Hi Maria, Data from the phase 2a trial of lysate-pulsed dendritic cell vaccine for low grade glioma was presented at the 2016 Society for Neuro-Oncology conference, which I attended. I briefly summarized the presentation here:
under the title "PHASE IIA CLINICAL TRIAL EVALUATING DENDRITIC CELL VACCINE FOR THE TREATMENT OF LOW-GRADE GLIOMAS"
Overall survival could not be analyzed because there was not long enough follow up yet. "low grade glioma has long survival, cannot analyze overall survival statistics yet"
and also "time to progression based on imaging - pseudoprogression may confound imaging studies"
One of the slides showed that the 5 patients receiving DC vaccine actually had shorter time to progression than a matched group receiving standard treatments or surgery only. Whether this is due to pseudoprogression could not be determined based on imaging studies alone.
One thing to consider is that IDH1-mutant gliomas have recently been shown to have reduced expression of many cytokines related to immune response and this is linked to the high levels of 2-hydroxyglutarate in and around the tumor. 2-hydroxyglutarate is the "oncometabolite" produced in abundance by tumors with IDH mutations. For patients with IDH1-mutant tumors pursuing immunotherapy vaccines, inhibiting 2-hydroxglutarate with a small molecule inhibitor of mutant IDH1 (there are several of these in trials but none approved yet), could potentially reverse the immunosuppression and allow the vaccine to be more effective. Trials may get around to testing this strategy eventually.
https://www.ncbi.nlm.nih.gov/pubmed/28319047 Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas
I'm assuming your tumor is IDH1 mutant, as over 80% of grade 2 oligodendrogliomas are of the IDH-mutant, 1p/19q codeleted variety, but it will be useful to confirm whether that is the case following surgery.
Thank you, Stephen. Can you please talk to me a little bit more about pseudoprogression? I understand it on it's face, obviously, but I'm not sure what would cause it exactly or how common it is.
Thank you for the study. Is it saying that immunotherapies combined with things like AG-221 or AG-881 could work synergistically to enhance each other?
Pseudoprogression is kind of a vague term that simply means what looks to be tumor progression on MRI imaging is actually caused by something else. This "something else" could be an inflammatory immune response as might occur after a vaccine, and it may also occur as a treatment effect following combined chemoradiation, especially in patients with MGMT methylated tumors. My understanding is that pseudoprogression is relatively common after anti-cancer vaccines, so that progression-free survival is not the best endpoint for immunotherapy trials.
Yes, the study is saying that small molecule inhibitors of mutant IDH enzymes (AG-221 is an inhibitor of mutant IDH2, AG-120 is an inhbitor of mutant IDH1, and AG-881 inhibits both mutant IDH1 and IDH2), by suppressing the production of 2-hydroxyglutarate, could make vaccines more effective for IDH-mutant gliomas.
Hi Stephen, Could you please help me out to understand, for Stage II Astrocytoma Glioma, with IDH1, P53 and K167 positive. MGMT negative. still haven't treated yet (not chemo nor radiation) for 6 years now since the seizures began. What is the prospect to use any kind of treatment with vaccine? Thanks Nadav
Were you diagnosed around the same time that seizures began (6 years ago)?
I'll assume that surgical resection of the tumor must have been a success if it hasn't recurred for that long without chemo or radiation. How long ago was the surgery?
Tumor lysate-pulsed vaccine (like DCVax or similars) is probably not an option in your case, unless the tumor tissue was frozen immediately after surgery, and even then it is considered ideal to use a recent sample for vaccine creation, not a 6 year old one.
This would also be a problem with personalized peptide vaccines based on the results of exome sequencing of tumor tissue - if the only tissue available is 6 years old, the results of sequencing probably wouldn't accurately reflect the current situation with the remaining tumor cells.
If the tumor returns (hopefully a long time from now, or never), there might be other options available that don't exist today.
