Autologous Vaccine DC-VAX-L with Dendritich Cells for Glioblastoma

The results of the Phase 3 clinical for the DCVax®-L autologous dendritic cell vaccine have just been released and the results are very encouraging. This is why I decided not to wait and immediately write an article about it. From the clinical trial file it seems that several centers in the US, Canada, UK and Germany participated in the research but I know for sure that similar trials are underway in Italy.

But let’s get to the results. So to sum up as we know glioblastoma is a particularly difficult tumor and is the most common and lethal of brain tumors: it is aggressive, immunologically cold, extremely heterogeneous, invasive and difficult to completely remove, it has a recurrence rate close to 100 % and standard of care is surgery (if possible) plus 6 weeks of concomitant chemotherapy and radiotherapy plus monthly maintenance chemotherapy as much as possible. The median survival for new diagnoses is 15-17 months from surgery (diagnosis) and the median time to first recurrence is 7-8 months from surgery (diagnosis) with a median survival from recurrence of approximately 8 months. The 5-year survival rate is less than 5%.

There have been many clinical trials but just as many failures. In particular, from 2005 to 2016 there were 417 clinical trials involving almost 3200 patients. Only 16 Phase 3 clinical trials with only one successful (Optune device). Other clinical trials have all failed involving checkpoint inhibitors, CAR-T, peptide vaccines, dendritic cell vaccines, gene therapy. The reason is certainly attributable to the remarkable heterogeneity of the glioblastoma (which until some time ago was called multiforme) and to the fact that involves the most delicate organ, it is protected by the brain-blood-barrier which makes it difficult for many drugs to pass through.

Now in this clinical trial, treatment consists of pulsed autologous dendritic cells (DCs) with autologous tumor lysate (DCVax®-L) administered via intrarmic injections into the arm. The study is randomized double-blind with crossover and involved 331 patients, 94 trial sites in 4 countries (one of the largest trials of personalized cell therapy). The experimentation began in 2007 and was then suspended from 2008 to 2011 for economic reasons. 92% of patients were enrolled from 2012 to 2015. Long-term survival follow-up allowed to determine the survival tails. The treatment program includes 3 treatments in the first month (days 0, 10, 20), 3 booster treatments in months 2, 4, 8 and treatments twice a year for maintenance.

The overall results report that the primary endpoint was met (mOS in nGBM) with statistical significance as well as the secondary endpoint (mOS in rGBM), with statistical significance with an excellent safety profile: out of 2,193 doses of DCVax®-L administer only 5 possibly related adverse events.

In particular for nGBM (newly diagnosed GBM):

• mOS (median overall survival): 19.3 months (22.4 months after surgery) compared with 16.5 months in the control arm.
• mMGMT (methylated glioblastoma) mOS: 30.2 months (33 months after surgery) compared to 21.3 months in the control arm.
• 5-year survival rate: 13% versus 5.7%.

For rGBMs (recurring GMBs):

• mOS: 13.2 months compared to 7.8 months from the recurrence.
• Long-term survival: 20.7% versus 9.6% at 24 months after recurrence and 11.1% versus 5.1% at 30 months after recurrence.

Basically it is the first Phase 3 study of a systemic treatment in 17 years showing a significant extension of mOS in nGBM and the first Phase 3 study of any type of treatment in 27 years showing a significant extension of mOS in rGBM . One of the first if not the first Phase 3 study to show a significant increase in long-term survival for both nGBM and rGBM.

Furthermore, DCVax-L is suitable for combinations with a wide range of other treatments (checkpoint inhibitors, oncolytic viruses, cytokines, chemo, etc.). When a patient with DCVax-L has one or more recurrences, new batches of DCVax-L can be created. DCVax-L can be administered in major cancer centers.
The significant proportion of long-term survivors, consistent with an effect on immune memory by T lymphocytes, changed the natural history of GBM from a uniformly fatal disease to a manageable, chronic disease.
Specific subpopulations have showed an unexpected advantage: older patients and patients with metylated MGMT promoters.
The use of dendritic cells allows combination therapy using other approaches such as immunosuppressive cytokine blockade, CAR-T cells, viral oncolytic therapy, electric field therapy, DNA vaccines, etc. because I am more and more convinced that a combination therapy and a cocktail of treatments will be necessary to definitively defeat glioblastoma.