T Cell Gene therapy for cancer

Cancer immunotherapy, more specifically T cell receptor (TCR) gene therapy, is the research focus of the consortium coordinated by Prof. Thomas Blankenstein (MDC) and Prof. Peter-M. Kloetzel (Charité). T cells play a central role in the immune defense system. TCRs on the surface of these cells can recognize exogenous structures. The idea at work here is to modify the TCRs on T cells of patients in such a way that the T cells recognize specifically altered antigens of cancer cells. The modified TCRs can be isolated and used to manufacture patient-specific engineered T cells capable of destroying a tumor. The results of this new research approach will form the basis of a subsequent clinical trial. Seven experimental and clinical research groups affiliated with the MDC and the Charité are involved in this project.

Targeting somatic mutations in human cancer by T cell receptor gene Therapy

Coordination

Prof. Thomas Blankenstein
Max Delbrück Center for Molecular Medicine and Institute of Immunology, Charité - Universitätsmedizin Berlin

Prof. Peter-M. Kloetzel
Institute of Biochemistry, Charité - Universitätsmedizin Berlin

Three questions for Prof. Thomas Blankenstein on the research project

Prof. Thomas Blankenstein
Prof. Thomas Blankenstein

1. What is the consortium’s overriding goal?

We are developing a new form of cancer therapy that is called T cell receptor gene therapy. The therapy consists of genetically altering the T cells of cancer patients in such a way that they specifically recognize and destroy cancer cells. This procedure is facilitated by the fact that the T cells recognize an individual structure (a small peptide from a protein; called an antigen) in a highly specific way, and this specificity is mediated by the T cell receptor. Substantial advances have been made in meeting the technical challenge of efficiently producing patient-specific T cells through T cell receptor gene transfer in a cell culture for the sake of subsequent re-infusion into patients. The decisive open questions are as follows: Which antigens on the cancer cell should be selected as the target structure? How can suitable T cell receptors be acquired? How can the destruction of healthy tissue be prevented?

2. What defines your project’s translational and systems medicine approach?

Cancer is a disease of the genes triggered by genetic mutations which can in turn lead to altered proteins and are partly responsible for the degeneration of cancer cells. Some forms of cancer are characterized by up to 100 or more altered proteins. Some mutations are found in subgroups of patients, others are found only in individual patients. Technically speaking systems medicine procedures have meanwhile advanced to the point where the genome (the sum of all genes) of one or another form of cancer can be quickly decoded and the somatic mutations identified. Through suitable predictive programs and biochemical analysis, this allows selection of suitable antigens from the altered proteins and isolation of specific T cell receptors from transgenic mice produced for this purpose. After transfer into isolated T cells of the patient, such mutation-specific T cell receptors should be more effective than present cancer therapies and lead to fewer side effects.

3. How can patients benefit from your research?

Although a great deal of experimental work is still necessary, we see the future of cancer therapy as follows: the primary tumor will continue to be surgically removed and will be available for decipherment of the cancer genome and identification of the mutated antigen(s). In a few years this procedure will routinely take no more than a few weeks. The clinical challenge results from metastases often having formed since the primary diagnosis. Over time we will compile a library of mutation-specific T cell receptors directly at the disposal of patients with known, repeatedly appearing mutations. The complexity of the situation is increased by the fact that the mutated target structure (the peptide) can only be recognized by the T cells in the context of so-called histocompatability antigens (HLA antigens), which differ from patient to patient. This means that at the beginning, T cell receptor gene therapy will only be available for a small number of patients; through gradual expansion of the T cell receptor library the number of patients that can benefit from this therapy will steadily increase. At first we will focus on lung and colorectal cancer since these forms of cancer display many mutations, meaning that the probability of identifying suitable target structures (mutations) is higher.

Subprojects

  1. Identifying immunogenic mutant epitopes: Peter Kloetzel, Institute for Biochemistry, Charité, CCM
  2. Mutation-specific T cell receptors: Thomas Blankenstein, MDC and Institute of Immunology, Charité, CBB
  3. Targeting unique tumor-specific antigens: Hans Schreiber, Einstein Visiting Professor, Charité
  4. Tumor rejection capacity of mutant-specific TCRs: Wolfgang Uckert, MDC and Institute of Biology, Humboldt University
  5. A transposon-based TCR gene transfer for clinical use: Zsuzsanna Izsvák, MDC
  6. Identification of cancer-specific immunogenic mutations and their expression: Michael Hummel, Institute of Pathology, Charité, CBF
  7. Moving mutation-specific TCR gene therapy into the clinic and preclinical efficacy comparison to lymphoma lineage-specific TCRs: Antonio Pezzutto, Dept. of Hematology, Charité, CBF and MDC