Development of Dual-Targeting CAR-T Cells for Enhanced Specificity and Efficacy in Solid Tumors
Jeya Chelliah B.Vsc Ph.D.
Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies, achieving remarkable success in patients with acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). However, its application in solid tumors remains a challenge due to issues such as tumor heterogeneity, immune suppression in the tumor microenvironment, and potential off-target toxicity.
The primary objective of this research is to develop a dual-targeting CAR-T cell therapy that can recognize and eliminate solid tumor cells with higher specificity and reduced off-target effects. The project aims to combine two different CAR constructs that recognize distinct tumor-associated antigens, leading to T-cell activation only when both antigens are present on the target cell.
We hypothesize that dual-targeting CAR-T cells will have:
- Enhanced specificity: Reduced binding to normal tissues expressing only one of the target antigens.
- Increased efficacy: Overcoming the tumor heterogeneity by targeting multiple antigens.
- Target Identification and Validation
- Conduct genome-wide expression analysis to identify tumor-specific antigens that are overexpressed in a wide range of solid tumors.
- Validate the targets using immunohistochemistry in patient tissue samples.
- CAR Construct Design
- Develop two separate CAR constructs targeting the identified antigens.
- Engineer a single T-cell to express both CAR constructs.
- In Vitro Validation
- Evaluate the specificity and cytotoxicity of dual-targeting CAR-T cells against a panel of tumor cell lines using flow cytometry and killing assays.
- In Vivo Studies
- Utilize mouse models to evaluate the efficacy, biodistribution, and potential toxicity of the dual-targeting CAR-T cells.
- Clinical Translation
- Phase I/II clinical trials to evaluate safety and preliminary efficacy in human subjects.
- Development of dual-targeting CAR-T cells with reduced off-target toxicity.
- Demonstration of the efficacy of dual-targeting CAR-T cells in preclinical models.
- Initiation of clinical trials for further validation.
- Year 1: Target identification and validation
- Year 2: CAR construct design and in vitro validation
- Year 3: In vivo studies and preparation for clinical trials
- Year 4-5: Phase I/II clinical trials
- Estimated total cost: $3 million
This project aims to overcome some of the current limitations of CAR-T cell therapy in treating solid tumors by developing a novel dual-targeting approach. If successful, this research could pave the way for more effective and safer immunotherapies for a wide range of cancers.
This research idea is novel and builds on existing knowledge of CAR-T cell therapy, aiming to tackle the specific challenges associated with treating solid tumors. It has the potential for high impact and could open new avenues for cancer immunotherapy