Researchers Pioneer a Faster Way to Innovate Cancer Treatments

New Approach Yields a Promising Lymphoma Therapy

BOSTON — Researchers from Beth Israel Deaconess Medical Center (BIDMC) and Dana-Farber Cancer Institute have developed a faster way to identify and engineer cancer-fighting therapies. In a study published in Nature Communications, the team used the new approach to create an investigational treatment that showed strong activity against aggressive B-cell lymphomas in laboratory experiments.

Among the most common blood cancers, B-cell lymphomas arise from normal B-cells, a type of white blood cell that helps protect the body from infection. Although immunotherapy treatments such as rituximab have transformed care for many patients, some lymphomas become resistant to therapy or return after treatment, creating the need to develop new therapeutic options.

Led by senior author Kipp Weiskopf, MD, PhD, Head of Antibody Therapeutics and Biologics in the Cancer Research Institute at BIDMC and a medical oncologist at Dana-Farber, the team used what Weiskopf calls “tactical surfaceome profiling,” a novel strategy for identifying the most promising targets for immune-based therapies among the molecules on the surface of the malignant cells (collectively called the surfaceome).

“The goal is to help macrophages — immune cells that identify, engulf and dispose of diseased cells — recognize lymphoma cells more effectively,” said first author Carlota Pagès-Geli, PhD, a postdoctoral scholar in the Weiskopf lab.

Cancer cells, however, often evade the immune system by displaying molecules on their surface that can “fool” macrophages, blunting the body’s immune response to the disease.

Weiskopf and colleague’s tactical surfaceome profiling flips the script on decades of cancer research. The new approach begins by identifying the surface proteins that induce the desired immune response. Traditional drug discovery often takes the opposite approach, building a drug tailored to a target and testing whether it demonstrates therapeutic potential only much later in the process.

To find the surface proteins most likely to help macrophages recognize and destroy cancer cells, the Weiskopf lab and colleagues used collections of antibodies targeting hundreds of proteins found on cell surfaces, including 173 mouse proteins and 241 human proteins. The team then evaluated the 414 antibodies using a high-throughput screening platform, measuring how effectively each one flagged lymphoma cells for immune attack. The surface proteins corresponding to those top-performing antibodies emerged as the molecules most likely to serve as effective drug targets.

Among those candidates, one emerged as a standout. The researchers engineered their experimental antibodies to be bispecific; that is, their design combines two separate targeting strategies. The researchers’ top contender targets a protein commonly found on lymphoma cells while also blocking a known molecular signal that tumors use to confuse and evade macrophages.

In laboratory studies, the experimental antibody triggered killing of lymphoma cells by macrophages, including cells resistant to rituximab, and outperformed both rituximab and another drug used to treat blood cancers, called daratumumab, in several preclinical tests. In mouse models of aggressive B-cell lymphoma, it slowed tumor growth, extended survival and, when combined with rituximab, completely eliminated tumors in some animals.

The investigators hope to advance these new therapies to clinical trials in patients in the near future. Additionally, they are now applying this same approach to other types of cancer, including gastric cancer, lung cancer, and ovarian cancer.

Co-authors included Carlota Pagès-Geli, PhD, and Thomas Wienclaw of Beth Israel Deaconess Medical Center and Harvard Medical School; Juliano Ribeiro of Harvard Medical School and the Harvard-MIT Health Sciences and Technology Program; Anna M. Meglan, Lauren Sloat, Jasmine Blandin, José Velarde, Kyle Vaccaro and Carolin Sebastiany of the Whitehead Institute for Biomedical Research; Matheus Silva of Beth Israel Deaconess Medical Center; Cynthia K. Hahn, MD, PhD, of Dana-Farber Cancer Institute, Harvard Medical School and the Broad Institute of MIT and Harvard; Patricia Fernández-Guzmán and Marta Crespo, PhD, of the Vall d'Hebron Institute of Oncology and Universitat Autònoma de Barcelona.

This study was supported by the Valhalla Foundation; the AACR-AstraZeneca Career Development Award for Physician-Scientists in Honor of José Baselga; an anonymous grant; Richard Reisman in honor of Jane Reisman and Lilian Reisman; the U.S. Department of Defense (W81XWH2210141); the National Cancer Institute (R01 CA279259); the Research Foundation for the Treatment of Ovarian Cancer; the ALK Positive Lung Cancer Foundation; the Torrey Coast Foundation; a European Association for Cancer Research Travel Fellowship; Asociación Española Contra el Cáncer (LABAE18014CRES); and Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI21/01190), co-sponsored by the European Union FEDER program.

Pagès-Geli, Ribeiro, Meglan, Vaccaro and Weiskopf are inventors on patents and patent applications related to macrophage-directed cancer therapies, including an application directly related to this work. Vaccaro is a former employee and equity holder of DEM Biopharma. Crespo has received research funding from Janssen, Genentech and AstraZeneca. Weiskopf reported patents and royalties, equity interests and advisory roles involving multiple biotechnology companies, including ALX Oncology, DEM Biopharma and Solu Therapeutics. The remaining authors declared no competing interests.

About Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center is a leading academic medical center, where extraordinary care is supported by high-quality education and research. BIDMC is a teaching affiliate of Harvard Medical School, and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is the official hospital of the Boston Red Sox.

Beth Israel Deaconess Medical Center is a part of Beth Israel Lahey Health, a healthcare system that brings together academic medical centers and teaching hospitals, community and specialty hospitals, more than 4,700 physicians and 39,000 employees in a shared mission to expand access to great care and advance the science and practice of medicine through groundbreaking research and education.