High-risk hematological malignancies present unique challenges for immunotherapy-based treatments. In acute myeloid leukemia (AML), for example, there is significant overlap in antigen expression between normal and malignant cells, and the microenvironment is incredibly effective at suppressing the immune response. Our lab is interested in defining interactions between the tumor microenvironment and T cells. This information will help us engineer chimeric antigen receptor (CAR) T cells with better specificity and efficacy. Additionally, we aim to discover novel antigens and develop effective multi-antigen targeting capabilities to bypass immune escape. Our work spans preclinical and translational domains, with the goal of improving outcomes for patients with hematological malignancies.
The Team
The Velasquez Lab Team is an enthusiastic and interactive group of scientists and trainees focused on developing immune-based therapies for pediatric hematological cancers.
Our laboratory is focused on developing immune cell therapies for hematological malignancies with a particular emphasis on AML and T-cell acute lymphoblastic leukemia (T-ALL). We have projects that address antigen discovery, tumor immune evasion, persistence and efficacy of CAR T cells and cell-cell interaction within the tumor microenvironment. There are challenges unique to T-ALL and AML and developing innovative ways to overcome those hurdles will continue to define the driving force in our laboratory.
A focus on AML
As tumors are exposed to CAR T cells designed for a specific antigen, they have the potential to downregulate that same target. Not only is there a need to identify novel targets that are specific to the malignant cells, but it is essential to develop bi- or multi- antigen targeting techniques. Our lab is using a multi-omics approach, leveraging information from transcriptomics, proteomics, and genomics to determine what antigens are expressed on leukemia cells that aren’t expressed on normal tissues or native T cells and lead to antigen discovery. In addition, we are partnering with the Department of Structural Biology (Babu Lab) to develop potential antigen combinations and configurations that would prevent tumor adaptation and immune evasion.
Our work on bi-specific targeting techniques focuses on design and computational modeling of CAR T-cell immunotherapy for AML. To optimize bi-specific CAR T-cell design, our exploration focuses on a single molecule with two binding domains connected by a flexible linker that facilitates a more successful dual-targeting approach. Our collaboration with the Babu lab allows us to assess the success of this approach via computational modeling and continue to study how this design can be applied to other types of cancers beyond leukemia.
A focus on T-ALL
T-ALL presents a unique set of challenges due to the overlapping antigen expression between T cells and malignant ALL cells. This overlapping expression makes targeting the appropriate antigens difficult, so our research focuses on finding ways to bypass these challenges. Our recent work explores using naturally occurring CD7-negative T cells in the context of CD7 or CD19-positive hematological malignancies, with results showing promising antitumor activity in vitro and in vivo. As we continue to explore CARCD7-T cells, our hope is that this promising T-cell subset can be used in the targeted treatment of T-ALL and other hematological malignancies.
Models
Leukemias, especially AML, maintain a highly immunosuppressive environment, so we need to identify ways to bypass or evade the immune response. To enhance the anti-tumor activity and persistence of CAR T cells, we are expressing different types of co-stimulatory molecules on our engineered effector cells. It will also be critical to evaluate our cells in accurate models that reflect the patient condition. As such, we are exploring the use of immunocompetent AML models.
Our work aims to improve treatments related to hematological disease, but our ultimate goal is to perform collaborative research that identifies new antigens in disease states that can lead to enhanced immunotherapies for a broad spectrum of childhood cancers.