Hello, that's a really tough question, given that a year ago the vaccine outcomes for low grade gliomas weren't optimal (Stephen posted that above). I don't think much changed until today. Maybe your best bet would be to message dr. Van Gool from IOZK (immunotherapy clinic), if they maybe treated low grade gliomas with any success...especially because there is new research coming out all the time and he can probably give you the best educated guess. Are you having surgery now and what treatments did you receive when diagnosed ?
Hi, sorry for the very late response , I wasn’t aware to the replies. First, it is not about me but my brother. The tumor was discovered at Dec 2011, after he started seizuring. Since than without any treatments since we understood that it would not prolong the life expectancy and since the tumor was already very big sergury was not an option. We were afraid that radiation would do more harm than good at these brain areas. So we have decided to wait and see, since then, the tumor keeps growing (slowly). We are trying some alternative treatment which helps psychologically, which is important too. At our recent follow up, our Doctor said that he thinks that it is time for radiation since stasitically these tumors tend to upgrade them selfs for grade 3 and 4 at this point of time since the discovery, radiation could give the tumor a setback but would not prolong the life expectancy. And if that the case so why take the chance with radiation ? We are still hoping for a new treatment in that field.
Who told you radiation doesn't prolong life expectancy?
There was a trial published in 2005 (patients recruited 1986 - 1997) that showed improvement in progression-free survival, but not overall survival when radiation was given upfront as opposed to at recurrence. This is quite different from saying radiation at any time doesn't improve survival over never having radiation. Also, this was before the discovery of the IDH1 mutation, so even those conclusions published in 2005 don't necessarily hold for all the subgroups according to IDH1 status.
https://www.ncbi.nlm.nih.gov/pubmed/16168780
Apart from surgery, radiation is probably the most important *conventional* treatment for lower grade, IDH1-mutatn astrocytomas.
Which country is he in? In the USA there is a trial testing mutant IDH1 inhibitors. https://clinicaltrials.gov/ct2/show/NCT03343197
and AG-120 (ivosidenib) was recently approved by the FDA for IDH1-mutant leukemia, which removes legal barriers for using off-label for brain tumors, though the cost will be one remaining barrier.
Lets put aside the IDH1 issue for the moment since I am not aware of any data in regard to radiation with IDH1. If you are familiar with such, it would be a meaningful input to consider.
While considering any treatment we have two major parameters in mind: 1. Current life quality 2. Overall life expectancy.
In our case, life quality is ok (he still have seizures, none of the anti epileptic meds helped in that matter. His cognitive abilities are slowly degrading but he is still functional. The outcome of radiation over a wide brain area is something that no one can guarantee.
Now, if radiation doesn’t prolong the total life expectancy and has a major risk for life quality, why take the risk? btw, the doctors kept their mind about doing radiation in entire period, but we decided not to.
But now, the doctors thinks that we are in a crucial time spot, where low grade tumors are turning into high grade and want to postpone it with radiation. But again, if total life expectancy would not change.... That is the reason that we are looking for “out of the box” treatments. Going back to the vaccine, I understand that again, results are inconclusive, right? Any other options that you familiar with?
I really appreciate your feedbacks, many thanks Nadav
There are both theoretical and empirical reasons to believe that IDH1-mutant gliomas are more sensitive to radiation than IDH1 non-mutant gliomas of the same grade.
For one, they have diminished ability to detoxify from oxidative stresses such as radiation, due to diminished levels of NADPH and reduced glutathione. See my review of this topic in the "Oxidative Stress" section here: http://astrocytomaoptions.com/exploring-strategies-for-idh1-mutated-gliomas/
In clinical trials when radiation alone is applied to IDH1 mutant gliomas (astrocytomas or oligodendrogliomas), outcomes are better compared to IDH1 non-mutant tumors of the same grade. For example, in the EORTC 22033 trial for grade 2 gliomas, radiation alone led to progression-free survival of 61.6 months for the IDH1-mutant oligodendrogliomas, 55.4 months for the IDH1-mutant astrocytomas, but only 19 months for the IDH non-mutant gliomas. 5-year progression-free survival was 58.5%, 42.5% and 0% for the same groups.
IDH1 status is critical when predicting response to radiation as well as chemotherapy.
