II. PROPOSAL NARRATIVE
A. Title of Research Project: Microengineered human lymphoid tissue-on-chip to study cancer immunity
B. Introductory Statement, Background, Preliminary Data, and Rationale: The biology of circulating cells is different from that of tissue resident immune cells. The types and proportions of cell types, mechanical forces, extracellular matrix and the resulting biological interactions are quite distinct in lymphoid tissues compared to peripheral blood mononuclear cells (PBMC). Yet, researchers rely on conventional in vitro culture of human PBMC to study human immunity and immunotherapy. PBMC are the only easily accessible human tissue for most laboratories but they are not predictive of safety or efficacy. In-vivo studies are either performed on mouse homologues (1) or humanized mice. Mouse immunity is quite distinct from human: mice do not show the immune related adverse events seen in patients treated with checkpoint blockade. Humanized mice have immunocompromising mutations that reduce rejection of the implanted human immune organs such as bone marrow, thymus, liver etc. Despite complicated genetic engineering, treatment with cytokines and surgery, humanized mice continue to have poor survival, impaired immune responses and complications from graft vs. host disease. Interactions with non-immune cells, such as human endothelial cells, are not captured in humanized mice, and the organization of lymphoid structures is disrupted (2). Not surprisingly, humanized mice do not predict the donor dependent cytokine release syndrome seen in patients treated with autologous T cells reengineered to attack tumors (chimeric antigen receptor-CAR T cells. CAR T cells and understanding of CAR T cell trafficking, expansion and persistence cannot be studied in humanized mice.
A poignant example of the lack of correspondence between animal and human studies (3) and loss of tissue relevant immune function in PBMC assays is the life threatening cytokine release syndrome caused by CD28 superagonist TGN1412 in 6 patients. The toxicity of TGN1412 was not predicted despite extensive animal studies and PBMC testing. Similar lack of predictivity has been described for anti-cancer antibodies such as rituximab (anti-CD20) and alemtuzumab (anti-CD52), used to treat B-cell malignancies (4). Thus, we need better in vitro models of human tissue relevant anti-cancer immunity.