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.