A Gene-Modified T Cell Platform For Spatially Controlled Therapeutic Protein Delivery In Response To Radiation

SUMMARY

Engineered T cells to release cancer-killing proteins only when activated by targeted radiation, enabling precise, localized tumor treatment while minimizing side effects and improving the effectiveness of CAR-T therapy for solid tumors

The Unmet Need: Precise spatial and temporal delivery of potent immunomodulatory agents with the tumor microenvironment

• Cancer immunotherapy and radiation therapy are two cornerstone modalities in the treatment of malignancies, each with unique strengths and limitations. Immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapy, have revolutionized the management of certain blood cancers but have demonstrated limited efficacy in solid tumors due to the complex and immunosuppressive tumor microenvironment. Radiation therapy, on the other hand, is widely used for local tumor control and can occasionally induce systemic immune responses, known as the abscopal effect, but this phenomenon is rare and unpredictable. The need for more effective, targeted, and safer cancer treatments has driven research into approaches that combine the strengths of both immunotherapy and radiation, aiming to enhance anti-tumor responses while minimizing systemic toxicity.

• Current oncology therapeutic strategies face significant challenges that limit their effectiveness. CAR-T cells often struggle to infiltrate solid tumors and can be rendered ineffective by antigen heterogeneity and local immunosuppression. Systemic administration of cytokines or other immune-activating agents, while potentially beneficial, is frequently associated with severe off-target effects and toxicity, restricting their clinical utility. Radiation therapy, although effective at shrinking tumors locally, rarely translates into durable systemic immune responses, and attempts to combine it with immunotherapies have not consistently overcome these barriers.

The Proposed Solution: Genetically engineered T cells incorporating a synthetic radio-inducible promoter controlling therapeutic payload production amplifying local tumor killing

• The faculty inventor developed a cancer therapy platform that integrates genetically engineered T cells—including CAR-T cells—with radiation therapy to achieve precise, localized delivery of therapeutic proteins within tumors. The core of the system is a synthetic, radiation-inducible promoter optimized through tandem repeats and minimal promoter elements. Engineered T cells are programmed to express potent antitumor agents, such as tumor necrosis factor alpha (TNF), only when exposed to ionizing radiation. After adoptive transfer of these cells into a patient, localized radiotherapy at the tumor site activates the promoter, triggering robust secretion of the therapeutic payload specifically within the irradiated tumor microenvironment. This approach enables spatial and temporal control over cytokine release, amplifies local tumor destruction, and minimizes systemic toxicity.

• What differentiates this technology is its “molecular switch” mechanism, which tightly confines therapeutic protein expression to irradiated tissues, overcoming major limitations of both radiation and CAR-T cell therapies. By coupling radiation-induced gene expression with adoptive cell transfer, this platform synergistically combines the direct cytotoxicity of radiation, the targeted action of CAR-T cells, and the potent local effects of cytokines like TNF. The modular promoter system ensures minimal background activity and robust induction only upon irradiation, allowing for precise dosing and reduced off-target effects. Additionally, the platform’s adaptability enables the use of various therapeutic payloads, offering broad potential for treating diverse tumor types and improving the safety and efficacy of cellular immunotherapies.

ADVANTAGES

ADVANTAGES

• Localized therapeutic protein expression minimizes systemic toxicity and enhances safety

• Spatial and temporal control of gene expression allows precise activation only within irradiated tumor sites

• Combines radiation therapy with engineered T cells/CAR-T cells to synergistically improve tumor killing

• Enhances CAR-T cell infiltration and overcomes immunosuppressive tumor microenvironments in solid tumors

• Modular promoter system enables adaptation for various therapeutic payloads beyond TNF

• Improves efficacy of radiation therapy by amplifying local and potential systemic (abscopal) anti-tumor effects

• Optimized promoter design ensures robust induction with minimal background expression

APPLICATIONS

• Solid tumor CAR-T cell therapy.

• Radiation-triggered cytokine delivery

• Localized immunotherapy for cancer

• Spatially controlled gene therapy

• Preclinical models demonstrate significant tumor control with reduced systemic cytokine exposure