(53b) Orchestrating Innate Immunity Against Cancer Using Nanotechnology

Immunomodulatory
therapeutic approaches to date have focused on enhancing T-cell responses.
Despite unprecedented clinical results, most cancer patients still do not
benefit from these treatments due to the low response rate and immunological
toxicities. Targeting innate immunity in cancer has the potential to program
the immunosuppressive ‘cold tumor’ into inflammatory ‘hot tumor’ that is more
responsive to current T-cell focused immunotherapies.

As a key player of the innate
immunity, tumor-associated macrophages (TAMs) usually express an M2 phenotype,
which enables them to perform immunosuppressive and tumor-promoting functions.
Reprogramming these TAMs toward an M1 phenotype could thwart their pro-cancer
activities and unleash anti-tumor immunity, but efforts to accomplish this are
nonspecific and elicit systemic inflammation.

Here we describe a targeted
nanocarrier that can deliver in vitro-transcribed mRNA encoding M1-polarizing
transcription factors to reprogram TAMs without causing systemic toxicity (Figure
1). We demonstrate in models of ovarian cancer, melanoma, and glioblastoma that
infusions of nanoparticles formulated with mRNAs encoding interferon regulatory
factor 5 in combination with its activating kinase IKKb reverse the
immunosuppressive, tumor-supporting state of TAMs and reprogram them to a phenotype
that induces anti-tumor immunity and promotes tumor regression. We also show that
treatment with these nanoparticles promoted the CD8+ and CD4+ T-cells
infiltration into the tumor microenvironment, which also contributes to the
tumor regression. We further establish that these nanoreagents are safe for
repeated dosing.

Based
on these data, our next step is to translate this technology into a clinical
trial as a new approach to treat ovarian cancer patients who were not
responsive to other therapies. Implemented in the clinic, this new
immunotherapy could enable physicians to obviate suppressive tumors while
avoiding systemic treatments that disrupt immune homeostasis.

Figure 1. Scheme to genetically transform tumor associated
macrophages (TAMs) into tumoricidal cells using targeted mRNA nanoparticles