(590c) Localized Multi-Component Delivery Platform Generates Local and Systemic Anti-Tumor Immunity

Introduction: Tumors employ complementary overlapping
mechanisms to evade immune surveillance, many emerging cancer immunotherapies
attempt to target multiple pathways to eradicate malignant cells. Though
modulation of independent pathways by simultaneous administration of multiple immune
has shown great promise, the clinical impact remains limited due to severe
toxicity associated with high systemic dosages. Localized injections at tumor sites may reduce systemic toxicity, however
such approaches still require frequent injections of large amounts of drug (soluble
proteins are rapidly diluted by lymphatic drainage and systemic circulation). For
example, intra-tumoral injections of anti-CTLA-4 and anti-OX40 plus CpG were
successful in generating systemic immunity to tumors, but required daily
intratumoral injections of 100 µg/day/mouse for 5 days. Therefore, novel platforms for efficient delivery of combination
therapies at lower doses would be enabling. Here, we describe immunomodulatory
molecule delivery system (iMods), which provides sustained extracellular
delivery of checkpoint inhibitor (anti-PD-L1) and, targeted intracellular
delivery of a tumor antigen (OVA) along with adjuvant (poly(I:C)), and the
indoleamine deoxygenase (IDO) inhibitor 1-MT.

Methods: Contralateral
melanoma B16F10 model was
utilized. iMods containing OVA-poly(I:C), 1-MT, anti-PD-L1, in all possible
combinations were injected in the periphery of the tumor (after the tumor was
palpable). The size of the tumor was monitored till 30 days or till tumors were
unbearable.

Results: In
melanoma bearing mice, combinatorial delivery of these factors with iMods led
to regression of both treated and untreated (contralateral) melanoma tumors and
100% survival. These promising therapeutic outcomes were attributed to
significantly enhanced ratios of anti-tumor CD8 T-cell / tumor-protective
regulatory T-cell (Treg) in tumors and tumor draining lymph nodes.

Figure.
(A) Melanoma mouse model. (B) Survival
curve for treatment groups and CD8/Treg ratios.

Conclusions:  In
summary, iMods develop potent systemic in vivo immune responses in the form of
reduced numbers of Treg, and increased numbers of active CD8 T-cells in the
tumor environment. Moreover, iMods formulations were able to generate systemic
anti-tumor immunity via one-time local injection without lethal toxicity.
iMods, as a platform, may be useful for the comparing a wide variety of combinatorial 
immunomodulating molecules in the context of cancer immunotherapy.

References:
1. Acharya et.al. Advanced
Functional Materials 2017, 2. Acharya et.al. Journal of Drug Targeting
2016.