Nice post hoc suggestive spin on data you got going on. It doesn't align with the facts. But, it's typical of you to skip on the finer details. Go NWBO. Enjoy!!
In 2009, we started a phase-II trial for patients with newly-diagnosed GBM based on immunotherapy with ex-vivo tumor lysate-pulsed, autologous dendritic cells (DC) following fluorescence-guided surgery (FGS) using 5-aminolevulinic. After resection, immunotherapy was used as up-front therapy in combination with standard therapy. We hypothesized that the more extensive resection possible with this surgical technique[8,9] would create the best situation to begin immunotherapy, and that immunotherapy itself could be more useful as a front-line strategy.
To avoid the potential selection biases shown in other immunotherapy trials[5-7], we aimed at including a wide population of patients and enrolling them right after surgery. Main limitation for entry is that FGS surgery must achieve residual tumor less than 1 cc.
In this report, we present 5 previous cases that constitute a pilot group of this clinical trial.
Mean age was 66 years, median KPS was 70, four patients were RPA class V and one was class IV. MGMT promoter was unmethylated in one and methylated in four cases. Mean preoperative tumor volume was 54 cc (34-112) Resection was total in three cases, while the other two cases had 0.25 cc and 0.27 cc residual tumor.
All patients were followed until death.
OS of the patients in this pilot study was compared to that of patients undergoing standard therapy with the published nomograms from EORTC 26981/22981 NCIC trial[13] and to a matched historic cohort. The historic cohort was selected from patients operated in our center with FGS, and similar age, Karnofsky performance status (KPS), recursive partitioning analysis (RPA), MGMT methylation status and residual tumor volume (four complete resections, one less than 1cc). From the nomograms, each patient was assigned an expected OS; if our treated population survival had been similar to the EORTC series, the proportion exceeding median OS should have been 0.5. Binomial test with proportion 0.5 was used to assess statistical relevance. The OS of the treated patients was compared also to historic controls using log-rank (Mantel-Cox).
For three patients (UPN 1, 2, 5) one leukoapheresis sufficed to produce the amount of DC to be used for several doses (16, 16 and 18, respectively). In one case (UPN 4), two leukoaphereses were instead necessary, since the number of DC obtained allowed the preparation of 4 and 11 vaccine doses, respectively. The fifth patient (UPN 3) underwent only one leukoapheresis, though the production of DC was limited to 4 doses, because at the time of his first DC vaccination radiological signs of a possible progression had already been detected.
UPN 2 received only four vaccine doses because of rapid clinical deterioration, while UPN 3 received only four doses due to the low cell amount obtained through the leukoapheresis. The other patients (UPN 1, 4 and 5) received 11, 15 and 12 vaccine doses, respectively.
UPN 2, 3 and 4 experienced administrative delays and could not receive the first dose prior to radiotherapy. As for UPN 2 and 3, possible early radiological progression signs were detected at the time of the first vaccination. In both patients, bevacizumab was started after a second MRI indicated that these signs were not suggestive of pseudo-progression. UPN 1, 4 (except for the timing of the first vaccine dose) and 5 followed the vaccination calendar as described above without deviations.
All five patients exceeded the OS expected with standard of care calculated with EORTC nomograms[13], with a mean difference of 11.4 mo (25.1-13.7). Median OS expected in a group with these prognostic factors would be 12.3. Yet, the OS of our group exceeded it by 14.7 mo (27 to 12.3). Even with only five patients, the binomial test, was almost significant (P = 0.06). The five patients have also lived longed than the historic controls, median 31.2 vs 11.5, this difference was significant by log-rank (Mantel-Cox), P = 0.02.
The patient sample presented here is not selected by young age, good functional status or absence of early progression. Therefore, it is representative of a wide population of GBM patients; 80% were in RPA class V and mean age was 67. Patients with first-line immunotherapy in the work of Prins et al had a mean age of 49.7 years and 60% were RPA class III, while in the work of Ardon et al[6] mean age was 50.3 and 7 out of 8 patients were RPA IV, and one RPA III.
Despite the small number of cases, the survival time is clearly unexpected for a group with these characteristics. MGMT promoter methylation was the only positive prognostic factor, and yet the cohort with methylated MGMT promoter in the EORTC-NCIC shows a median OS of 23 mo, while all of our 4 methylated patients have lived longer than 27 mo, with two still alive. The median OS in our group exceeds the OS expected using the EORTC nomograms by almost 15 mo (27.0 to 12.3). Even with the intrinsic limitations of the small sample size, we conclude that this DC-based immunotherapy is likely to have added to the results of standard of care and provided an OS clearly superior to the expectations, suggesting a strong benefit from immunotherapy in an unfavorable group of patients.