The NOA-4 trial in Germany for grade 3 gliomas showed that radiation alone was more effective than chemotherapy alone for the IDH1-mutant astrocytomas (progression-free survival of 50.6 months with radiation alone versus 25.1 months with chemotherapy alone)
I'm not sure where the idea that radiation doesn't improve life expectancy for lower grade gliomas comes from. It certainly has risks and quality of life issues to worry about, and I look forward to a time when it won't be necessary, but it is also an effective therapy for certain tumor subgroups.
IDH1-mutant lower grade tumors are very immunologically non-reactive, there have been multiple studies showing this in the past few years. There is little data to prove or disprove that these tumors are less responsive to vaccine treatment than other types of gliomas, but I suspect that is the case.
IDH1 inhibitors such as AG-120 and AG-880 are interesting for low grade, non-enhancing IDH1-mutant gliomas, and if he could join the trial (in the US), or get AG-120 (ivosidenib, recently FDA approved for leukemia) off-label, this could potentially delay the requirement for immediate radiation.
Chemotherapy alone could also be effective (though perhaps not as effective as radiation), but I would be hesitant about temozolomide alone, as it can lead to hypermutated recurrences further down the line. Lomustine would be my choice of chemo. You could also explore chemo + PARP inhibitor, but currently approved PARP inhibitors such as olaparib don't cross intact blood-brain barrier very well, but can accumulate in contrast enhancing tumor areas. Brain penetrant PARP inhibitors such as BGB-290 are available in trials, but not yet approved.
Accutane (a type of retinoic acid, or active form of vitamin A, used for treating acne) is also an interesting therapy, but I would not combine it with chemo or radiation. Disulfiram + copper, and omega 3 fish oils are also interesting given their mechanism of creating or potentiating oxidative stress, which the mutant IDH1 cells are more vulnerable to.
Hi Maria,
ReplyDeleteData from the phase 2a trial of lysate-pulsed dendritic cell vaccine for low grade glioma was presented at the 2016 Society for Neuro-Oncology conference, which I attended. I briefly summarized the presentation here:
http://astrocytomaoptions.com/sno-2016-clinical-highlights-scottsdale-arizona/
under the title "PHASE IIA CLINICAL TRIAL EVALUATING DENDRITIC CELL VACCINE FOR THE TREATMENT OF LOW-GRADE GLIOMAS"
Overall survival could not be analyzed because there was not long enough follow up yet. "low grade glioma has long survival, cannot analyze overall survival statistics yet"
and also "time to progression based on imaging - pseudoprogression may confound imaging studies"
One of the slides showed that the 5 patients receiving DC vaccine actually had shorter time to progression than a matched group receiving standard treatments or surgery only. Whether this is due to pseudoprogression could not be determined based on imaging studies alone.
One thing to consider is that IDH1-mutant gliomas have recently been shown to have reduced expression of many cytokines related to immune response and this is linked to the high levels of 2-hydroxyglutarate in and around the tumor. 2-hydroxyglutarate is the "oncometabolite" produced in abundance by tumors with IDH mutations. For patients with IDH1-mutant tumors pursuing immunotherapy vaccines, inhibiting 2-hydroxglutarate with a small molecule inhibitor of mutant IDH1 (there are several of these in trials but none approved yet), could potentially reverse the immunosuppression and allow the vaccine to be more effective. Trials may get around to testing this strategy eventually.
https://www.ncbi.nlm.nih.gov/pubmed/28319047
Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas
I'm assuming your tumor is IDH1 mutant, as over 80% of grade 2 oligodendrogliomas are of the IDH-mutant, 1p/19q codeleted variety, but it will be useful to confirm whether that is the case following surgery.
Thank you, Stephen. Can you please talk to me a little bit more about pseudoprogression? I understand it on it's face, obviously, but I'm not sure what would cause it exactly or how common it is.
DeleteThank you for the study. Is it saying that immunotherapies combined with things like AG-221 or AG-881 could work synergistically to enhance each other?
