SEPTEMBER 2017 – Unbiased identification of T cell receptors targeting immunodominant peptide-MHC complexes for T cell receptor immunotherapy

Abstract

T cell receptor (TCR) immunotherapy uses T cells engineered with new TCRs to enable detection and killing of cancer cells. Efficacy of TCR immunotherapy depends on targeting antigenic peptides that are efficiently presented by the best suited major histocompatibility complex (MHC) molecules of cancer cells. However, efficient strategies are lacking to easily identify TCRs recognizing immunodominant peptide-MHC (pMHC) combinations utilizing any of the six possible MHC class I alleles of a cancer cell. We generated an MHC cell library and developed a platform approach to detect, isolate and re-express TCRs specific for immunodominant pMHCs. The platform approach was applied to identify a human papillomavirus (HPV16) oncogene E5-specific TCR, recognizing a novel, naturally processed pMHC (HLA-B*15:01), and a cytomegalovirus-specific TCR targeting an immunodominant pMHC (HLA-B*07:02). The platform provides a useful tool to isolate in an unbiased manner TCRs specific for novel and immunodominant pMHC targets for use in TCR immunotherapy.

Interview

In September, Wolfgang Uckert and his team received the Paper of the Month award. We asked them about the research and the project.

What are you researching? What is the core of your research?

The Research Group for Molecular Cell Biology and Gene Therapy at MDC is mainly engaged in research in the field of immunotherapy to combat cancer. We use molecular biological, immunological, and virological methods to modify certain immune cells (T cells) such that they can be utilized successfully for therapy. In order to achieve this objective, we take advantage of the ability of T cells to recognize certain structures (antigens) on the cell surface and bind to these antigens via a receptor (T-cell receptors). Using gene technology methods, the normal T cells of a patient are outfitted with a tumor-specific T-cell receptor. This means that in addition to their own T-cell receptor, these cells now possess a second “therapeutic” T-cell receptor which can be used to treat cancer.
Immune therapy with genetically modified T cells is a form of therapy which requires numerous work steps before it can be implemented in the patient. The mastery of these complex work steps in order to ultimately manufacture “therapeutic” T cells and use them clinically in cancer patients is a major challenge and the driving force behind our research.

What is the core message of your publication and how does your study differ from the work of other scientists in this field?

“Therapeutic” T-cell receptors can be obtained in various ways, such as directly from a patient’s T cells or by immunizing certain mouse strains. However, both procedures more or less come with huge limitations.
Our procedure allows us to find the most reactive T cells against cancer-specific antigens in an unbiased manner and then to isolate the T-cell receptors from these cells, characterize them, and subsequently utilize them to produce “therapeutic” T cells. Unlike other procedures, we do not specify which part of a cancer antigen is presented to the T cell. This is a factor which would further limit therapy options. Hence, we can greatly expand the group of patients which could benefit from TCR therapy.

Which cooperation partners have contributed to the publication? Who was significantly involved?

This publication was compiled through long-standing collaboration with researchers from the Institute for Molecular Immunology at Helmholtz Zentrum München under the leadership of Prof. Dolores Schendel.

What next steps are planned for the project and what are the possible implications of your results for patients?

Together with other publications for methods which were developed either in our research group or in collaboration with other researchers at MDC, the platform described in the publication for creating tumor-reactive T cells via T-cell receptor gene transfer served as the foundation for establishing a Helmholtz Innovation Lab. This lab – the Max-Delbrück Center Cell Engineering Lab (MD-CEL) – will, among other things, utilize the procedure we have developed to provide genetically modified T cells for T-cell receptor therapy for various forms of cancer. The long-term objective is to clinically utilize these cells for treating selected types of cancer.