introduction to cancer vaccines

🌈 Abstract

The article discusses the development of cancer vaccines that target neoantigens, which are modified surface proteins on cancer cells. It covers the key steps involved in creating personalized cancer vaccines, the current methods for protein characterization (DNA sequencing and mass spectrometry), the limitations of AlphaFold-type approaches, and other related methods like cryo-EM and nanopore protein analysis. The article also compares cancer vaccines to other cancer treatment approaches like replication disruptors and mitochondria-mediated apoptosis. Finally, it concludes with suggestions for prioritizing research on individualized cancer vaccines.

🙋 Q&A

[01] Cancer Neoantigens

1. What are the key requirements for cancer cells to become cancerous?

• Cancer cells must have mutations that cause uncontrolled replication and prevent apoptosis.
• Cancers often begin with damage to mutation-preventing mechanisms, leading to many mutations not required for their growth.
• These mutations often cause changes to the structure of some surface proteins, creating "neoantigens".

2. What is the approach being researched for cancer treatment using neoantigens?

• Identify specific neoantigens of a patient's cancer and create a personalized vaccine to cause the immune system to recognize them.
• Such vaccines would use either mRNA or synthetic long peptides.

3. What are the key steps required to develop a personalized cancer vaccine targeting neoantigens?

• The cancer must develop neoantigens that are sufficiently distinct from human surface proteins and consistent across the cancer.
• Cancer cells must be isolated and their surface proteins characterized.
• A surface protein must be found that the immune system can recognize well without much cross-reactivity to normal human proteins.
• A vaccine containing that neoantigen or its RNA sequence must be produced.

4. What are the challenges with developing personalized cancer vaccines targeting neoantigens?

• The steps required must be done for every patient, which is expensive.
• Cancers can mutate to stop producing some surface proteins (tumor antigen loss).
• It's difficult to guess how DNA will be transcribed, how proteins will be modified, and which proteins will be displayed on the surface.
• There is a risk of cross-reactivity with normal surface proteins.

[02] Protein Characterization

1. What are the current methods for characterizing the surface proteins of cancer cells?

• DNA sequencing to identify mutant proteins
• Mass spectrometry to identify proteins bound to MHC for presentation on the cell surface

2. What are the limitations of these methods?

• Guessing how DNA will be transcribed and which proteins will be displayed on the surface is difficult.
• Mass spectrometry requires more cells than sequencing and doesn't find all mutant surface proteins.
• Peptide sequencing with mass spectrometry is not easy.

3. How can nanopore sequencing help with protein characterization?

• Nanopore sequencing can detect protein post-translational modifications like phosphorylation or glycosylation.
• The changes in ion flow through the nanopore can provide data about protein sequences that can be combined with mass spectrometry data.

[03] AlphaFold and Related Methods

1. How does AlphaFold work and what are its limitations?

• AlphaFold uses a neural network to predict the relative positions of atoms in a protein based on its amino acid sequence.
• It can predict local structures and distant binding interactions using evolutionary history.
• Limitations include being less effective for "unnatural" proteins, not predicting protein functions, and requiring evolutionary history.

2. How does cryo-EM compare to AlphaFold-type approaches for protein characterization?

• Cryo-EM can produce structures from small protein crystals or even without crystallization.
• It is a powerful technique, but it is currently easier to determine protein sequences with mass spectrometry.
• Nanopore approaches have more potential to reduce costs for this application.

[04] Other Cancer Treatment Approaches

1. How do replication disruptors work as a cancer treatment approach?

• Replication disruptors target the increased replication rate of cancer cells compared to normal cells.
• Examples include drugs like cisplatin that disrupt the complex process of mitosis.
• However, this approach has serious side effects and cancers often find ways to replicate anyway.

2. What is the mitochondria-mediated apoptosis approach to cancer treatment?

• Normal cells have safeguards that cause apoptosis before they become cancerous, often involving mitochondria-mediated apoptosis.
• Cancer cells often disrupt normal mitochondria function, so targeting this difference is a potential approach.
• This can be done by reactivating mitochondria-mediated apoptosis or disrupting mitochondria-independent metabolism.

[05] Vaccine Production

1. What are the considerations for producing personalized cancer vaccines using mRNA or synthetic long peptides?

• mRNA vaccines require complex in vitro transcription for production, while synthetic long peptides can be directly synthesized.
• The immune system often recognizes non-human proteins, but cancer neoantigens that provoke an immune response can also lead to the cancer cells being killed.
• Cancers are selected to have fewer and more human-like neoantigens, making them harder to target and increasing the risk of cross-reactivity.
• Adjuvants can be used with mRNA vaccines to trigger a broader immune response, but this relies on the neoantigens being recognizable enough.

[06] Conclusion

1. What are the key priorities for research on individualized cancer vaccines suggested in the article?

• Combining mass spectrometry and nanopore data for improved protein characterization
• Continued development of nanopore sequencing
• Continued surveying of cancer genomes
• Developing lower-cost methods for isolation of cell surface proteins
• Developing equipment and methods for lower-cost production of long polypeptides