Cornell University researchers have developed a 3-D lymphoma organoid that mimics the complex cellular environment of non-Hodgkin lymphomas (B- and T-cell tumors) in the body. This technology allows for the ex-vivo study of lymphoma development, and is a unique tool for testing novel anti-tumor drugs. This work, entitled “Integrin-specific hydrogels as adaptable tumor organoids for malignant B and T cells,” was recently published in the Biomaterials journal.
Drug development for non-Hodgkin lymphomas has been hampered by the complex lymphoma cellular environment (composed of different malignant and non-malignant cells), by the fact that patient samples do not survive outside the body, and by the lack of drug testing methods that effectively mimic the lymphoma microenvironment. Gathering reliable information about the effects of possible anti-tumor drug for lymphoma is thus extremely challenging.
The recently developed 3-D lymphoma organoid, or tissue culture that mimics this complex environment, can help to overcome these issues. Dr. Ankur Singh, Assistant Professor of the Mechanical and Aerospace Engineering Department of Cornell University and one of the senior authors of the paper, said in a press release: “We want to create a more realistic system for lymphomas. More precisely, we want to create a functional organoid similar to where these tumors arise and reside.”
Dr. Ari Melnick, the Gebroe Family Professor of Hematology/Oncology and Professor of Medicine at Cornell University and another senior author of the paper, added: “This is a game-changing technology for the field of lymphoma. These organoids allow us to better understand the complex architecture of lymphomas and how that informs the way we treat the disease — what drugs we should use and for whom, and how they interact with each other. This is a fundamental advance; no one in the world has the technology to treat patients in this way.”
The team created the organoid by culturing immune, support and lymphoma cells inside a synthetic hydrogel, forming cellular clusters that resemble the lymphoma microenvironment. Drugs can then be added and their effects on cell proliferation, survival and on the surface expression of particular proteins studied by analyzing cells purposely removed from the gel.
This research group determined in a separated study that T-cell lymphomas express a unique class of cell matrix receptors called integrins that mediate cell adhesion. According to Dr. Singh, “If you block the integrin pathway it will lead to tumor cell death in patient-derived lymphomas.” Nonetheless, the “three-dimensional organoids recreate a realistic environment for integrins and signaling cells called stromal cells, which are both necessary for studying lymphomas. B- and T-cell lymphomas express different types of integrins but 3-D organoids provide a flexible, modular system to study them.”
Using this system, researchers showed that the tumor microenvironment contributes for lymphoma resistance to chemotherapies and to Panobinostat (commercialized as Farydak from Novartis).
Dr. Leandro Cerchietti, Assistant Professor of Medicine at Cornell University and the third senior author of the paper, said: “It is impossible to predict from standard culture techniques, that lack of microenvironment signals and cells, how these drugs will behave in patients. Moreover, these new drugs are slow-acting and must be administered for significant longer times than classical chemotherapy agents, something that can only be done in 3-D lymphoma organoids.”
The research team is currently using 3-D lymphoma organoids to gather data for use in future clinical trials. They expect that it will take only about a year before the tangible effects of this technology are evident.