Research Program "Cancer Immunotherapy (CI)"
The overall long-term aim of this Program is to cure cancer by immune reactions. After a century of visionary concepts on cancer elimination by the patient's immune system a breakthrough was achieved only a few years ago with the introduction of checkpoint-inhibitory antibodies. These unblock therapeutic T cell responses against neoantigens such as Human Leukocyte Antigens (HLA). HLA-presented mutations are recognizable by T cells that arise due to neoantigen encoding mutations in the tumor.
Based on the analysis of now thousands of treated patients, the clinical response has been positively correlated with the number of mutations in tumors. The presently emerging view - both from clinical observations, in particular T cell specificity analysis, and from HLA ligandomics - is that neoantigens are rather rare, which explains why even melanoma patients with hundreds of exome mutations in their tumors can be clinical nonresponders to checkpoint inhibition, possibly due to a lack of suitable neoantigens. According to this view, the majority of cancer patients will not benefit from checkpoint inhibition alone.
The investigators of the DKTK Cancer Immunotherapy Program, with their combined expertise, are ideally suited to build on these newly established fundaments. The four pillars of the Program, Advanced Tumor Vaccines, New Therapeutic Antibodies, Advanced Cellular Therapeutics, and Combinatorial Immunomodulation, are based on the now accepted fact that the immune system of patients is able to destroy tumors. If one or more neoantigens are found in a tumor of a given patient, individualized vaccination with peptides or RNAs representing the neoantigens is a promising strategy for achieving therapeutic efficiency similar to that of checkpoint blockade but without off-target toxicity. For those patients, and these will be many, whose tumors lack neoantigens, there is still a large selection of reasonably tumor-specific antigenic germline epitopes that are suitable for vaccination in particular in the minimal residual disease (MRD) setting. In patients with more advanced disease, these tumor antigens are suitable targets for adoptive transfer strate¬gies with T cell receptor (TCR)- or chimeric antigen receptor (CAR)-modified T cells, or with new generation antibodies against tumor-associated cell surface antigens. Combinations of these strategies, in particular combining immunovirotherapy or other non-antigen-specific perturbation of the tumor microenvironment, or antigen-specific vaccination or cell transfer, with checkpoint inhibition or other recently developed immunomodulations are especially promising.
- GMP-facility for peptides (see also paragraph E.8.3..); approval for drug production, first deliveries and DKTK clinical studies at different partner sites; approval for GMP antibodies in 2015 (with TÜ-based Synimmune GmbH; Nalivaiko et al., Mol Ther in press; Durben et al., Mol Ther 2015).
- Identification of mutant IDH1 as a suitable target for cancer immunotherapy by peptide vaccination (Schumacher et al., Nature 2014).
- Development of a new immunocytokine format that targets IL-15 activity to tumors.
- Manufacturing license for several advanced cellular therapeutics (TUMCells).
- Acceleration of HLA ligandomics (see also paragraph E.8.4.); ligandome-based identification of a myeloperoxidase-specific TCR with potent anti-leukemic activity (Klar et al. Leukemia 28: 2355, 2014).
- Human TCR generation from the repertoire of the mouse, first TCR for clinical study
approved; design of several novel CARs.
- Clinical studies on immunovirotherapeutics, innovative dendritic cell technology, and chemokine receptor antagonist.
- Development of oncolytic measles virus vectors encoding anti-CTLA-4 and anti-PD-L1.