Our Research
Cellular immunotherapies and functional cancer genomics
The development of cancer occurs through malignant transformation – a stepwise process in which normal cells acquire genetic alterations, leading to their uncontrolled cell division and escape from immune cell recognition. Therapeutic approaches aim at reverting this process by inhibiting tumor cell proliferation and re-establishing recognition and clearance of malignant cells by the immune system. The Feucht and Leibold labs work at the interface of cancer biology and tumor immune cell interactions. Through insights into cancer cell intrinsic immune surveillance and escape mechanisms the labs aim to identify novel and personalised treatment strategies involving Chimeric Antigen Receptor (CAR) T and NK cells for patients with late stage malignancies.
Feucht Lab
Recent advances in cellular immunotherapies have altered the treatment landscape of patients with cancer. Chimeric antigen receptors (CARs) are synthetic receptors introduced into immune cells to reprogram their specificity, metabolism, and function.
CAR T cell therapy has achieved remarkable clinical success in certain hematological diseases, resulting in the approval of CAR therapy by the FDA and the EMA. Despite the clinical success, treatment with currently approved CAR designs is curative only in a fraction of patients.
Our research group aims at improving and extending cellular therapies by reprogramming immune cells through innovative gene editing and cell engineering strategies. We have contributed to the development of enhanced CAR designs that are now evaluated in clinical studies (Feucht*, Sun* et al., Nature Medicine, 2019) and of CAR T cells targeting senescence cells, which open novel treatment applications for cancer and beyond (Amor*, Feucht*, Leibold* et al., Nature, 2020).
We seek to enhance CAR efficacy by preventing exhaustion, augmenting functional persistence and by enhancing metabolic fitness. In collaboration with the Leibold Lab, our group uses clinically relevant mouse models to gain improved understanding into CAR biology, to reveal underlying mechanisms of therapeutic failures and to explore treatment-associated toxicities. Through these approaches, we aim to advance treatment strategies with engineered immune cells by tailoring CAR activity to treatment- and disease-specific settings.
Our overall goal is to translate our insights into improved cellular therapies for patients.
Leibold Lab
The Leibold Lab studies cancer genetics, the tumor microenvironment and tumor-immune cell interactions, aiming to identify therapeutic vulnerabilities and to develop innovative treatment strategies. One approach involves the induction of cellular senescence in tumor cells. Cellular senescence is a tumor suppressive program induced upon various kinds of cell-intrinsic and cell-extrinsic stresses and is comprised of two components: 1) a stable cell cycle arrest and 2) a secretory program called senescence-associated secretory phenotype (SASP). The physiological role of this secretory program is to alert immune cells to the stressed cells and induce their clearance to restore tissue homeostasis. Importantly, many of the standard therapeutic approaches applied clinically to treat patients with cancer such as chemotherapy, radiotherapy, and targeted therapies lead to the induction of senescence in a portion of the tumor cells. Leveraging this program can thus unleash potent cell-intrinsic and cell-extrinsic anti-tumor effects (Ruscetti*, Leibold*, Bott* et al., Science 2018).
The Leibold Lab uses clinically relevant and flexible models involving CRISPR/Cas9 and transposon-based somatic tissue engineering approaches to study the cell-intrinsic components and determinants of the senescence program (Leibold*, Ruscetti*, Cao* et al., Cancer Discovery 2020; Paffenholz et al., PNAS 2022). In collaboration with the Feucht Lab, our group additionally applies innovative treatment strategies including cellular immunotherapies such as Chimeric Antigen Receptor (CAR) T and NK cells to efficiently clear arrested and proliferating tumor cells (Amor*, Feucht*, Leibold* et al., Nature 2020). Our goal is to translate these therapies into novel treatment approaches for patients with late-stage disease and an otherwise detrimental prognosis.
Funding
