CAR-T cells
Chimeric antigen receptor (CAR) T cells are genetically engineered T lymphocytes designed to express a synthetic receptor that combines the antigen-binding domain of an antibody with the intracellular signaling domain of a T cell receptor. This design facilitates HLA-independent antigen recognition, enabling CAR T cells to retain potent cytotoxic functionality.
CAR T cell therapy has shown substantial efficacy in treating pediatric leukemias, though these responses are often short-lived, and CAR T cells have not yet demonstrated significant efficacy in solid tumor settings.
The Gerdemann Lab focuses on identifying the mechanisms underlying CAR T cell efficacy and toxicity through comprehensive correlative biological studies. Additionally, the lab aims to enhance CAR T cell efficacy by inegrating novel genetic modifications.
Genetic Engineering to Enhance CAR T Cell Function
Despite promising initial outcomes in B cell-targeting CAR T cell therapies, over 50% of patients with B cell malignancies experience relapse, and achieving significant therapeutic success in other hematologic malignancies or solid tumors has remained challenging. Key obstacles to CAR T cell efficacy include limited function and persistence.
To address these challenges, our research focuses on genetically engineering CAR T cells to enhance their durability and potency. One strategy involves targeting negative regulators of T cell function, such as the tyrosine phosphatase PTPN2, which suppresses activating signals from the T cell receptor and cytokines. Using CRISPR/Cas9 to delete PTPN2, we have observed improved efficacy in both in vitro CAR T cell assays and our unique in vivo non-human primate model.
Our lab’s non-human primate model of CAR T cell therapy offers a distinct advantage, as it closely mirrors clinical conditions of efficacy and toxicity and allows immediate clinical translation.
Additionally, to identify further regulators that may limit CAR T cell function, we are conducting cutting-edge in vivo CRISPR screens in both murine and non-human primate models.
These efforts aim to advance CAR T cell therapies for broader application, enhancing their effectiveness for patients with hematologic malignancies and solid tumors alike, with an eye toward rapid clinical translation.
Uncovering Mechanisms of CAR-T cell Efiicacy, Resistance and Toxicity
Our lab is dedicated to identifying mechanisms of efficacy, resistance, and toxicity in CAR T cell therapies through molecular and sequencing analyses on samples from treated patients. With a substantial data and sample bank from primary patient samples, we are well-positioned to uncover novel mechanisms underlying CAR T cell function. Using advanced tools like single-cell RNA sequencing, single-cell ATAC sequencing, and TCR tracking, we investigate factors driving CAR T cell exhaustion, resistance, and persistence. Our goal is to identify key molecular drivers impacting therapy success and leverage these insights to develop improved CAR T cell strategies.
Recently, we utilized our Non-Human Primate (NHP) CD20 CAR T cell model to perform single-cell RNA sequencing on CAR-positive and CAR-negative cells, focusing on CAR-negative bystander T cell activation. This revealed a distinct transcriptional signature in bystander-activated T cells within NHPs, which we validated in patients undergoing B cell-targeting CAR T therapies. These activated CD8 bystander cells exhibit an NK cell-like phenotype, potentially aiding in leukemia cell elimination.
In parallel, we conducted single-cell RNA sequencing on CD19-targeting CAR T cells in cerebrospinal fluid (CSF) and peripheral blood from patients with CNS lymphoma, identifying a unique CSF-driven signature that may explain differences between CAR T cell responders and non-responders.
Our extensive sample repository and these recent discoveries will drive the development of more tailored, next-generation CAR T cell therapies aimed at improving patient outcomes.
Improving Outcomes after Stem Cell Transplantation
As a stem cell transplant physician, Uli is deeply interested in the role of alloreactive and autoreactive T cells, which are key drivers of severe graft-versus-host disease (GVHD), solid organ transplant rejection, and autoimmune disorders. Dissecting the immune environment in these conditions and developing immune-modifying therapies offer promising avenues to counteract these harmful T cells.
In collaboration with the Kean and Tkachev labs, the Gerdemann Lab is committed to uncovering the mechanisms of allo- and autoimmunity and advancing novel cellular therapies.
Our approach combines transcriptional mechanistic studies with therapeutic strategies, targeting these cells using specific molecules, CAR T cells, and other immune modulators. Through these efforts, we aim to improve outcomes for patients undergoing stem cell and organ transplants, as well as those suffering from autoimmune diseases.
Lab Mission and Opportunities
Our goal is to create safe, effective, and scalable therapies that can be translated into real-world clinical settings. We offer diverse project opportunities across both experimental and computational research spaces, making our lab an ideal environment for hands-on and analytical scientists alike.