Yeku Lab: Oladapo Yeku, MD, PhD, FACP

Overview

Our lab is interested in new approaches to meet the therapeutic challenge of immunotherapy treatment response and resistance in gynecologic malignancies. Gynecologic cancers such as Ovarian cancer, Endometrial cancer, Cervical cancer, and Vulvar cancer are lethal when they recur after definitive therapy, and immunotherapy has variable success in each of these gynecologic cancers.

We use preclinical xenograft, and syngeneic tumor models to systematically dissect the immunosuppressive tumor microenvironment in gynecologic cancers. Using several different approaches such as adoptive cellular immunotherapy, bispecific T-cell engagers, immune checkpoint inhibitors and antibody drug conjugates, our research leverages cutting edge immunotherapeutic modalities that can be readily translated to clinical trials.

Our Current Projects

MUC16

MUC16/CA125 is a large glycoprotein expressed in large variety of malignancies, including Ovarian cancer. MUC16 undergoes proteolytic cleavage, and the shed portion is the commonly measured CA125 utilized as a tumor marker. Our lab has shown that the retained portion of MUC16 is not only transforming but is also an effective target for immunotherapeutic and small molecule development. Our antibody platform targeting MUC16^ecto has been extensively validated in preclinical models, including a phase 1 Chimeric Antigen Receptor (CAR) T-cell clinical trial. 

BiTEs

Bispecific T-cell engagers (BiTEs), which utilize two tandem linked single chain variable fragments (scFv) to recruit T-cells to the tumor, have shown efficacy in hematologic cancers and in preclinical models of ovarian cancer. Our lab has engineered highly specific and efficacious BiTEs directed at the retained portion of MUC16 (MUC16^ecto- BiAbs), and we show that this therapy is significantly more effective when combined with anti-angiogenic therapy. We are leveraging other insights into the immunosuppressive tumor microenvironment to develop next-generation MUC16^ecto- BiAbs.

CAR T-Cells

Chimeric Antigen Receptor (CAR) T-cell immunotherapy is a modality wherein T-cells are collected from a patient and modified to express a receptor that targets them to tumor cells. When these modified T-cells, now CAR T-cells, are infused back into the patient, they seek out and eradicate the tumor. This treatment has been very active and has now been FDA approved for certain blood cancers. However, due to the different composition of solid tumors such as ovarian cancer, this treatment has not shown a similar degree of efficacy. We have made progress in modifying CAR T-cells to make them more potent against ovarian cancer, but little is known about how they traffic to the tumor. Our lab has identified key pathways that potentially limit CAR T-cell trafficking and infiltration into tumors. We are activity working on strategies to overcome these limitations in preclinical models with plans to translate this to clinical trials.

Mono-BiTEs

Bispecific T-cell engagers (BiTEs) are currently limited to targeting a single tumor-associated-antigen at a time, leading to concerns for tumor immune escape. Furthermore, since BiTEs rely on T-cells for efficacy, the immunosuppressive constraints that hamper immune checkpoint blockade therapy could also potentially inhibit BiTEs. Monocytes are recruited to ovarian cancer whereupon they are polarized to immunosuppressive TAMs and MDSCs and these cells correlate with poor outcomes in ovarian cancer. Our lab is engineering monocytes that can be “Armed” to deliver therapeutic cargo the tumor microenvironment in ovarian cancer. An example of this are Armed monocytes that secrete BiTEs targeting MUC16.

Bench to Bedside and Back Again

Our lab is singularly focused on rapid translation of our best ideas to the clinic. Evaluating promising synergistic immunotherapy combinations in clinical trials for women with gynecologic cancers is an important focus of our laboratory. We embarked on an investigator- initiated clinical trial to evaluate the synergy between cisplatin chemotherapy, immune checkpoint inhibitors, and radiation therapy in vulvar cancer. At key portions during this trial, we are evaluating important translational endpoints. Insights from our aggregate analysis of this study will tested in animal models and subsequently validated in our next clinical trials.

