Cancer NanoVaccines?

Only 0.7% of nanoparticles have been successfully delivered to the tumor (median value)

https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6774033&blobtype=pdf Immunotoxicity Considerations for Next Generation Cancer Nanomedicines, 2019

A striking review by Wilhelm et al. in 2016 revealed that after extensively reviewing 10 years of nanoparticle research (2005–2015)

only 0.7% of nanoparticles have been successfully delivered to the tumor (median value).

Although not adjusting this value for tissue size (i.e., a tumor may be larger than a liver or spleen), this is still

a worrying statistic for cancer nanomedicines,

and one that puts this technology in a bad light in the public eye.

Horizon is the biggest supporter of innovative technology in the European Union with a seven-year budget plan of €80 billion. Nanotechnology is proving to be at the heart of this funding.[2] In the United States, the National Nanotechnology Initiative has provided at least €1.2 billion annually since 2013.[3] Despite this funding, there is growing necessity to improve translation as there are many pitfalls in current preclinical assessment.[4]

Immunotoxic effects related to cancer nanomedicines are major clinical roadblocks that must be carefully considered to improve translation in the future.[5]

Nanoparticles aim to reduce immunotoxicities associated with conventional drugs but can also indirectly induce many immunotoxic effects of their own.

Their unique physiochemical characteristics (PCC), such as size and large surface area, make them susceptible to undesirable interactions when administered intravenously that can hinder their development as potential cancer nanomedicines.

This review highlights

the broad range of unintentional immunological interactions

associated with various nanoparticles researched in the area of cancer nanomedicine.

If a nanoparticle undesirably interacts with a component of the coagulation system, an activation or inhibition of coagulation factors can disrupt the hemostatic balance either reducing the coagulation response below healthy levels or enhancing coagulation resulting in procoagulant activity.[15]

This disruption is associated with many toxic effects within the coagulation system including disseminated intravascular coagulation (DIC)[16] which, depending whether it occurs acute or chronically,

can induce abnormal hemorrhaging[17] or intravascular thrombosis[18] respectively.

DIC occurs through depletion of coagulation factors and, if left untreated,

can lead to organ failure and even death.[19]

Alterations to the hemostatic balance can be induced directly or indirectly through various mechanisms by nanoparticles including

platelet factor upregulation, platelet membrane damage, and endothelial cell interactions

(Table 1).

Moreover, circulating tumor cells are known to have a procoagulant phenotype and, therefore,

unintentional procoagulant effects may potentially enhance tumor progression

by contributing to metastasis.[30]

A striking review by Wilhelm et al. in 2016 revealed that after extensively reviewing 10 years of nanoparticle research (2005–2015) only 0.7% of nanoparticles have been successfully delivered to the tumor (median value).

Opsonins are foremost an immune response, considering nanoparticles as foreign pathogens due to their similarities in size to viruses (which are also in the nanometer range).[36]

The alternative pathway can directly induce opsonization of nanoparticles as well as contributing to protein corona formation

It can also be hijacked however, to deliver non-biodegradable nanoparticles to specific organs (e.g., liver, bone marrow, and spleen)[43] through the reticuloendothelial system (RES) or sites of inflammation (e.g., cancer, arthritis) which macrophages preferably localize to.[44] Unfortunately, this phagocytic uptake can also cause healthy tissue damage to the host leading to symptoms like rash, dyspnea, flushing, hypertension, hypotension (pseudoallergic reactions), and even fatal cardiopulmonary syndrome in rare cases.[45]

Recent papers have pinpointed these PEG-associated effects to naturally occurring anti-PEG antibodies detected in 44.3% of healthy human donors.[58]

This matches up well with the values suggested for hypersensitivity reactions mentioned previously.

In the last 10 years, however, four initially successful IONP (Iron Oxide Nano Particles) have been discontinued in the clinic by either the FDA (U.S. Food and Drug Administration) or EMA: Combidex in 2007, Feridex in 2008, Resovist in 2009, and Gastromark in 2012.[48,71]

CARPA and severe anaphylactic reactions has been a noted side effect with clinically approved IONP and are one of the major reasons behind these withdrawals.[48]

CARPA is one of the most significant immunotoxicity challenges for cancer nanomedicines in the pipeline, contributing to the clinical withdrawal of a host of IONP and resulting in the release of safety reports for both liposomal and iron oxide nanoformulations by EMA.

Moreover, immunotoxic studies without consideration to endotoxin contamination within the nanoformulation offer little to the reader in attempting to understand these associated effects.

Considering the regulatory position on this matter, cancer nanomedicines have been approved as both drug products and medical devices. Both of these categories have their own established regulatory paths and endotoxin limits agreed between the FDA and EMA.

As discussed here and in a recent paper by Li et al.,[155] there is

a serious lack of consideration to potential endotoxin contamination

in the literature when it comes to the assessment of immunotoxicity with nanoparticles.

Very little of the available literature includes an endotoxin contamination assessment, making interpreting these results extremely difficult.

Remarkably,

of the 63 papers depicting immunological effects with nanomedicines described previously, only 8 papers (12.7%) included any endotoxin contamination assessment of their nanomedicine

(values exclude papers testing already clinically approved cancer nanomedicines). Furthermore, endotoxins wide range of signaling means it can give false positive/negative results on a wide array of immunological pathways. It is therefore necessary to assess endotoxin contamination before any immunological assessment to avoid these common mistakes.

3.2. Sterilization and Depyrogenation

Further considerations to avoiding contamination in nanoformulations involve sterilization and depyrogenation. The current recommended sterility assurance level of a final product is 10−6 , [156] meaning for a nanoformulation to be sterile there can be no more than one viable microorganism in one million parts of the final product. Many methods of sterilization and depyrogenation are available but can potentially alter the PCC of nanoparticles. Vetten et al. reviews these depyrogenation and sterilization methods and concludes that there is not one single method sufficiently capable of purifying all nanoparticles and each nanoformulation must be considered in a case-by-case basis.[157]

3.3. In Vitro Immunotoxicity Assays

As discussed above, there is

a broad spectrum of interactions with nanoparticles when introduced into the blood circulation.

cancer nanomedicines administered intravenously will interact with the immune system, and have the potential to cause an array of unintentional immunotoxic effects

Currently, there are no regulatory approved guidelines for evaluating immunotoxicity specifically for nanomedicines.

Cost and availability are major issues to consider from an academic perspective when it comes to evaluating immunotoxicity.

Endotoxin assessment, for example, is quite an expensive assay for academic laboratories, especially if comparisons between two assays are expected.

Safe and effective for pregnant women, babies, just anyone - it's a crime simply.

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