasound-dependent CAR expression, assess the cytotoxic potential against target tumor cells (utilizing 2D and advanced 3D tumor models, such as spheroids or organoids), profile cytokine release (e.g., IFN-γ, TNF-α, IL-2), and evaluate long-term persistence and anti-tumor activity of Smarter™ Sonogenetic CAR T-cells.
- Advanced T-Cell Phenotyping for Exhaustion and Memory Markers: Utilizing multi-parameter flow cytometry and, where applicable, single-cell RNA sequencing analysis, we characterize the phenotype of Smarter™ Sonogenetic -CAR T-cells post-activation. This confirms the reduced exhaustion markers and enhanced memory T-cell formation observed in preclinical studies of this technology.
- In Vivo Efficacy, Safety, and Biodistribution Studies in Orthotopic Solid Tumor Models: We perform robust in vivo studies using clinically relevant animal models. These studies assess focused ultrasound guided tumor regression, monitor CAR T-cell trafficking and persistence, and critically evaluate systemic safety, with a particular focus on the absence of on-target, off-tumor toxicities.

FAQs

Q1: What fundamentally distinguishes sonogenetic Smarter™ Sonogenetic CART-cells from standard CAR T-cells in the context of solid tumors?

A1: Smarter™ Sonogenetic -CAR T-cells offer two primary distinctions: 1) Spatiotemporal Control: Their activity is triggered by focused ultrasound specifically at the tumor site, drastically reducing systemic exposure and on-target, off-tumor toxicity. 2) Sustained Activity: An engineered positive feedback loop ensures that once activated, tumor engagement leads to prolonged CAR expression and effector function, combating T-cell exhaustion and improving persistence.

Q2: What are the principal safety advantages offered by the Smarter™ Sonogenetic CART-cell approach?

A2: The primary safety advantage is the significant reduction in on-target, off-tumor toxicity. By restricting CAR expression and activity to the focused ultrasound-targeted tumor area, systemic exposure of healthy tissues expressing the target antigen at low levels is minimized.

Q3: How does Creative Biolabs ensure the quality and reproducibility of Smarter™ Sonogenetic CART development projects?

A3: Creative Biolabs employs rigorous quality control measures at every stage of development. This includes validated assays, standardized operating procedures, meticulous record-keeping, and the use of well-characterized reagents and models. Our scientific team comprises experts with extensive experience in cell therapy development.

Q4: What is the anticipated development timeline for the Smarter™ Sonogenetic CART therapy when partnering with Creative Biolabs?

A4: The timeline can vary depending on the project's specific scope, target complexity, and starting point. However, Creative Biolabs' integrated "one-stop" service model is designed to optimize efficiency and reduce overall development timelines compared to managing multiple disparate service providers.

Contact Us

Creative Biolabs is dedicated to advancing the next generation of cancer immunotherapies. If you are developing or considering a sonogenetic CAR T-cell program, or wish to explore how the Smarter™ Sonogenetic -CAR T platform can transform your solid tumor therapeutic strategy, we invite you to connect with our experts. Partner with Creative Biolabs to harness the power of precision-guided, sonogenetically controlled CAR T-cell therapies and bring hope to patients with challenging solid tumors.

Reference

Xiao, Bu-Fan, et al. "Chimeric antigen receptor T-cell therapy in lung cancer: potential and challenges." Frontiers in Immunology 12 (2021): 782775. Distributed under Open Access License CC BY 4.0, without modification.

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