Maria
Pseudoprogression is kind of a vague term that simply means what looks to be tumor progression on MRI imaging is actually caused by something else. This "something else" could be an inflammatory immune response as might occur after a vaccine, and it may also occur as a treatment effect following combined chemoradiation, especially in patients with MGMT methylated tumors. My understanding is that pseudoprogression is relatively common after anti-cancer vaccines, so that progression-free survival is not the best endpoint for immunotherapy trials.
DeleteYes, the study is saying that small molecule inhibitors of mutant IDH enzymes (AG-221 is an inhibitor of mutant IDH2, AG-120 is an inhbitor of mutant IDH1, and AG-881 inhibits both mutant IDH1 and IDH2), by suppressing the production of 2-hydroxyglutarate, could make vaccines more effective for IDH-mutant gliomas.
Hi Stephen,
DeleteCould you please help me out to understand, for Stage II Astrocytoma Glioma, with IDH1, P53 and K167 positive. MGMT negative.
still haven't treated yet (not chemo nor radiation) for 6 years now since the seizures began.
What is the prospect to use any kind of treatment with vaccine?
Thanks
Nadav
Were you diagnosed around the same time that seizures began (6 years ago)?
DeleteI'll assume that surgical resection of the tumor must have been a success if it hasn't recurred for that long without chemo or radiation.
How long ago was the surgery?
Tumor lysate-pulsed vaccine (like DCVax or similars) is probably not an option in your case, unless the tumor tissue was frozen immediately after surgery, and even then it is considered ideal to use a recent sample for vaccine creation, not a 6 year old one.
This would also be a problem with personalized peptide vaccines based on the results of exome sequencing of tumor tissue - if the only tissue available is 6 years old, the results of sequencing probably wouldn't accurately reflect the current situation with the remaining tumor cells.
If the tumor returns (hopefully a long time from now, or never), there might be other options available that don't exist today.
Hello all my grade 2 tumour has progressed after 7 years so pcv chemo is my second time treatment , can s Vac help me
DeleteHello,
Deletethat's a really tough question, given that a year ago the vaccine outcomes for low grade gliomas weren't optimal (Stephen posted that above). I don't think much changed until today.
Maybe your best bet would be to message dr. Van Gool from IOZK (immunotherapy clinic), if they maybe treated low grade gliomas with any success...especially because there is new research coming out all the time and he can probably give you the best educated guess.
Are you having surgery now and what treatments did you receive when diagnosed ?
Hi, sorry for the very late response , I wasn’t aware to the replies.
ReplyDeleteFirst, it is not about me but my brother.
The tumor was discovered at Dec 2011, after he started seizuring. Since than without any treatments since we understood that it would not prolong the life expectancy and since the tumor was already very big sergury was not an option. We were afraid that radiation would do more harm than good at these brain areas.
So we have decided to wait and see, since then, the tumor keeps growing (slowly).
We are trying some alternative treatment which helps psychologically, which is important too.
At our recent follow up, our Doctor said that he thinks that it is time for radiation since stasitically these tumors tend to upgrade them selfs for grade 3 and 4 at this point of time since the discovery, radiation could give the tumor a setback but would not prolong the life expectancy. And if that the case so why take the chance with radiation ?
We are still hoping for a new treatment in that field.
Who told you radiation doesn't prolong life expectancy?
DeleteThere was a trial published in 2005 (patients recruited 1986 - 1997) that showed improvement in progression-free survival, but not overall survival when radiation was given upfront as opposed to at recurrence. This is quite different from saying radiation at any time doesn't improve survival over never having radiation. Also, this was before the discovery of the IDH1 mutation, so even those conclusions published in 2005 don't necessarily hold for all the subgroups according to IDH1 status.
https://www.ncbi.nlm.nih.gov/pubmed/16168780
Apart from surgery, radiation is probably the most important *conventional* treatment for lower grade, IDH1-mutatn astrocytomas.
Which country is he in? In the USA there is a trial testing mutant IDH1 inhibitors.
https://clinicaltrials.gov/ct2/show/NCT03343197
and AG-120 (ivosidenib) was recently approved by the FDA for IDH1-mutant leukemia, which removes legal barriers for using off-label for brain tumors, though the cost will be one remaining barrier.
