A growing repertoire of cell and molecule-based immunotherapies is offering patients with indomitable cancers new hope by mobilizing their immune systems against tumor cells. An emerging class of such immunotherapeutics, known as T cell bispecific antibodies (TCBs), are of growing importance with several TCBs that the U.S. Food and Drug Administration (FDA) approved for the treatment of leukemias, lymphomas, and myelomas. These antibody drugs label tumor cells with one of their ends, and attract immune cells with another end to coerce them into tumor cell killing.
One major challenge in the development of TCBs and other immunotherapy drugs is that the antigens targeted by TCBs can be present not only on tumor cells, but also healthy cells in the body. This can lead to “on-target, off-tumor” cell killing and unwanted injury of vital organs, such as the kidney, liver, and others, that can put patients participating in clinical trials at risk. Currently, there are no human in vitro models of the kidney that sufficiently recapitulate the 3D architecture, cell diversity, and functionality of organs needed to assess on-target, off-tumor effects at a preclinical stage.
Now, a new cross-disciplinary, cross-organizational study created an immune-infiltrated kidney tissue model for investigating on-target, off-tumor effects of TCBs and potentially other immunotherapy drugs. The team of bioengineers and immune-oncologists who performed the study at the Wyss Institute for Biologically Inspired Engineering at Harvard University, Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), Harvard Medical School (HMS), and the Roche Innovation Centers in Switzerland and Germany, developed an immune-infiltrated human kidney organoid-on-chip model composed of tiny kidney tissue segments that contain vasculatureand forming nephrons, which can be infiltrated by circulating immune cells. They used this model to understand the specific toxicity of a pre-clinical TCB tool compound that targets the well-characterized tumor antigen Wilms’ Tumor 1 (WT-1) in certain tumors. Importantly, WT-1 is also expressed at much lower levels in the kidney, making it an important organ to study its potential on-target, off-tumor effects in. Their findings are published in PNAS.
“Together with our collaborators at Roche, we extended our vascularized kidney organoid-on-chip model to include an immune cell population that contains cytotoxic T cells with the potential to kill not only tumor cells, but also other cells that present target antigens,” said Wyss Core Faculty member Jennifer Lewis, Sc.D., the study’s senior author. “Our pre-clinical human in vitro model provides important insights regarding which cells are targeted by a given TCB and what, if any, off-target damage arises.” Lewis is also the Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS and co-leader of the Wyss Institute’s 3D Organ Engineering Initiative.
Incorporating immunity into a kidney organoid-on-chip
In 2019, Lewis’ group, together with that of Joseph Bonventre, M.D., Ph.D. at Brigham and Women’s hospital along with co-author Ryuji Morizane, M.D., Ph.D., found that exposing kidney organoids created from human pluripotent stem cells to the constant flow of fluids during their differentiation enhanced their on-chip vascularization and maturation of glomeruli and tubular compartments, relative to static controls. The researchers’ observations were enabled by a 3D printed millifluidic chip, in which kidney organoids are subjected to nutrient and differentiation factor-laden media flowed at controlled rates during their differentiation. The chip device allows researchers to directly observe the tissue using confocal microscopy through a transparent window in real-time.
“Given that this in vitro model represents most of the cell types in the kidney and incorporates the immune system, itcould support the assessment of on and off-target effects from TCBs as well as complex cellular interactions,” said Kimberly Homan, Ph.D., a former postdoctoral researcher in Lewis’ lab, first author of the initial work, and a co-corresponding author of this new study. Homan has since left Lewis’ lab to join Genentech as Director of the Complex in vitro Systems lab where she continued to provide expertise to the project collaborators. More