DCP Early Career Scientist Spotlight Research Seminar Series (Past Research Talks)

Tuning the organ-selectivity of mRNA expression through dendrimer-based lipid nanoparticles
Fan Zhang, PhD
Assistant Professor, Department of Pharmaceutics, University of Florida

Fan Zhang, Ph.D. received his Ph.D. from Johns Hopkins University in Materials Science & Engineering. His graduate work established the guiding principles for designing nanomedicines to target neuroinflammation. To expand the clinical impact of his research, he then undertook postdoctoral training at the clinical research division of Fred Hutchinson Cancer Research Center. This experience solidified his foundation in immuno-oncology, cell & gene therapy, and experimental tumor models. Dr. Zhang’s research focuses on developing synthetic nanoplatforms to direct immune cells as ‘living therapeutics’. To this end, his laboratory integrates materials science, immunology, synthetic biology, and translational medicine to create novel nanotherapeutics for controlled modulation of the immune system. The overarching goal of his research is to establish a fundamental understanding of nanotherapeutic design and the ways it interacts with the immune system. The ultimate goal of his research is to translate nanomedicine to the clinic.

Abstract:
The predominant liver-targeting of lipid nanoparticles (LNPs) significantly limited the general application of IVT-mRNA as a systemic therapy. To identify novel LNPs that deliver mRNA beyond the liver, we constructed a library of ionizable lipids using dendrimer as a scaffold. Through a combination of in vitro and in vivo screening, we discovered that the structure of internal amines (i.e., secondary, tertiary, or quaternary amines) within the ionizable lipids determines the selectivity of mRNA expression in either spleen, liver, or lung; The apparent pKa of the DLNPs further influence the amount of expression in these organs. Guided by this mechanism, we designed 9 patentable lead mRNA formulations with superior in vivo transfection than FDA-approved LNPs. This discovery provides guiding principles for rationally designing LNP for spleen targeting. Implemented in clinics, this delivery platforms can be used for targeted delivery of RNAs to spleens as prophylactic or therapeutic vaccines for immune-related disorders.

Harnessing the Potential for Immune Interception in Pancreatic Cancer High-Risk Cohorts
Neeha Zaidi, MD
Assistant Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University

Neeha Zaidi is a physician-scientist and oncologist who focuses on the development of vaccine strategies for the treatment and interception of pancreatic cancer. Specifically, her work focuses on targeting mutated KRAS which is expressed in up to 90% of pancreatic cancers as well as associated precursor lesions. She is leading the first trial to test a mutant KRAS vaccine for pancreatic cancer interception in high–risk cohorts either with germline predisposition and/or high–risk intrapapillary mucinous neoplasia. Their work utilizes single cell technologies to analyze the vaccine-induced T cell transcriptome and repertoire, as well as spatial transcriptomics to assess changes in the cellular architecture in premalignant tissue. In tandem, mouse models are used to test strategies to enhance vaccine efficacy by (a) identifying MHC II neoantigens; (b) using molecular dynamics to predict immunogenic neoantigens; and (c) studying the temporal sequence of changes in cellular composition as premalignancy progresses to PDAC.

Abstract:
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease and is projected to be the third leading cause of death by 2030. Contemporary immunotherapies have shown little to now response in PDAC. However, we and others find the premalignant lesions PanINs (or pancreatic intraepithelial neoplasia) are less immunosuppressive and more amenable to vaccine interception strategies. Mutated KRAS is the earliest driver that is expressed in up to 90% of precursor lesions and thus serves as an attractive off-the-shelf vaccine target for interception. Notably, at least 10% of PDACs arise from a genetic predisposition. We have tested a pooled long peptide vaccine targeting the six most common KRAS mutations in high-risk cohorts after establishing both safety and immunogenicity in patients who had undergone PDAC resection and received standard-of-care adjuvant chemotherapy. In both studies, we have demonstrated an induction of de novo, high quality T cell responses post-vaccination.

