Giedre Krenciute Lab

The Krenciute Lab has a diverse research team bringing together scientists from four of the seven continents with backgrounds in everything from physics to pharmacy.

Our lab focuses on engineering T cells to make them specific for pediatric brain tumors and understanding T-cell regulation to improve immunotherapeutic approaches for patient populations. By reeducating the immune system, we hope to improve tumor detection along with the persistence, efficacy and safety of immune effector cells. Chimeric antigen receptor (CAR) T cells enable the targeting of specific tumor-associated antigens. Our laboratory leverages expertise in CAR T design, genetic engineering, and production with collaborative partnerships in neuro-oncology, computational biology, and immunology across and beyond St. Jude. 

Synergizing CAR T cells with the tumor microenvironment

The context in which a tumor grows and sustains itself, known as the tumor microenvironment (TME), often plays a role in the success of treatment. Our work seeks to understand how the cells within the TME affect CAR T–cell function so we can then identify therapeutic targets to  enhance CAR T activation and persistence. To do this, we investigate tumor associated macrophages (TAMs) specific to brain TMEs by utilizing immunocompetent murine models to characterize “good” TAMs that support sustained anti-tumor CAR T–cell function. Further characterization of the brain TME includes identification of other immune-cell populations, such as dendritic cells, neutrophils and monocytes, to understand their impact on CAR T–cell efficacy. These aims allow us to identify the TME state that synergizes with CAR T–cell function and understand how best to target components of the TME to increase CAR T–cell antitumor activity.

Establishing clinically actionable combination CAR T-cell therapy

Determining the best treatment for highly aggressive pediatric brain tumors, such as diffuse midline gliomas (DMGs), is difficult. We are actively looking to devise strategies to improve and prolong CAR T–cell function for aggressive brain tumors. We aim to test combination therapies of chemical therapeutics paired with CAR T cells. Our goal, conducted in collaboration with the Department of Chemical Biology & Therapeutics and the laboratory of Anang Shelat, PhD, is to perform a focused, high-throughput screen (HTS) to identify novel compounds that synergize with and increase the antitumor effect of CAR T cells, validate those results in vitro and in vivo and assess the safety of these combinations. 

Improving CAR T-cell efficacy

One of our primary interests is exploring how best to overcome antigen-negative relapse as a means to increasing CAR T–cell therapy efficacy. Our work focuses on two novel approaches, the first of which establishes a computational workflow to assess successful CAR expression and the second of which explores synthetic T-cell receptors. 

To best guide the design of bispecific CARs, we utilize computational protein modeling and prediction pipelines to predict CAR folding/structure to determine the structures less likely to aggregate. This work, conducted in collaboration with the Center of Excellence for Data Driven Discovery and Madan Babu, PhD, aims to not only discern the best CAR bispecific design in a resource-conscious manner, but further contribute to the world-class translational immune-oncology and immunotherapy program at St. Jude. Our work to improve CAR T–cell efficacy further extends into the study of synthetic T-cell receptors, such as split CARs, which are modular, adaptable and capable of targeting multiple antigens, and TRuCs, which target multiple brain tumor antigens. We additionally continue to investigate negative T-cell regulators, building off our work to delete DNMT3A, an epigenetic T-cell regulator controlling CAR T-cell persistence and efficacy. We have identified RASA2 as a potential target and found evidence that loss of RASA2 in CAR T cells improved their antitumor activity, especially in the context of diffuse intrinsic pontine gliomas (DIPGs)/brain tumors, which has been a previously unexplored area of research.

Clinical evaluation of CAR T cells

Our laboratory is participating in the Loc3CAR clinical study to evaluate the safety and efficacy of locoregional delivery of B7-H3-CAR T cells in patients with primary central nervous system (CNS) tumors. Beyond safety and efficacy, we are investigating exploratory objectives, including the in vivo persistence of B7-H3-CAR T cells, the immunophenotype and assessing the TME after treatment and tumor progression based on cell-free DNA in cerebrospinal fluid (CSF). 

Beyond Lo3CAR, our laboratory continues to expand our work into clinical research by participating in the collaborative development of a phase I study to determine safety and maximum tolerated dose (MTD) of autologous CD19/CD22-CAR DNMT3A KO T cells in patients less than 21 years of age with recurrent/refractory CD19- and/or CD22-positive leukemia. 

The scope of our research aims to expand our understanding of how CAR T–cell therapy can be successfully utilized in pediatric brain tumors. Through our collaborative investigations that utilize the invaluable expertise and resources available at St. Jude, we hope to expedite the identification, assessment and translation of viable immunotherapeutic options from the laboratory to the clinic, thus expanding effective treatment options to children with rare or difficult-treat brain tumors.