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: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/28319047Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomasI'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? 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.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?ThanksNadav
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.