Think of it this way, the Phase III study ramped up screening in late 2014 through to the screening halt of August 2015. Many of those patients who were enrolled with immune compromised WBC counts (Germany: lower WBC inclusion criteria), particularly in the placebo arm, contributed to progression events that occurred Fall/winter 2015 to spring/summer 2016. Many of those early progression events (depending on patient enrollment) converted to deaths during June 2016-February 2017 time period. And so the event pace that the company used contained mainly placebo patients, but perhaps some vaccine patients too, who either were not the best MGMT methylation responders (due to tampering of TMZ drugs due to toxicity) or who had tumors that would not benefit from standard of care treatments (I.e, unMethylation tumors).
While the vaccine might be able to extend survival a bit in those early progression patients, it probably is not as effective as it could be in patients who are not immune compromised. Virtually all GBM tumors come back. Even fully resected ones. And the best possible patients to treat at crossover -- to extend the time from progression to death -- would ideally come from the placebo and vaccine patients who were responders to RT and TMZ adjuvant treatments. Both the vaccine and the placebo patients may have had who progressed near the end of the study to make up the 248 progression endpoint events. These patients I reason would be some of the best standard of care responding patients. These are the patients who likely have all the best prognostic characteristics. The longer the patients are out from surgery and treatments, the higher the likelihood that some of those treatments could be repeated at sign of first progression. Then add the fact that RANO criteria, with its non-enhancement disease component (T2/FLAIR), can spot true progression 1-2 months before it shows up as disease enhancement on a scan -- which is verifiable by other imaging techniques. That means earlier progression events for placebo patients (including long tail ones) verses the outdated MacDonald criteria. And the sooner the progression is caught, the easier it is to apply salvage care at a time that it may be most useful to reverse the course of the disease in the patients -- before big bulky tumor shows up.
And so in the end what I'm trying to make clear is that patients who make it far out to have a long tail PFS response, are more likely to have a very long distance from first progression to death. We could be sitting on 222 OS events and waiting on 10 patients to expire at this point to reach 233 OS events. Now let's imagine that the 248 progression pool has continued to accumulate and the trial is at 263 progression events. It's not as simply as thinking it should take 5-7 months for at least10 of the 30 progression patients (263 progression events -- if 15 more accumulate the last month or two) to convert to the last OS events needed. We could be waiting a while for patient progression events to convert to death. And obviously the healthier those patients are at first progression (which longer PFS patients would be), and the further out they are from their last RT and TMZ adjuvant treatments, the higher the likelihood that they have longer second progressions and later subsequent death events.
For me to state that I see the events conversion rate is going to slow down and take longer near the end of the study has only to do with the fact that the patients who event near the end are likely to be the patients with all the best prognostic factors -- before (placebo crossover late progression events) and after (vaccine progression late events, improved immune disposition) considering the effects the vaccine may have as an adjuvant on overall effects. Many of these patients will easily survive a very long time after their first progression event. It's impossible to know how long it will take. Therefore, in my opinion the Company “anticipated” pace of death events used based from the June 2016-February conversion period is essentially meaningless.
Picture the late progression patients from this DCVax-L treated Phase I/II. And perhaps you'll see why I see. I don't have the exact progression data in front of me. But patient #17 who died at 52 months, he could have experienced a his first progression event at 33 months -- a long PFS event. That patient could have been eligible for a second surgery and subsequent salvage therapy and experienced his second progression event 8- 12 months later; and finally third progression at 2 -4 months later. Until ultimately there was nothing left to try and he died 4 -10 months later and he progressed from his growing disease. Had he been one of the 30 patients we were waiting on to pass away, his first recurrent disease could take a long time to convert to a death event.
