Therapeutic cancer vaccines

Berinstein, Neil L.; Spaner, David

doi:10.1016/b978-1-4160-3611-1.50045-3

Cited by 2 publications

(2 citation statements)

References 164 publications

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“…Since the first report in 1958 [ 6 ], 12 ADCs have been approved to date, while over 80 are currently undergoing clinical trials. Another example of using proteins for a purpose other than as API is in the case of protein-based vaccines, with the first approved hepatitis B vaccine some 30 years ago [ 7 ]. In this case, the protein is acting as an agonist to stimulate an immune response, thereby increasing the efficacy of the vaccine.…”

Section: Introductionmentioning

confidence: 99%

A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future

Holz¹,

Darwish²,

Tesar³

et al. 2023

Pharmaceutics

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Over the past few decades, the complexity of molecular entities being advanced for therapeutic purposes has continued to evolve. A main propellent fueling innovation is the perpetual mandate within the pharmaceutical industry to meet the needs of novel disease areas and/or delivery challenges. As new mechanisms of action are uncovered, and as our understanding of existing mechanisms grows, the properties that are required and/or leveraged to enable therapeutic development continue to expand. One rapidly evolving area of interest is that of chemically enhanced peptide and protein therapeutics. While a variety of conjugate molecules such as antibody–drug conjugates, peptide/protein–PEG conjugates, and protein conjugate vaccines are already well established, others, such as antibody–oligonucleotide conjugates and peptide/protein conjugates using non-PEG polymers, are newer to clinical development. This review will evaluate the current development landscape of protein-based chemical conjugates with special attention to considerations such as modulation of pharmacokinetics, safety/tolerability, and entry into difficult to access targets, as well as bioavailability. Furthermore, for the purpose of this review, the types of molecules discussed are divided into two categories: (1) therapeutics that are enhanced by protein or peptide bioconjugation, and (2) protein and peptide therapeutics that require chemical modifications. Overall, the breadth of novel peptide- or protein-based therapeutics moving through the pipeline each year supports a path forward for the pursuit of even more complex therapeutic strategies.

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Section: Introductionmentioning

confidence: 99%

A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future

Holz¹,

Darwish²,

Tesar³

et al. 2023

Pharmaceutics

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show abstract

“…There are several FDA-approved vaccines for cancer prevention such as the hepatitis B vaccine and the human papillomavirus (HPV) vaccines, which work by preventing infection from cancer-causing viruses. By preventing the viral infection, these vaccines block processes that may eventually result in runaway cancer cell growth; however, most cancers are not caused by viruses 3 . On the other hand, therapeutic vaccines are used as a method of treatment.…”

Section: Introduction 11 Overviewmentioning

confidence: 99%

Harnessing iNKT cells to improve in situ vaccination for cancer therapy

Prasit¹

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<p>Toll-like receptor (TLR) agonism in combination with the activation of type I NKT (iNKT) cells through systemic administration of their respective agonists has been shown to have a cooperative effect on activating antigen-presenting cells, stimulating cytokine production, and inducing adaptive immune responses to co-administered antigens. Here, it was hypothesised that it might be possible to harness these activities to treat solid tumours locally via intratumoural treatment to combat tumour growth while reducing toxicity to other organs. An intratumoural treatment model combining the stimulatory activity of unmethylated DNA oligonucleotides consisting of synthetic cytosine-guanine motifs (CpG), a TLR9 agonist, with activation of iNKT cells through administration of the CD1d-binding iNKT agonist α-galactosylceramide (α-GalCer) intratumourally was shown to have significant anti-tumour activity. The treatment regimen showed superior efficacy to that achieved with either agent alone in several in vivo models representing different types of cancer. In some models, the combination of α-GalCer and CpG was effective at inducing the complete rejection of both treated and untreated tumours through the induction of a systemic adaptive immune response. Post tumour rejection, a memory response protected against rechallenge with the same, or similar, tumours. Intratumoural administration of the agents was associated with increases in IFN-α in the tumour (rather than the serum), and blockade or removal of the IFN-α receptor abrogated the anti-tumour response. The importance of the draining lymph node and spleen in anti-tumour activity (as shown by the excision of these organs), and liver enzyme responses, suggested that some of the agonists/antigens may have dispersed into the lymphoid organs and liver to support the response. Nonetheless, the anti-tumour effect was dependent on local effects of the intratumoural administration on the tumour microenvironment, as subcutaneous and peritumoural routes of administration only minimally affected tumour growth despite the reagents potentially having greater exposure to lymphoid organs. Through the use of various techniques including knockout mice, neutralising monoclonal antibodies, confocal microscopy and flow cytometry, it was shown that the combination of α-GalCer and CpG was dependent on the effector activity of CD8+ cells. However, optimal activity was associated with changes in other immune cell types, notably recruitment of iNKT cells into the tumour bed, and was also associated with induction of serum antibodies that could transfer some protection to naïve hosts. Induction of a successful response was dependent on conventional dendritic cells (DCs) of the “cDC1” phenotype, which are known to be effective at antigen cross-presentation to CD8+ T cells, while full tumour rejection also required the activity of plasmacytoid DCs, which are significant producers of IFN-α. In less immunogenic tumour models, the addition of relevant tumour associated antigens (TAAs) improved the anti-tumour response. The TAAs could be added as part of an admix, but improved responses were obtained when TAAs were chemically conjugated to α-GalCer via an enzymatically cleavable linker. Alternatively, intratumoural administration of α-GalCer and CpG as free agents could be combined effectively with low dose systemic chemotherapy to induce curative responses, potentially through a mechanism involving immunogenic cell death to improve the immunogenicity of TAAs in situ.</p>

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Therapeutic cancer vaccines

Cited by 2 publications

References 164 publications

A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future

A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future

Harnessing iNKT cells to improve in situ vaccination for cancer therapy

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