The group of researchers led by Dr. Antonia Busse, Head of the Molecular Immunotherapy Group and Senior Physician, Department of Hematology, Oncology and Cancer Immunology, Charité Campus CBF, and Prof. Dr. med. Antonio Pezzutto: Senior Professor of Translational Research, Charité – Universitätsmedizin Berlin, is developing a novel T-cell receptor (TCR) therapy that specifically recognizes the MyD88 L265P mutation, one of the most common driver mutations found in B-cell lymphomas. The researchers have recently published the results of a preclinical study in the Journal for ImmunoTherapy of Cancer.*
The group has developed an autologous in vitro culture system to isolate neoantigen-specific and thus completely tumor-specific TCRs from the human system for later clinical application in the context of adoptive T-cell therapy. Using this technology they were able to identify a TCR called TCR2304 that specifically recognizes the mutant epitope of the MyD88 signaling protein with the L265P driver point mutation, but not the corresponding wild-type peptide. Recognition of the antigen by the TCR is dependent on the MHC molecule HLA-B7. MHC molecules are found in almost all cells of the organism and present peptides on the cell surface to activate immune cells to recognize foreign epitopes that come from pathogens, tumors or other sources.
The project has been funded by SPARK-BIH since January 2020. SPARK-BIH is a mentoring program of Charité BIH Innovation, originally from Stanford, that supports early stage academic inventions with education, project management, mentorship and milestone-based funding. With the help of SPARK-BIH funding, the team was able to focus on advancing the preclinical development of the novel TCR candidate. Furthermore, the team is continuously supported by the Patents & Licenses team of Charité BIH Innovation, such as with the patent application and a WIPANO grant. In their study, Dr. Antonia Busse, Prof. Antonio Pezzutto and their colleagues have now shown that TCR2304-transduced T cells specifically recognize and destroy HLA-B7-positive lymphoma cells that endogenously express the MyD88 L265P mutation. The findings demonstrate not only the efficacy of the TCR, but also that the mutant epitope can indeed be processed by the proteasome and presented on the cell surface by HLA-B7-positive cells. In addition, the group of researchers was able to demonstrate the effectiveness of adoptive T-cell therapy with this mutation-specific TCR in various xenograft mouse models. The goal is now to bring this TCR into clinical use and to establish the cell product manufacturing process.
The TCR is being developed primarily for the treatment of MyD88 L265P mutated highly malignant B-cell lymphomas, such as diffuse large B-cell lymphoma (DLBCL) and primary CNS lymphoma (PCNSL). The aim is to achieve long-term remission with this absolutely tumor-specific therapy while maintaining a favorable side effect profile.
As a precision immunotherapy, it is only suitable for a small group of patients with highly malignant lymphomas. Besides the presence of the MyD88 L265P mutation, HLA-B7 expression on the lymphoma cells is an essential prerequisite. Yet due to its potentially higher efficacy compared to standard therapies, TCR has the potential to be a “niche buster.” Unlike CAR T-cell therapy, TCR T-cell therapy can also address intracellularly expressed antigens and, most importantly, targeted neoantigens. This means TCR T-cell therapy against the oncogenic MyD88 L265P mutation may enable targeted, personalized tumor-specific therapy for lymphoma patients.
*Original publication: Özcan Çınar, Bernadette Brzezicha, Corinna Grunert, Peter Michael Kloetzel, Christin Beier, Caroline Anna Peuker, Ulrich Keller, Antonio Pezzutto #, Antonia Busse #, “High-affinity T-cell receptor specific for MyD88 L265P mutation for adoptive T-cell therapy of B-cell malignancies”; Journal for ImmunoTherapy of Cancer. 2021 Jul;9(7):e002410. doi: 10.1136/jitc-2021-002410.