Immune

Jun 21, 2023

A multi-center research effort has created an immune-infiltrated kidney tissue model that can be used to study on-target, off-tumor effects of T cell bispecific antibodies (TCBs) and potentially other immunotherapies. TCBs are an emerging class of drugs that attach to tumor cells with one end and attract immune cells with the other end to force them to kill tumor cells. The new research was published recently in PNAS.

The new kidney-on-a-chip model is designed to help investigators tackle one of the challenges of treating solid tumors with bispecific antibodies—on tumor, off-target cell killing. Currenlty, there are no human in vitro models of kidney tissue that can sufficiently mimick the 3D architecture, cell diversity and organ functionality need to assess these effects during preclinical research.

Research collaborators were a team of bioengineers and immune-oncologists from 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.

“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, ScD, 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.”

In 2019, Lewis and collaborators 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 kidney 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, it could support the assessment of on and off-target effects from TCBs as well as complex cellular interactions,” sasaysid Kimberly Homan, PhD, a former postdoctoral researcher in Lewis’ lab, first author of the initial work, and a co-corresponding author of the new study.

The preclinical WT-1-targeting tool TCB (WT1-TCB) was created to specifically bind to the WT-1 antigen when presented by the HLA protein on the surface of target cells, in that case WT-1-expressing tumor cells. The team first investigated whether the normal WT-1 protein was expressed in any of the key kidney cell populations. They found that WT-1 was expressed by podocytes, but was undetectable in the proximal and distal tubule cells. Moreover, they found that a significant proportion of these differentiated kidney cell types also expressed HLA.

To understand specific targeting effects of WT1-TCB, the researchers compared them to those produced by a non-specific TCB that could bind antigens on all kidney cell types and a TCB that could only bind immune cells. The three compounds elicited strikingly different effects when introduced into the kidney organoid-on-chip model alongside PBMCs under high-flow conditions over five days. DP47 caused very few cells to die, while the ESK1-like TCB targeted and killed all cell types in a dose-dependent manner by recruiting immune effector cells.

“Importantly, our central finding was that the WT1-TCB tool compound resulted in the selective killing of WT-1-expressing podocytes in the kidney organoids, while it did not affect cells in the distal and proximal tubules,” notes co-first author Katharina Kroll, PhD, a postdoctoral fellow in the Lewis lab. “This compellingly demonstrates that our engineered human in vitro kidney organoid-on-chip system has utility as a preclinical drug development tool for assessing on-target, off-tumor toxicities of TCBs as a new class of immunotherapeutics.”

An important distinction of the current kidney organoid-on-chip system is the TCBs and PBMCs are not delivered via the same route as they would be in vivo, where they access kidney cells through the perfusion and filtration of blood within the glomerular compartment. The authors hypothesize though that in vivo access to the WT1 target on glomerular cells by TCBs would be minimal.

Kroll is now leading an effort to make the team’s model more physiologically relevant by creating a perfusable vascularized kidney organoid-on-chip model.

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