The Role of Neoantigen-Specific T-Cells in Cancer Interception and Immune Monitoring of Lynch Syndrome
Fahriye Duzagac, PhD
Division of Cancer Prevention & Population Sciences Cancer Prevention Research Training Program (CPRTP) Postdoctoral Fellow, Department of Clinical Cancer Prevention, MD Anderson Cancer Center

Fahriye Duzagac is a postdoctoral researcher at MD Anderson Cancer Center, focusing on cancer prevention, especially in Lynch Syndrome and mismatch repair-deficient cancers. Her undergraduate works included studying cancer stem cells and immune cells within tumor microenvironments using a microfluidic chip-based model to address tumor heterogeneity. Fahriye’s research encompasses two primary objectives: deciphering the molecular and cellular mechanisms of colorectal cancer with an emphasis on immune prevention, including analyzing immune responses in Lynch Syndrome and tracking the transformation from pre-cancerous lesions to invasive colon cancer. Additionally, she is identifying and validating recurrent frameshifted peptide neoantigens in Lynch Syndrome through extensive genomic and transcriptomic analyses and studying the clonal dynamics of neoantigen-specific T cells, key for developing preventive vaccines and improving early cancer detection. Her dedication to this field has been recognized with the CPRIT Postdoctoral Fellowship in Cancer Prevention, and more recently, her selection as an NCI-DCP Early Career Scientist.

Abstract:
Lynch Syndrome (LS) is a hereditary condition marked by mutations in mismatch repair genes, leading to a high risk of colorectal (50-80%) and endometrial (40-60%) cancers, among others. These mutations generate neoantigens, triggering an immune response even in pre-cancerous lesions. Our single-cell omics analysis of LS carriers' colonic tissue revealed a robust immune presence, with T-cell activation and differentiation evident. However, our findings also indicated signs of T-cell exhaustion and dysfunction in active cancer stages, underscoring the critical need for early detection and timely intervention. We explored the potential of neoantigen-based vaccines by identifying and testing immunogenic neoantigens, with a 65% validation rate. Our ongoing research focuses on the immune responses of these neoantigen-specific T cells, aiming to develop TCR-based immune monitoring and vaccination strategies for early cancer interception in LS carriers. This approach could significantly impact the management and prevention of cancer in this high-risk population.

CD8+ T Cell Clonal Dynamics in Response to ICB Therapy in Surgically Resectable (Sx) NSCLC
Jonathan Villena-Vargas, MD
Assistant Professor of Clinical Cardiothoracic Surgery, Weill Cornell Medicine

As a Thoracic Surgeon and Early-Stage Investigator at Weill Cornell Medicine, I specialize in T cell-based immunotherapy for lung cancer. Through my endeavors, I've established a novel biobank and mouse model to investigate metastatic relapse in early-stage lung cancer, emphasizing the role of ICB therapy on tumor-draining lymph nodes. My research has garnered support from an NIH supplement grant, diverse funding sources, and a significant collaboration with Kadmon Therapeutics to explore IL-15 immunomodulators. I've presented my preliminary findings at major National and International conferences in both 2022 and 2023. Importantly, I aim to leverage nodal memory response to augment our understanding of immune correlates. This ambition sets the stage for enhanced biomarkers and the evolution of next-gen ICB to tackle the global issue of resectable lung cancer. Committed to bridging lab discoveries with clinical applications, I envision a future as a leading surgeon-scientist at WCM.

Abstract:
Metastasis is the primary cause of mortality in surgically resectable (Sx) non-small cell lung cancer (NSCLC), with early detection advancements failing to curb metastatic recurrence. The PD-1/PD-L1 pathway inhibition, while standard, fails in up to 80% of patients, underscoring the need for effective treatments, predictive biomarkers, and strategies against metastatic relapse. This research focuses on the role of PD-1 blockade in developing tumor-specific functional T cell memory essential for post-Sx immune surveillance. We aim to identify CD8+ T cell subsets critical for post-surgical immunity, hypothesizing that stem cell-like CD8+ T cells in tumor-draining lymph nodes are critical for immunity. Our objectives include elucidating these cells' role in anti-tumor immunity and their contribution to immune responses. This study will advance understanding of T-cell immunosurveillance, impacting therapeutic strategies, clinical trials, and vaccine development in NSCLC, utilizing a novel "live T cell" biobank and a Sx murine model for comprehensive analysis.