Small-molecule agonists of the RIG-I-like receptor pathway as cancer immunotherapeutics - PROJECT SUMMARY
This SBIR Phase II research program is focused on developing a small-molecule cancer immunotherapy drug
that targets and activates the RIG-I like receptor (RLR) pathways, pattern-recognition receptors that function as
intracellular sensor of RNA virus infection. Our small molecule agonists directly activate dendritic cells to prime
an anti-tumor T cell response, and they induce immunogenic cell death (ICD) in cancer cells, a programmed
cell death pathway that elicits an innate immune activation cascade within the tumor microenvironment. ICD
primes a T cell response against tumor neoantigens and recruits activated T cells into the tumor. When
administered by intratumoral injection, our lead series compounds, represented by the proof of concept
example KIN1312, inhibit tumor growth in mice, and mice exhibiting complete tumor regression are immune to
re-challenge with live tumor cells of the same type. In our Phase I studies, we used a structure-activity
relationship (SAR) approach to identify KIN1312 analogs with improved drug-like properties, target binding,
cellular potency, and efficacy. We obtained orthogonal confirmation of in vivo efficacy by demonstrating tumor
regression in mouse CT26 and B16F10 tumor models, and we established that our agonists induce apoptosis
in human cancer cell lines, but not in non-malignant primary cells. In addition, we demonstrated that combining
KIN1312 with an anti-CTLA4 immune checkpoint inhibitor in the CT26 tumor model improved tumor regression
and survival beyond that provided by either treatment alone. In Phase II, our goal is to select a lead preclinical
candidate for advancement to investigational new drug (IND)-enabling studies as a new cancer
immunotherapy. In Aim 1, we will use advanced SAR, structural biology, and formulation approaches to further
optimize our innate immune agonists and to enable systemic administration. In Aim 2, we will determine the in
vivo efficacy of these compounds in diverse tumor models and compare intratumoral and systemic routes of
delivery. Compounds will be examined both as a monotherapy and in combination with immune checkpoint
inhibitors and other immunotherapies. In Aim 3, we will define mechanisms of action and immune correlates of
efficacy. High-priority compounds that exhibit synergistic activity with immune checkpoint inhibitors or other
immunotherapies will be evaluated in toxicokinetic assays. Together, these studies will allow us to select
intratumoral or systemic delivery for clinical proof of concept, and to select a lead preclinical candidate for
advancement to IND-enabling studies. When used in combination with immune checkpoint inhibitors or
engineered T cell therapies that target solid tumors, our RLR agonists have the potential to substantially
expand the number of patients that could benefit from cancer immunotherapy.
