Project Summary / Abstract
Despite the success of immune checkpoint blockade (ICB) in many tumor types, breast cancers have
shown limited responses. Antigen presenting cells (APCs) are critical to initiate anti-tumor immunity and for
efficacy of ICB, and are known to be defective in breast cancers. Importantly, APCs need to be activated through
pathways such as the CD40 pathway in order to promote anti-tumor activity rather than immune tolerance. We
demonstrated that CD40 agonists synergize with Flt3 ligand (Flt3L) which is a growth factor that promotes
differentiation of DC1 cells which are important for antigen presentation, and anthracycline chemotherapy to
eradicate triple negative breast cancers in mouse studies. Based on this, we hypothesize that combining
chemotherapy with a CD40 agonist and Flt3L enhances antigen presentation and increases long-term
adaptive immunity, thereby improving triple negative breast cancer (TNBC) disease control. In order to
test this hypothesis, I propose:
Aim #1: To assess safety, clinical activity, and immunologic efficacy of CD40 agonist in combination with Flt3L
and anthracycline chemotherapy (triplet therapy) in patients with metastatic TNBC (mTNBC) and identify
biomarkers of response and resistance. I will be Lead Principal Investigator on a phase 1 pilot trial of CD40
agonist + Flt3L + pegylated liposomal doxorubicin in patients with mTNBC. Longitudinal tissue samples will be
collected and analyzed to study pharmacodynamics, biomarkers of response, and resistance mechanisms.
Aim #2: To discover mechanisms of response and resistance to triplet therapy using syngeneic and humanized
mouse models, including tumors reflecting different TNBC subtypes. 4T1-HA syngeneic model will be used to
study how different agents in the CD40 agonist + Flt3L + pegylated liposomal doxorubicin regimen contribute to
response and what immune cell types are mediating response, with a focus on CD8 T cells and DC1 cells. We
will additionally study how underlying TNBC subtype impacts response to triplet therapy using syngeneic murine
and humanized patient derived xenograft models.
Results of this work will guide future development of this combination in TNBC and other solid tumors.
I am an Assistant Professor at UT Southwestern (UTSW) Medical Center and the principal investigator
on this proposal. I am a breast medical oncologist focused on improving outcomes of breast cancer patients
through immunotherapy. To most effectively advance the field, I plan to integrate clinical investigation of agents
stimulating antigen presentation with patient tissue based translational science and preclinical studies. To
supplement my background in immune monitoring, this proposal details a training plan under the mentorship of
translational breast cancer expert Dr. Carlos Arteaga and cancer immunologist Dr. Yang-Xin Fu. This is further
supported by an expert advisory committee, relevant coursework, and the resources and supportive environment
of UTSW to help me transition to independence as a physician scientist focused on breast immuno-oncology.