Overcoming Resistance to CAR-T Cell Therapy due to Antigen Loss or Modulation by New Chimeric Receptors Targeting Intracellular-Derived HLA Peptidome
Grant Amount: NIS 1.925 Million
About the Project
The use of autologous engineered T cells carrying a chimeric antigen receptor (CAR) directed against surface antigens expressed on cancer cells has shown marked efficacy in patients with refractory hematological malignancies. However, resistance to CAR T therapy with subsequent relapse attributable to antigen loss was observed in 60% of patients and remains an unmet challenge. The approach of this study is to exploit another pool of targets, which is naturally utilized by the immune system to differentiate between self and non-self; specific peptides bound to class I major histocompatibility complex (MHC) proteins to generate peptide-MHC complexes presented on the cell surface. Disease-specific class I MHC/peptide targets will be targeted with TCR-like antibodies, which mimic the TCR specificity. The TCR-like antibody approach combines two main advantages of the immune system: The fine specificity of T cells, which use the MHC internal surveillance mechanism to detect cells that express any foreign or abnormal protein, and the biological and pharmacological properties of an antibody that is not susceptible to most of the tumor regulatory influences that limit T cells. The new strategy with TCR-like antibody-based targeting CD19-derived peptide-HLA complex (pCD19) will be tested as a proof-of-concept and evaluated for the potential of this approach to restore functional outcome in CD19 negative relapse. The research may lead to a new family of therapeutic methods for cancer and additional diseases.
Research Team
Prof. Yoram Reiter
Technion – Israel Institute of Technology (Biology)
Prof. Myriam Ben-Arush
Rambam Health Care Campus (Pediatric Hemato-oncology)
Dr. Adi Shapira
Rambam Health Care Campus (Pediatric Hemato-oncology)
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