Research we fund

I will advance precision combination therapy for blood cancers by computational and experimental pharmacology. In large B-cell lymphoma we will analyze and model subtype-guided pola-vedotin, genome-guided targeted therapy trials, and MRD-based care. In T-cell lymphomas, drug profiling and CRISPR screens will identify response predictors for subtype-specific regimens. In multiple myeloma we will analyze trials to resolve when intensified first-line regimens are superior to sequential therapy.

While T cell engager therapy in multiple myeloma can induce dramatic disease reduction, response duration is variable and curative outcomes remain elusive. The project will explore the novel hypothesis that durable response to T cell engager therapy for patients with myeloma is based on an initial inflammatory response that ignites secondary activation of myeloma specific immune cells. Characterizing this transition and the targets that are recognized is critical for unlocking the curative potential of this treatment.

Chimeric antigen receptor T cell (CAR T) therapy has revolutionized the treatment of multiple myeloma and can lead to deep, long-lasting remissions even in patients with advanced disease. However, some patients experience severe long-term adverse effects, including inflammatory conditions of the gut and brain, Parkinson-like symptoms, and secondary malignancies such as CAR T cell lymphoma, which significantly affect their quality of life. Leveraging one of the world’s largest clinical databases and biorepositories of patients treated with CAR T cells and integrating long-term follow-up with longitudinal and spatially-resolved single-cell multi-omics data, this project seeks to uncover how and why these toxicities develop by tracing the behavior of CAR T cells over time and across different tissues. The insights gained will help improve early diagnosis, prevention, and management of these adverse effects, ultimately making CAR T cell therapy safer and more sustainable for patients.

CAR T cell therapy has changed the outlook for many people with multiple myeloma, but the benefits often fade too soon. This research will determine when in a patient’s treatment course T cells are healthiest, so they can be collected and used to make more powerful, longer-lasting CAR T therapies.

At least half of multiple myeloma (MM) patients have mutations of KRAS or NRAS genes and in our preclinical studies, several types of Ras inhibitors slow MM cell growth in lab cultures and in mice, but resistance eventually develops. Gene-editing or activation (CRISPR) studies indicate that the mechanisms of this resistance can vary substantially between MM cells with different genomic features but, notably, defects in the Bcl‑2 family of genes are a recurrent theme. We will apply a lab method called dynamic BH3 profiling to determine how Ras inhibitors alter the myeloma cell dependence on Bcl-2 proteins to inform combination-based therapies. The results from these studies will be validated in cell lines and patient samples in the lab and in vivo models to identify the most effective combinations and guide future personalized therapies for people with KRAS or NRAS mutant multiple myeloma.

This project aims to enhance CAR T-cell therapy, a promising treatment for blood cancers, by leveraging the ketogenic diet and its key byproduct, beta-hydroxybutyrate (BHB). We found that BHB enhances the metabolism of CAR T cells, improving their effectiveness and durability in the body. Our study will explore this innovative approach using murine models of blood cancers and healthy donors, aiming to better understand how BHB can augment CAR T-cell function. The ultimate goal is to pave the way for more potent, accessible cancer therapies.

Despite an array of promising immunotherapies, the blood cancer multiple myeloma still remains without any known cure. Patients with high-risk disease in particular still relapse most frequently after current BCMA-targeting therapies such as CAR-T cells. Here we identify CD70 as an alternative CAR-T target in these high-risk patients who need new treatment options, and further use innovative artificial intelligence-inspired strategies to develop a best-in-class CAR-T design targeting CD70. The goal of our proposal is to perform additional validation studies to prove the efficacy and safety of this novel CAR-T cell, with the goal of moving toward near-term clinical trials in high-risk myeloma by the completion of the award period.

The overall focus of my research is improving outcomes with immunotherapy in multiple myeloma.  I will accomplish this through 1) novel clinical trials of bispecific antibodies and CAR-T therapy; 2) outcomes research including real world evidence and patient reported outcomes to understand the safety, efficacy and areas of unmet need with standard of care immunotherapy; and 3) correlative studies focused on understanding factors impacting the efficacy and toxicity of these therapies.

We will conduct a decentralized randomized controlled trial of a high-fiber plant-based dietary intervention among patients with multiple myeloma undergoing induction chemoimmunotherapy. The study will assess whether the intervention (meals and virtual coaching) leads to improved rates of complete response, and quality of life mediated by improvements in weight and insulin resistance. The study is expected to provide rigorous evidence of the effectiveness of this intervention in patients with newly diagnosed multiple myeloma and support the development of low-cost, minimal-risk nutrition as a strategy to improve cancer treatment outcomes.

Winship Cancer Institute is the only NCI-Designated Comprehensive Cancer Center in Georgia, the largest state by land area east of the Mississippi River, and 8th largest state by population. The Winship IMPACT program will leverage existing relationships throughout the state to bring hematology trials to patients in their communities. The goals are to strengthen our relationship with community sites and to increase opportunities for patients to access cutting edge trials throughout our state.