Who We Are

Fabian Kraus, MD
Postdoctoral Research Fellow

Fabian Kraus, MD, received his medical degree from the Technical University of Munich, Germany, with clinical rotations and research stays at Great Ormond Street Hospital and University College London Hospital, London, UK, Memorial Sloan Kettering Cancer Center and New York-Presbyterian Weill Cornell Medical Center, NYC, USA. For his experimental doctoral thesis, he investigated the therapeutic potential of adoptive cell transfers involving genetically engineered CD4+ T cells in a T cell lymphoma and a pancreatic cancer model at the Department of Clinical Pharmacology, Ludwig-Maximilians-University (LMU), Munich, Germany. Prior to joining the Yeku lab, Dr. Kraus worked as a fourth-year resident in the Department of Obstetrics and Gynecology at the LMU, Munich, Germany. His current research in the Yeku lab involves characterization of the differences in the susceptibility of various ovarian cancer cell lines to immune-mediated killing.

Raj Kumar, PhD
Senior Research Scientist

Raj Kumar, PhD, is an accomplished cancer biologist with a PhD in oncogene regulation, complemented by an MS in Biotechnology from Jawaharlal Nehru University, India. Following his doctoral studies, Dr. Kumar conducted postdoctoral research at the Wellman Center for Photomedicine, Department of Dermatology, at the Massachusetts General Hospital (MGH). His contributions have resulted in numerous research articles published in international journals and earned him prestigious awards, recognizing his dedication to advancing cancer research. His expertise spans various aspects of cancer biology, including tumor microenvironment, molecular signaling pathways, and therapeutic resistance mechanisms.

As a Senior Research Scientist in the Yeku laboratory at MGH Cancer Center, Dr. Kumar leads pioneering projects to enhance chimeric antigen receptor (CAR) T-cell trafficking and infiltration in solid tumor malignancies. He focuses on optimizing adoptive cell therapy to target ovarian cancer and other gynecologic malignancies. Dr. Kumar employs cutting-edge molecular biology and genetic engineering techniques, and high-throughput screening to identify novel therapeutic targets and biomarkers with a keen focus on developing personalized immune therapies to overcome resistance mechanisms and improve patient outcomes.

Dr. Kumar is driven by a desire to make a meaningful impact in the fight against cancer and he is dedicated to advancing scientific knowledge and translating discoveries into improved patient outcomes.

Irva Veillard
Research Technician II

Irva Veillard received her Bachelor of Science degree in Biomedical and Clinical Laboratory Sciences from Boston University. Before joining MGH, Irva worked as a Research Assistant at Boston Medical Center’s Nephrology Department, focusing on vascular diseases in kidney failure and cancer-related vascular pathologies.

Veillard currently works in the Yeku lab as a senior research technologist and has broad-ranging expertise in preclinical and translational research including collection and processing of specimens from clinical trial participants. Her major interest is contributing towards to the development of immunotherapy approaches to ovarian cancer, but she is committed to improving the standard of care for all gynecologic cancers through her research.

William Manning, MD
Clinical Research Fellow

William Manning, MD, earned his medicine degree from the University of Texas Health Science Center at San Antonio. Subsequently, he completed his residency in Obstetrics and Gynecology at Women and Infants Hospital of Rhode Island | Brown University before matching into a fellowship in Gynecologic Oncology at Massachusetts General Hospital. He is currently exploring resistance mechanisms to antibody-drug conjugates in Gynecologic malignancies.

Mengyao Xu, PhD
Postdoctoral Fellow

Mengyao Xu, PhD, received her doctorate in Oncology from the Nankai University school of medicine in China in 2022. During her thesis research, she focused on the identification of genes regulating metastasis in ovarian cancer using CRISPR-Cas9 screening. Dr Xu’s current research endeavors center around the development of novel immune-based therapies for ovarian cancer. This research encompasses MUC16-based Antibody Drug Conjugates, Bispecific T-cell engagers, and Chimeric Antigen Receptor (CAR) T-cells alone or in combination with other immunomodulatory agents in vitro and in vivo and evaluating relevant mechanisms of resistance. During her spare time, she enjoys hiking, skiing, traveling, watching movies, and working out.