Chmielewski, Markus - assoc. RG 30

Adoptive cell therapy of malignant diseases takes advantage of the cellular immune system to recognize and eliminate cancer cells. This is impressively demonstrated by redirecting T cells with a chimeric antigen receptor (CAR) towards CD19, inducing complete and lasting remission of leukemia in patients in early phase trials.

Second-generation CARs with a CD28 or 4-1BB costimulatory domain are currently entering clinical practice. T cells engineered with such CARs targeting CD19 showed robust clinical efficacy in the treatment of adult and childhood CD19+ acute B-cell lymphoblastic leukemia in independent trials. However, while CAR T-cell therapies have a curative potential, 30-60% patients relapse after treatment. The mechanisms of resistance to CAR T-cell therapy are only incompletely understood. Therefore, understanding the mechanisms that underlie post-CAR relapse and establishing corresponding prevention and treatment strategies is important.
Moreover, there are some side effects which need clinical attention. A major issue of CAR-mediated toxicity is the so-called ‘on-target off-tumor’ toxicity which results from the engagement of the cognate target on healthy tissues. Such toxicity became obvious by depletion from healthy B cells upon leukemia treatment with CD19-specific CAR T cells. The next generation CAR T cells should exhibit superior safety and efficacy, as well as bring more hopes to patients with malignant tumors.

• Replacement of second generation CARs by CARs of the next generation with improved efficiency and safety profile for the treatment of B cell malignancies
• Development of new strategies for the treatment of solid tumors, especially pancreatic carcinoma
• Generation of clinic-related B-cell lymphoma mouse models for testing CAR T cells
• Clinical implementation of next generation CAR products for the treatment of r/r CLL RT (Richter Transformation) and r/r DLBCL

We are going to investigate interactions between CAR T cells and tumor cells and identify inhibiting processes in order to offer improved CAR-T cell products for the treatment of DLBCL and high risk CLL. The mechanistic relationships to be investigated are universal and transferable to other tumor entities. The proposed studies are also intended to help overcome hurdles to the treatment of solid tumors with CAR T cells, as CAR T cells have not yet made a decisive breakthrough in this area. Finally, the pro-posed studies are aimed to be translated into early clinical trials.