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PD1 Inhibitor DNA Vaccine Combination Trial in GBM

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



Transcript: 

Andrew S. Chi, MD: INO-5401 is delivered intramuscularly. It’s a DNA vaccine that is injected into a muscle. Uniquely, it’s given with electroporation. In simple terms, it’s an electric shock into the muscle. Electroporation briefly opens membranes in cells. Then the DNA is driven into the cells and the cells take up those pieces of DNA. It has been shown that the cells efficiently produce the transcripts that those DNA plasmids encode with very specific promoters on those DNA plasmids.

So, it’s a novel way of introducing antigen into the tumor. It is truly a vaccine. The vaccine strategy, in general, tries to get these educated T cells into the tumor. Again, glioblastomas have very few T cells within the tumor mass. That’s likely a reason why an immune checkpoint inhibitor alone isn’t functional.

One other interesting thing about this drug and this trial that’s going to be conducted in glioblastoma is that they are also using a DNA vaccine that’s encoding IL-12. IL-12 is a proinflammatory cytokine. It turns on the immune system in multiple ways, using various mechanisms. One of the principal ways is that it can turn naïve T cells into what we call a Th1 phenotype and can turn on and sustain memory T cells. So, using that IL-12 vaccine as an adjuvant to the very specific tumor antigens that they’re also injecting DNA plasmids for is a strategy that will hopefully increase the antigenicity of the vaccine against the tumor.

In this trial, they’ll be injecting DNA vaccines intramuscularly and giving them through electroporation. The patients will also get cemiplimab, which is a PD-1 inhibitor. So, it’s an antibody against PD-1. It works similarly to other anti–PD-1 inhibitors that are available, either on the market or in development. Again, it inhibits that PD-1, PD-L1 signaling access in T cells so that, of course, the signaling access can attenuate the function of T cells.

This trial will combine novel DNA vaccines with tumor-associated antigens, as well as IL-12, to drive T cells into the tumor. And then, in conjunction, it will use a PD-1 inhibitor. When those T cells arrive at the tumor mass, it can be turned on, or inhibited, so that it can go ahead and perform its function and, hopefully, eradicate tumor cells.

The trial will be conducted in newly diagnosed glioblastoma patients, rather than at recurrence. Again, we think that immunotherapies need some time to take effect. In the recurrent setting, patients really may not have enough time for immunotherapies to take effect. As part of this trial, they’re giving standard therapy; specifically, radiation and temozolomide chemotherapy. The other unique thing that they’re doing, in this trial, is stratifying patients based on their MGMT status. MGMT is a potent prognostic marker in glioblastoma. Patients with MGMT methylation within the tumor certainly live much longer than patients without MGMT methylation. The other thing that we’ve learned about with MGMT is that it’s a very good predictor of response to temozolomide chemotherapy. Patients with methylated MGMT will respond to chemotherapy, and those patients will live longer. Patients without MGMT methylation are less likely to respond to temozolomide chemotherapy.

In this trial, they’ve stratified patients by MGMT status. Notably, the patients without MGMT promoter methylation will not get temozolomide after radiation. MGMT status does not just predict that they may not respond to temozolomide. We also know that temozolomide can be very suppressive. It can be very immunosuppressive, when you give patients temozolomide over an extended period of time.

In principle, they’re trying to limit the amount of immunosuppression that these patients get exposed to during standard therapy. That may counteract with what they’re trying to do—in increasing the number of T cells that are infiltrated into the tumor. So, in the unmethylated MGMT arm, they’re skipping temozolomide.

The other novel thing that they’re doing, in this study, is shortening the course of radiation. There’s also some evidence—old evidence from the 1980s and 1990s—with prolonged fractionation. Many days or weeks of fractionated radiation can be more suppressive than shorter courses of immunotherapy. So, they’re shortening the amount of time that patients get radiation, from 6 weeks to 3 weeks, to try to limit the amount of immunosuppression that patients experience during standard therapy while they’re trying to activate T cells against the tumor.

In the MGMT-methylated arm, where patients can certainly do well for a very long time with just even standard therapy, patients will get the full course of temozolomide chemotherapy that they would typically get. On the other hand, this trial will also shorten the course of radiation that they get as part of that standard chemoradiation regimen, from 6 weeks to 3 weeks, in an attempt to try to minimize the immunosuppression that people get exposed to in this trial.

The major objectives of this trial will really be about safety and tolerability. These agents have not been tested in patients with glioblastoma. We really don’t know what the safety profile is going to be until patients are treated, that is they tolerate the injections as well as the electroporation. Secondary objectives will look at efficacy, how long patients will live before their tumors progress, or the overall survival as well. The trial will also look at a number of immune markers—in the serum and, hopefully, within the tumor—in posttreatment tumor samples to see whether T cells get activated in the very specific antigens that they are vaccinating against in this trial.

One of the eligibility criteria for this trial will be patients who have had a significant resection of their tumor. That won’t be 100% of the patients. Many patients are only able to get a biopsy. We call this a stereotactic biopsy, where a needle can go in and get a sample of the tumor to establish a diagnosis and get some genetic markers. For those patients, this trial wouldn’t be recommended; nor would they be eligible. But for most patients with glioblastoma, if they’re able to have good surgeries where the majority of their tumors can get resected, I think this is an excellent trial. It will be inclusive of whether or not patients have MGMT methylated or unmethylated status. They will be getting what we consider to be standard therapy for newly diagnosed glioblastoma. So, they won’t be withholding standard therapy. If patients have the opportunity to be on this trial, it would be a very good option.

