Project Summary
This research project focuses on testing and finding cures for patients diagnosed with chronic lymphocytic
leukemia (CLL), the most common adult blood cancer. CLL is still an incurable type of cancer derived from B
cells, which normally produce antibodies to protect the human body from infections. Although ibrutinib and
venetoclax have been approved by the FDA to treat CLL, a large group of CLL patients suffer from chronic
toxicities and have to stop using these two drugs. In addition, some CLL patients develop drug resistance and
their disease becomes diffuse large B cell lymphoma (DLBCL), which is even harder to treat than CLL. We
have shown that both mouse and human CLL cells require activation of a protein called spliced X box-binding
protein-1 (XBP-1s) to support their growth and survival. We have developed a drug named B-I09 that can
effectively suppress XBP-1 and kill CLL cells. In addition, our new results have shown that CLL cells
significantly reduce their expression of a protein called stimulator of interferon genes (STING). Based on our
results suggesting that reduced STING in CLL cells may contribute to their survival, we propose to use ADU-
S100, a STING activator currently in clinical trials, to stimulate the remaining STING to kill CLL cells. Based on
the link between XBP-1s and STING in regulating the same survival mechanism, namely, B cell receptor
(BCR) signaling, we propose to test whether B-I09 and ADU-S100 can synergize to kill cultured mouse and
human CLL cells. To enable these studies, we have engineered a novel mouse model in which CLL cells
produce no STING. We will use this model to test whether ADU-S100 can activate the immune system to
synergize with B-I09 to effectively eradicate CLL. Finally, based on our recent progress in successfully
developing stimuli-responsive inhibitors of the IRE-1/XBP-1 pathway, we propose to conjugate B-I09 to a
single-domain antibody (or nanobody) against human CD20, an integral membrane protein expressed at high
levels in CLL cells in order to target the drug to these cells. The resulting nanobody-drug conjugate (NDC) will
be evaluated in cells and in vivo for suppression of XBP-1s, reduction of tumor burden, and synergy with ADU-
S100 in a novel STING-deficient, human CD20-expresssing CLL mouse model. These studies will serve as the
foundation for initiating phase I clinical trials to treat human patients diagnosed with CLL, DLBCL, or potentially
other solid tumors with an inhibitor of XBP-1s in combination with an activator of STING. The development of
the first NDC to target XBP-1s will open a new and important avenue to enable cell-specific inhibition of XBP-
1s in various cell types as long as such cells express a unique cell surface marker. These novel XBP-1s-
targeting NDCs can also be used to interrogate the biology of the IRE-1/XBP-1 pathway in various cell types,
and as therapeutics.