TCR gene transfer for CLL

Reference Number TO 01-00717

The Challenge

The incidence of B cell neoplasms is increasing world wide. In chronic lymphocytic leukemia (CLL), still no established curative therapy is available at any point of diagnosis. For patients with progressing CLL, treatment with conventional doses of chemotherapy is not curative; selected patients treated with allogeneic stem cell transplantation have achieved prolonged disease-free survival. Immunotherapy has been shown to be highly successful in low grade lymphoma. Target specific therapies using monoclonal antibodies against CD20 (Rituximab) or CD52 (Alemtuzumab) are only partially efficient because of tumor escape due to down regulation of the target antigens from the cell surface.

The Technology
A T cell receptor (TCR) recognizing antigenic peptides derived from tumor-associated antigen FMNL1 and capable of inducing peptide specific killing of a target cell is provided. FMNL1 is a formin related protein in leukocytes which is highly expressed in >60% of CLL samples tested and aberrantly expressed in transformed cell lines of various tissues. Allo-HLA-A2 restricted peptide specific T cells have been generated which show specific cytotoxicity against malignant cell lines derived from lymphoma and renal cell carcinoma.

Scheme of allorestricted peptide-specific T-cell action

Commercial Benefit and Opportunity
The allorestricted FMNL1 peptide-specific T cells will be helpful for the development of efficient immunotherapies against malignant lymphoma, especially CLL, and other malignancies. Those T cells bearing TCR which have the capacity to recognize their MHC-peptide ligand on the tumor cells can be used for treating patients with significantly reduced risk of graft-versus-host-disease (GVHD).The technology is available for (no)-exclusive licensing. Parties interested in collaborative research and development are highly welcomed.

Development Status
Various T cell clones have been successfully tested in vitro with regard to specificity, TCR dependency, and cross-reactivity. Further optimization strategies as murinization of constant chains and codon optimization improved the TCR. In addition, the use of murinized constant chain chimera resulted in TCR with high functional efficiency.

Patent Situation
Patent applications are pending in EP (2027150) and US.

Relevant Publication
Schuster et al. (2007), Blood 110, 2931-2939