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DNA Vaccine Creating Immunogenicity in GBM

Insights From: Andrew S. Chi, MD, NYU Langone Health
Published: Monday, Mar 05, 2018



Transcript: 

Andrew S. Chi, MD: INO-5401 is a DNA vaccine. It’s a novel way to introduce an antigen and create immunogenicity against an antigen by injecting a piece of DNA, or a plasmid, into a person. They do that, with this particular drug, intramuscularly. Ultimately, that DNA plasmid gets taken up into the host muscle cells and then turns on transcription and production of the specific protein that it’s encoding.

INO-5401 specifically carries DNA plasmids that are predicted to be a tumor antigen for glioblastoma. It carries DNA plasmids for human telomeres, WT1, and PSMA. These are proteins that are highly overexpressed in most glioblastomas. The principal is that it is a tumor vaccine and it will stimulate the antigen response to these tumor-associated peptides. It does that, in a novel way, by injecting the actual plasmid DNA rather than injecting peptides, which is a classic way of creating a tumor vaccine.

The mechanism by which they introduce the plasmid is novel, and I think the principal of injecting DNA into a person is novel because of the way that the antigen is produced. Instead of just the peptides, themselves, the DNA is inserted and the host can actually continually, potentially, produce that antigen. And, as part of this trial, there are repeated injections of that DNA vaccine.

To me, one of the interesting things about that particular DNA vaccine is the mix of peptides or the mix of tumor antigens that they’re using in this product. WT1 and PSMA are proteins that have been studied and have been suggested to be overexpressed in glioblastoma. So, these are tumor-associated peptides where we think the majority of glioblastoma is a little overexpressed.

What is particularly interesting is that it’s going to express human telomeres. Very recently, glioblastomas have been characterized, on a genetic level, through multiregional sequencing and para tumor sequencing. In principle, we think it is important, in terms of finding a target. Whether you’re going to drug a target with a target inhibitor or with an immunotherapy agent, you want that target to be in every single tumor cell, within an entire tumor mass. You also want the target to be retained if the tumor grows through primary therapy or recurs.

I define glioblastomas very differently. There’s not 1 type of glioblastoma. There are several different subtypes, based on the molecular makeup. There are genetic driver mutations in these tumors. If you take a look at all of the glioblastomas, a very small percentage have driver mutations of IDH. A very small percentage of glioblastomas have driver mutations of BRAF. We exclude those. The vast majority of glioblastomas have driver mutations in the promoter region of hTERT (the human telomerase reverse transcriptase gene). It’s been shown that the hTERT mutation is clonal throughout the tumor, meaning that it’s in every tumor cell. Also, it’s retained at recurrence. So, it is a true clonal driver mutation. Therefore, it really represents an incredibly attractive target for any modality of therapy, whether it’s immunotherapy or targeted therapy.

The other interesting thing about tumor telomeres is that they have been studied as a vaccine, for quite a while. In principle, it’s an immunogenic antigen. It’s a clonal driver in glioblastoma. Therefore, targeting human telomeres is really an attractive strategy. So, that’s one of the things that makes that particular vaccine an interesting strategy in glioblastoma.

Transcript Edited for Clarity
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Transcript: 

Andrew S. Chi, MD: INO-5401 is a DNA vaccine. It’s a novel way to introduce an antigen and create immunogenicity against an antigen by injecting a piece of DNA, or a plasmid, into a person. They do that, with this particular drug, intramuscularly. Ultimately, that DNA plasmid gets taken up into the host muscle cells and then turns on transcription and production of the specific protein that it’s encoding.

INO-5401 specifically carries DNA plasmids that are predicted to be a tumor antigen for glioblastoma. It carries DNA plasmids for human telomeres, WT1, and PSMA. These are proteins that are highly overexpressed in most glioblastomas. The principal is that it is a tumor vaccine and it will stimulate the antigen response to these tumor-associated peptides. It does that, in a novel way, by injecting the actual plasmid DNA rather than injecting peptides, which is a classic way of creating a tumor vaccine.

The mechanism by which they introduce the plasmid is novel, and I think the principal of injecting DNA into a person is novel because of the way that the antigen is produced. Instead of just the peptides, themselves, the DNA is inserted and the host can actually continually, potentially, produce that antigen. And, as part of this trial, there are repeated injections of that DNA vaccine.

To me, one of the interesting things about that particular DNA vaccine is the mix of peptides or the mix of tumor antigens that they’re using in this product. WT1 and PSMA are proteins that have been studied and have been suggested to be overexpressed in glioblastoma. So, these are tumor-associated peptides where we think the majority of glioblastoma is a little overexpressed.

What is particularly interesting is that it’s going to express human telomeres. Very recently, glioblastomas have been characterized, on a genetic level, through multiregional sequencing and para tumor sequencing. In principle, we think it is important, in terms of finding a target. Whether you’re going to drug a target with a target inhibitor or with an immunotherapy agent, you want that target to be in every single tumor cell, within an entire tumor mass. You also want the target to be retained if the tumor grows through primary therapy or recurs.

I define glioblastomas very differently. There’s not 1 type of glioblastoma. There are several different subtypes, based on the molecular makeup. There are genetic driver mutations in these tumors. If you take a look at all of the glioblastomas, a very small percentage have driver mutations of IDH. A very small percentage of glioblastomas have driver mutations of BRAF. We exclude those. The vast majority of glioblastomas have driver mutations in the promoter region of hTERT (the human telomerase reverse transcriptase gene). It’s been shown that the hTERT mutation is clonal throughout the tumor, meaning that it’s in every tumor cell. Also, it’s retained at recurrence. So, it is a true clonal driver mutation. Therefore, it really represents an incredibly attractive target for any modality of therapy, whether it’s immunotherapy or targeted therapy.

The other interesting thing about tumor telomeres is that they have been studied as a vaccine, for quite a while. In principle, it’s an immunogenic antigen. It’s a clonal driver in glioblastoma. Therefore, targeting human telomeres is really an attractive strategy. So, that’s one of the things that makes that particular vaccine an interesting strategy in glioblastoma.

Transcript Edited for Clarity
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Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
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