Patient# (dose: 1, 5, 10); Cancer; Age: Gender: KPS Score; OS; HC Type; Adjuvant: Pre-Vacc Tx; Post-vacc Tx 1. (1) GBM 39 M KPS 90 OS 33.83 *; Adjuvant: Imiquimod Pre-vacc Tx: temozolomide; Post-vacc Tx: temozolomide, isoretinoin, celecoxib, Reoperation, SRS* *SRS= sterotactic radiosurgery 2. rGBM 39 M KPS 90 OS > 88.87; Mes, Adjuvant: Imiquimod; Pre-vacc Tx: Temozolomide; Post-vacc TX: temozolomide, isoretinoin, CCNU, Gliadel™ 3. GBM 34 M KPS 90 OS > 91.34 Mes, Imiquimod Pre-vacc Tx: Temozolomide; Post-vacc Tx: Temozolomide, Isoretinoin 6. GBM 63 F KPS 80 > 37.6 Mes Adjuvant: Imiquimod; Pre-vacc Tx: Temozolomide; Post-vacc Tx: Temozolomide 9. GBM 50 M KPS 90 OS > 9.03 * Adjuvant: Poly ICLC; Pre-vacc Tx: temozolomide 12 (5) GBM 26 M KPS 90 OS 81.4 PN Adjuvant: Imiquimod; Pre-vacc Tx: temozolomide, isoretinoin, CCNU; Post-vacc Tx: carboplatin, irinotecan, bevacizumab, dasatanib, simvastatin, rosiglitazone, procarbazine, CCNU, cyclophosphamide 13 (5) GBM 43 M KPS 90 OS >59.0 Mes Adjuvant: Imiquimod; Pre-vacc Tx: temozolomide 15 (5) GBM 53 M KPS 80 OS 22.33 Mes Adjuvant: Poly ICLC; Pre-vacc Tx: temozolomide, Gliadel™; Post-vacc Tx: irinotecan, bevacizumab 17 (10) GBM 59 M KPS 80 OS 52.6; Pro; Adjuvant: Imiquimod; Pre-vacc Tx: temozolomide, isoretinoin; Post-vacc Tx: irinotecan, bevacizumab, carboplatin, CCNU 19: (10) GBM 50 M KPS 90 OS 36.33 *; Adjuvant: Imiquimod; Pre-vacc Tx: temozolmide; Post-vacc Tx: irinotecan, bevacizumab 21 (10) GBM 66 M KPS 90 OS 37.73 Mes; Adjuvant: Imiquimod; Pre-vacc Tx: temozolomide; Post-vacc Tx: irinotecan, bevacizumab, CCNU, etoposide, procarbazine, tamoxifen
Trying to post less. Here's a recent UCLA abstract on DCVax-L. Thought I'd add here, not sure if all have seen it.
Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma
Joseph P. Antonios, Horacio Soto, Richard G. Everson, Diana Moughon, Joey R. Orpilla, Namjo P. Shin, Shaina Sedighim, Janet Treger, Sylvia Odesa, Alexander Tucker, William H. Yong, Gang Li, Timothy F. Cloughesy, Linda M. Liau, Robert M. Prins;
Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma. Neuro Oncol 2017
Background.
Adaptive immune resistance in the tumor microenvironment appears to attenuate the immunotherapeutic targeting of glioblastoma (GBM). In this study, we identified a tumor-infiltrating myeloid cell (TIM) population that expands in response to dendritic cell (DC) vaccine treatment. The aim of this study was to understand how this programmed death ligand 1 (PD-L1)–expressing population restricts activation and tumor-cytolytic function of vaccine-induced tumor-infiltrating lymphocytes (TILs).
Methods.
To test this hypothesis in our in vivo preclinical model, we treated mice bearing intracranial gliomas with DC vaccination ± murine anti–PD-1 monoclonal antibody (mAb) blockade or a colony stimulating factor 1 receptor inhibitor (CSF-1Ri) (PLX3397) and measured overall survival. We then harvested and characterized the PD-L1+ TIM population and its role in TIL activation and tumor cytolysis in vitro.
Results.
Our data indicated that the majority of PD-L1 expression in the GBM environment is contributed by TIMs rather than by tumor cells themselves. While PD-1 blockade partially reversed the TIL dysfunction, targeting TIMs directly with CSF-1Ri altered TIM expression of key chemotactic factors associated with promoting increased TIL infiltration after vaccination. Neither PD-1 mAb nor CSF-1Ri had a demonstrable therapeutic benefit alone, but when combined with DC vaccination, a significant survival benefit was observed. When the tripartite regimen was given (DC vaccine, PD-1 mAb, PLX3397), long-term survival was noted together with an increase in the number of TILs and TIL activation.
Conclusion.
Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.
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