Lets put aside the IDH1 issue for the moment since I am not aware of any data in regard to radiation with IDH1. If you are familiar with such, it would be a meaningful input to consider.
DeleteWhile considering any treatment we have two major parameters in mind:
1. Current life quality
2. Overall life expectancy.
In our case, life quality is ok (he still have seizures, none of the anti epileptic meds helped in that matter. His cognitive abilities are slowly degrading but he is still functional.
The outcome of radiation over a wide brain area is something that no one can guarantee.
Now, if radiation doesn’t prolong the total life expectancy and has a major risk for life quality, why take the risk?
btw, the doctors kept their mind about doing radiation in entire period, but we decided not to.
But now, the doctors thinks that we are in a crucial time spot, where low grade tumors are turning into high grade and want to postpone it with radiation.
But again, if total life expectancy would not change....
That is the reason that we are looking for “out of the box” treatments.
Going back to the vaccine, I understand that again, results are inconclusive, right?
Any other options that you familiar with?
I really appreciate your feedbacks, many thanks
Nadav
There are both theoretical and empirical reasons to believe that IDH1-mutant gliomas are more sensitive to radiation than IDH1 non-mutant gliomas of the same grade.
DeleteFor one, they have diminished ability to detoxify from oxidative stresses such as radiation, due to diminished levels of NADPH and reduced glutathione. See my review of this topic in the "Oxidative Stress" section here:
http://astrocytomaoptions.com/exploring-strategies-for-idh1-mutated-gliomas/
In clinical trials when radiation alone is applied to IDH1 mutant gliomas (astrocytomas or oligodendrogliomas), outcomes are better compared to IDH1 non-mutant tumors of the same grade. For example, in the EORTC 22033 trial for grade 2 gliomas, radiation alone led to progression-free survival of 61.6 months for the IDH1-mutant oligodendrogliomas, 55.4 months for the IDH1-mutant astrocytomas, but only 19 months for the IDH non-mutant gliomas. 5-year progression-free survival was 58.5%, 42.5% and 0% for the same groups.
IDH1 status is critical when predicting response to radiation as well as chemotherapy.
The NOA-4 trial in Germany for grade 3 gliomas showed that radiation alone was more effective than chemotherapy alone for the IDH1-mutant astrocytomas (progression-free survival of 50.6 months with radiation alone versus 25.1 months with chemotherapy alone)
I'm not sure where the idea that radiation doesn't improve life expectancy for lower grade gliomas comes from. It certainly has risks and quality of life issues to worry about, and I look forward to a time when it won't be necessary, but it is also an effective therapy for certain tumor subgroups.
IDH1-mutant lower grade tumors are very immunologically non-reactive, there have been multiple studies showing this in the past few years. There is little data to prove or disprove that these tumors are less responsive to vaccine treatment than other types of gliomas, but I suspect that is the case.
IDH1 inhibitors such as AG-120 and AG-880 are interesting for low grade, non-enhancing IDH1-mutant gliomas, and if he could join the trial (in the US), or get AG-120 (ivosidenib, recently FDA approved for leukemia) off-label, this could potentially delay the requirement for immediate radiation.
Chemotherapy alone could also be effective (though perhaps not as effective as radiation), but I would be hesitant about temozolomide alone, as it can lead to hypermutated recurrences further down the line. Lomustine would be my choice of chemo. You could also explore chemo + PARP inhibitor, but currently approved PARP inhibitors such as olaparib don't cross intact blood-brain barrier very well, but can accumulate in contrast enhancing tumor areas. Brain penetrant PARP inhibitors such as BGB-290 are available in trials, but not yet approved.
Accutane (a type of retinoic acid, or active form of vitamin A, used for treating acne) is also an interesting therapy, but I would not combine it with chemo or radiation. Disulfiram + copper, and omega 3 fish oils are also interesting given their mechanism of creating or potentiating oxidative stress, which the mutant IDH1 cells are more vulnerable to.