The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors

Abstract

While many classes of chemotherapeutic agents exist to treat solid tumors, few can generate a lasting response without substantial off-target toxicity despite significant scientific advancements and investments. In this review, the paths of development for nanoparticles, oncolytic viruses, and oncolytic bacteria over the last 20 years of research towards clinical translation and acceptance as novel cancer therapeutics are compared. Novel nanoparticle, oncolytic virus, and oncolytic bacteria therapies all start with a common goal of accomplishing therapeutic drug activity or delivery to a specific site while avoiding off-target effects, with overlapping methodology between all three modalities. Indeed, the degree of overlap is substantial enough that breakthroughs in one therapeutic could have considerable implications on the progression of the other two. Each oncotherapeutic modality has accomplished clinical translation, successfully overcoming the potential pitfalls promising therapeutics face. However, once studies enter clinical trials, the data all but disappears, leaving pre-clinical researchers largely in the dark. Overall, the creativity, flexibility, and innovation of these modalities for solid tumor treatments are greatly encouraging, and usher in a new age of pharmaceutical development.

Keywords: clinical trials; exosomes; nanoparticles; oncolytic bacteria; oncolytic viruses; solid tumors.

Figure 1

Representative oncotherapeutic modality details, size comparison, and structural characteristics. Nanoparticles: (A) polymersomes [21], (B) liposomes [22], and (C) exosomes [23]; oncolytic viruses: (D) adenovirus [24], (E) herpes virus [25], and (F) vaccinia virus [26]; (G) oncolytic bacteria: G. Salmonella [27], (H) vegetative Clostridium [28], and (I) Clostridium spore [28].

Figure 2

Representation of potential drug loading and targeting modifications strategies.

Figure 3

Summary of tumor localization mechanisms. (A) Nanoparticles use the Enhanced Permeability and Retention Effect (EPR) allowing molecules of less than 300 nm diameter to accumulate in tumor tissues due to abnormal tumor vasculature [17]. This figure depicts a generic nanoparticle targeting to a Cancer Stem Cell Marker (CSC) for entry and payload delivery; (B) Viruses also use the EPR effect in conjunction with upregulated cell surface markers for enhanced targeting specificity [68,69]. After entry the DNA or RNA payloads are delivered to the cell [70]; (C) Bacteria can follow chemokines to the site of the tumor before migrating to the hypoxic core to undergo sustained replication [71,72].

Figure 4

Comparison of payload delivery characteristics and capacity. (A) Nanoparticles use targeting motifs (e.g., cancer stem cell marker CSC) for specific targeting of tumor cells. Once localized, they will release their payloads with or without controlled stimuli [231,232]; (B) oncolytic viruses target tumors and take advantage of decreased viral clearance mechanisms. After they reach the cytosol, the virus will not only shed DNA/RNA transgenes resulting in constant replication, but they also block cellular replication or induce direct cell lysis. Examples of Oncolytic Viral payloads are depicted [70,102,104,144,146]; (C) Oncolytic bacteria migrate to tumor cells due to chemokine gradients. After reaching tumor cells oncolytic bacteria will either replicate within the tumor cell cytosol or further migrate to the hypoxic core before undergoing continuous replication and drug delivery. Examples of oncolytic bacteria drug delivery are shown for context [70,233,234,235,236].

Figure 5

Mechanisms to enhance drug delivery. Examples of the exogenous and endogenous stimuli resulting in various drug or payload release. References—NP: [234,235,248], OV: [261,262]. OB [198,209,210,211,212,213,214,215,216].

Figure 6

Clearance and biological barriers to novel oncotherapies. The outer ring depicts the initial interactions that occur for each therapeutic as it enters systemic circulation—including corona formation [249,303,304,305], innate immune responses [311,312], and adaptive immune responses [103,206,235,248,257,318]. Should treatments navigate these obstacles, the tumor microenvironment [133,146,150], metabolic pathways, and adaptive immune responses can complicate current and/or future treatments.

Figure 7

Significant milestones for the development of nanoparticles, oncolytic viruses, and oncolytic bacteria as oncotherapies. References—NP: [344,346,361]. OV: [74,361,362,363,364,365]. OB: [157,204,366,367,368].

Figure 8

Running total of the number of clinical trials published since 1 March 2000 that investigated NP, OV, or OB as cancer treatments in phase I–IV clinical trials. Between 1 March 2000 and 1 September 2021, 321 total clinical trials related to NP (blue) treating cancers were published; 203 total clinical trials related to OV (green) treating cancers were published; and 85 total clinical trials for OB (red) treating cancers were published.