Development of Dual-Targeting CAR-T Cells for Enhanced Specificity and Efficacy in Solid Tumors

Research Proposal:
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.

Objective

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.

Hypothesis

We hypothesize that dual-targeting CAR-T cells will have:

1. Enhanced specificity: Reduced binding to normal tissues expressing only one of the target antigens.
2. Increased efficacy: Overcoming the tumor heterogeneity by targeting multiple antigens.

Methods

1. Target Identification and Validation

1. • 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.

1. CAR Construct Design

1. • Develop two separate CAR constructs targeting the identified antigens.
   • Engineer a single T-cell to express both CAR constructs.

1. In Vitro Validation

1. • Evaluate the specificity and cytotoxicity of dual-targeting CAR-T cells against a panel of tumor cell lines using flow cytometry and killing assays.

1. In Vivo Studies

1. • Utilize mouse models to evaluate the efficacy, biodistribution, and potential toxicity of the dual-targeting CAR-T cells.

1. Clinical Translation

1. • Phase I/II clinical trials to evaluate safety and preliminary efficacy in human subjects.

Expected Outcomes

1. Development of dual-targeting CAR-T cells with reduced off-target toxicity.
2. Demonstration of the efficacy of dual-targeting CAR-T cells in preclinical models.
3. Initiation of clinical trials for further validation.

Timeline

• 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

Budget

• Estimated total cost: $3 million

Conclusion

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