Colorectal cancer (CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo- and targeted therapies provide only a limited increase of overall survival for these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo- and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is α-amanitin antibody-drug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors.
In vitro transcribed mRNA constitutes a versatile platform to encode antigens
and to evoke CD8 T-cell responses. Systemic delivery of mRNA packaged
into cationic liposomes (lipoplexes) has proven particularly powerful
in achieving effective antitumor immunity in animal models. Yet, T-cell
responses to mRNA lipoplexes critically depend on the induction of
type I interferons (IFN), potent pro-inflammatory cytokines, which
inflict dose-limiting toxicities. Here, we explored an advanced hybrid
lipid polymer shell mRNA nanoparticle (lipopolyplex) endowed with
a trimannose sugar tree as an alternative delivery vehicle for systemic
mRNA vaccination. Like mRNA lipoplexes, mRNA lipopolyplexes were extremely
effective in conferring antitumor T-cell immunity upon systemic administration.
Conversely to mRNA lipoplexes, mRNA lipopolyplexes did not rely on
type I IFN for effective T-cell immunity. This differential mode of
action of mRNA lipopolyplexes enabled the incorporation of N1 methyl
pseudouridine nucleoside modified mRNA to reduce inflammatory responses
without hampering T-cell immunity. This feature was attributed to
mRNA lipopolyplexes, as the incorporation of thus modified mRNA into
lipoplexes resulted in strongly weakened T-cell immunity. Taken together,
we have identified lipopolyplexes containing N1 methyl pseudouridine
nucleoside modified mRNA as potent yet low-inflammatory alternatives
to the mRNA lipoplexes currently explored in early phase clinical
trials.
Cancer vaccines based on mRNA are extensively studied. The fragile nature of mRNA has instigated research into carriers that can protect it from ribonucleases and as such enable its systemic use. However, carrier-mediated delivery of mRNA has been linked to production of type I interferon (IFN) that was reported to compromise the effectiveness of mRNA vaccines. In this study, we evaluated a cationic lipid for encapsulation of mRNA. The nanometer-sized, negatively charged lipid mRNA particles (LMPs) efficiently transfected dendritic cells and macrophages in vitro. Furthermore, i.v. delivery of LMPs resulted in rapid expression of the mRNA-encoded protein in spleen and liver, predominantly in CD11c+ cells and to a minor extent in CD11b+ cells. Intravenous immunization of mice with LMPs containing ovalbumin, human papilloma virus E7, and tyrosinase-related protein-2 mRNA, either combined or separately, elicited strong antigen-specific T-cell responses. We further showed the production of type I IFNs upon i.v. LMP delivery. Although this decreased the expression of the mRNA-encoded protein, it supported the induction of antigen-specific T-cell responses. These data question the current notion that type I IFNs hamper particle-mediated mRNA vaccines.
TP53
is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of
TP53
and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies. Through in silico analysis, we identified
POLR2A
in the
TP53
-neighboring region as a collateral vulnerability target in TNBC tumours, suggesting that its inhibition via small interfering RNA (siRNA) may be an amenable approach for TNBC targeted treatment. To enhance bioavailability and improve endo/lysosomal escape of siRNA, we designed pH-activated nanoparticles for augmented cytosolic delivery of
POLR2A
siRNA (siPol2). Suppression of POLR2A expression with the siPol2-laden nanoparticles (siPol2@NPs) leads to enhanced growth reduction of tumours characterised by hemizygous
POLR2A
loss. These results demonstrate the potential of the pH-responsive nanoparticle and the precise
POLR2A
targeted therapy in TNBC harbouring the common
TP53
genomic alteration.
Modulating the activity of tumor-infiltrating dendritic cells (TiDC) provides opportunities for novel cancer interventions. In this article, we report on our study of the uptake of mRNA by CD8a þ cross-presenting TiDCs upon its intratumoral (i.
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