Transcript Edited for Clarity 
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Transcript: 

Andrew S. Chi, MD: INO-5401 is delivered intramuscularly. It’s a DNA vaccine that is injected into a muscle. Uniquely, it’s given with electroporation. In simple terms, it’s an electric shock into the muscle. Electroporation briefly opens membranes in cells. Then the DNA is driven into the cells and the cells take up those pieces of DNA. It has been shown that the cells efficiently produce the transcripts that those DNA plasmids encode with very specific promoters on those DNA plasmids.

So, it’s a novel way of introducing antigen into the tumor. It is truly a vaccine. The vaccine strategy, in general, tries to get these educated T cells into the tumor. Again, glioblastomas have very few T cells within the tumor mass. That’s likely a reason why an immune checkpoint inhibitor alone isn’t functional.

One other interesting thing about this drug and this trial that’s going to be conducted in glioblastoma is that they are also using a DNA vaccine that’s encoding IL-12. IL-12 is a proinflammatory cytokine. It turns on the immune system in multiple ways, using various mechanisms. One of the principal ways is that it can turn naïve T cells into what we call a Th1 phenotype and can turn on and sustain memory T cells. So, using that IL-12 vaccine as an adjuvant to the very specific tumor antigens that they’re also injecting DNA plasmids for is a strategy that will hopefully increase the antigenicity of the vaccine against the tumor.

In this trial, they’ll be injecting DNA vaccines intramuscularly and giving them through electroporation. The patients will also get cemiplimab, which is a PD-1 inhibitor. So, it’s an antibody against PD-1. It works similarly to other anti–PD-1 inhibitors that are available, either on the market or in development. Again, it inhibits that PD-1, PD-L1 signaling access in T cells so that, of course, the signaling access can attenuate the function of T cells.

This trial will combine novel DNA vaccines with tumor-associated antigens, as well as IL-12, to drive T cells into the tumor. And then, in conjunction, it will use a PD-1 inhibitor. When those T cells arrive at the tumor mass, it can be turned on, or inhibited, so that it can go ahead and perform its function and, hopefully, eradicate tumor cells.

The trial will be conducted in newly diagnosed glioblastoma patients, rather than at recurrence. Again, we think that immunotherapies need some time to take effect. In the recurrent setting, patients really may not have enough time for immunotherapies to take effect. As part of this trial, they’re giving standard therapy; specifically, radiation and temozolomide chemotherapy. The other unique thing that they’re doing, in this trial, is stratifying patients based on their MGMT status. MGMT is a potent prognostic marker in glioblastoma. Patients with MGMT methylation within the tumor certainly live much longer than patients without MGMT methylation. The other thing that we’ve learned about with MGMT is that it’s a very good predictor of response to temozolomide chemotherapy. Patients with methylated MGMT will respond to chemotherapy, and those patients will live longer. Patients without MGMT methylation are less likely to respond to temozolomide chemotherapy.

In this trial, they’ve stratified patients by MGMT status. Notably, the patients without MGMT promoter methylation will not get temozolomide after radiation. MGMT status does not just predict that they may not respond to temozolomide. We also know that temozolomide can be very suppressive. It can be very immunosuppressive, when you give patients temozolomide over an extended period of time.

In principle, they’re trying to limit the amount of immunosuppression that these patients get exposed to during standard therapy. That may counteract with what they’re trying to do—in increasing the number of T cells that are infiltrated into the tumor. So, in the unmethylated MGMT arm, they’re skipping temozolomide.

The other novel thing that they’re doing, in this study, is shortening the course of radiation. There’s also some evidence—old evidence from the 1980s and 1990s—with prolonged fractionation. Many days or weeks of fractionated radiation can be more suppressive than shorter courses of immunotherapy. So, they’re shortening the amount of time that patients get radiation, from 6 weeks to 3 weeks, to try to limit the amount of immunosuppression that patients experience during standard therapy while they’re trying to activate T cells against the tumor.

In the MGMT-methylated arm, where patients can certainly do well for a very long time with just even standard therapy, patients will get the full course of temozolomide chemotherapy that they would typically get. On the other hand, this trial will also shorten the course of radiation that they get as part of that standard chemoradiation regimen, from 6 weeks to 3 weeks, in an attempt to try to minimize the immunosuppression that people get exposed to in this trial.

The major objectives of this trial will really be about safety and tolerability. These agents have not been tested in patients with glioblastoma. We really don’t know what the safety profile is going to be until patients are treated, that is they tolerate the injections as well as the electroporation. Secondary objectives will look at efficacy, how long patients will live before their tumors progress, or the overall survival as well. The trial will also look at a number of immune markers—in the serum and, hopefully, within the tumor—in posttreatment tumor samples to see whether T cells get activated in the very specific antigens that they are vaccinating against in this trial.

One of the eligibility criteria for this trial will be patients who have had a significant resection of their tumor. That won’t be 100% of the patients. Many patients are only able to get a biopsy. We call this a stereotactic biopsy, where a needle can go in and get a sample of the tumor to establish a diagnosis and get some genetic markers. For those patients, this trial wouldn’t be recommended; nor would they be eligible. But for most patients with glioblastoma, if they’re able to have good surgeries where the majority of their tumors can get resected, I think this is an excellent trial. It will be inclusive of whether or not patients have MGMT methylated or unmethylated status. They will be getting what we consider to be standard therapy for newly diagnosed glioblastoma. So, they won’t be withholding standard therapy. If patients have the opportunity to be on this trial, it would be a very good option.

Transcript Edited for Clarity 
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Provider and Caregiver Connection™: Addressing Patient Concerns While Managing GlioblastomaSep 29, 20182.0
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