Innovations and breakthroughs
In this pilot study, the authors enrolled five consecutive glioblastoma patients with poor prognosis. In most cases, they would have not been enrolled in the previous clinical trials mentioned above. Yet, following fluorescence-guided surgery and tumor lysate-pulsed dendritic cell vaccination, they all experienced remarkable progression-free survivals. In a couple of cases, this result is still ongoing over two years after surgery.
Applications
The study results suggest that tumor lysate-pulsed dendritic cell vaccination, after fluorescence-guided complete or near complete surgery, should be attempted in all resectable patients with glioblastoma multiforme, not only in those with better prognosis.
Terminology
Fluorescence - guided surgery: it is a surgical technique enhancing the ability of the neurosurgeon to remove nearly all the tumor by a better visualization of the tumor resection margins; tumor lysate: it is the product of mechanical disaggregation of the tumor removed during surgery; Dendritic cells: autologous - therefore patient - specific - antigen presenting cells which are derived from monocytes and matured in vitro.
Peer review
Despite the small number of patients enrolled in this pilot study, the results of this treatment are extremely promising and warrant expansion in the currently ongoing, larger clinical trial.
Table 1
Patients characteristics
Patient Age(yr) KPS(%) RPA Sex MMSE score Tumor volume (cc) MGMT promoter Tumor location PFS (mo) OS (mo)
1) 69 70 5 M 28 111.8 Methylated right frontal 19.5 27.0
2) 73 70 5 M 27 34.0 Unmethylated left temporal 3.1 9.1
3) 50 80 5 F 26 12.9 Methylated left temporal 3.2 > 36.0
4) 67 60 5 F 28 68.3 Methylated right frontal 16.1 27.4
5) 71 90 4 F 30 44.8 Methylated right frontal 20.3 > 32.0
KPS: Karnofsky performance status; MMSE: Mini mental state examination; MGMT: Status of O6-methylguanine-DNA methyltransferase; PFS: Progression free survival; OS: Overall survival; RPA: Recursive partitioning analysis.
And they did do a larger study:
IT-03. IMMUNOTHERAPY WITH TUMOR LYSATE-PULSED DENDRITIC CELLS FOR NEWLY-DIAGNOSED GLIOBLASTOMA FOLLOWING FLUORESCENCE-GUIDED RESECTION?Ricardo Diez Valle1, Sonia Tejada1, Suana Inoge ´s1, Miguel Angel Idoate1, Ascensio ´ n Lopez Diaz de Cerio2, Jaime Espinos1, Javier Aristu1,
Jaime Gallego1, Javier Perez Calvo1, and Maurizio Bendandi1; 1Clinica Universidad de Navarra, Pamplona, Spain; 2CIMA, Pamplona, Spain
BACKGROUND: Immunotherapy is a promising therapy for glioblasto- ma, however, different strategies and potential selection biases make it diffi- cult to evaluate efficacy. We hypothesized that treatment with tumor lysate-pulsed autologous dendritic cells would be effective when added to gross total resection and standard radio-chemotherapy in newly diagnosed glioblastoma. We designed a trial recruiting patients from the time of surgery to avoid selection biases. METHODS: All patient candidates for re- section during the study period were screened, and an attempt at maximum resection was made in every case using fluorescence-guided surgery; less than 1 cm2 residual tumor and glioblastoma pathology were required for entry confirmation. Adjuvant treatment included radio-chemotherapy with temo- zolomide up to 12 cycles. Vaccines were prepared as soon as possible after surgery using autologous dendritic cells pulsed with tumor lysate and matured ex vivo. The vaccination calendar started before radiotherapy. Overall survival was compared to a historic cohort and to European Organization for Research and Treatment of Cancer (EORTC)-published nomograms. RESULTS: We screened 32 patients and included 31 (96.9%); one was excluded because of the presence of residual tumor. The mean age was 58.6, and Karnofsky performance status score was 90-100 in 28% of the patients, 70-80 in 65%, and 60 in 6%; 10% of the patients were in RPA III, 42% RPA IV, and 48% RPA V. Immunotherapy was well tolerated and induced specific immune responses. Median overall survival at the moment of this writing is 27.4 months versus 14.7 months in patients treated with the control (p 1/4 0.003). Median survival in RPA class V patients is 26.9 versus 10.7 (p 1/4 0.007). Compared to EORTC nomograms, 23 patients have lived longer than predicted, 3 have lived shorter, and 5 do not have enough follow-up information (p , 0.001, binomial distribution). In multivariate analysis, vaccination was the most significant variable (p 1/4 0.012, odds ratio 2.7; 95% confidence interval: 1.24-5.77). CONCLUSION: Tumor lysate-pulsed, autologous dendritic cell vaccination is safe and effective when added to standard therapy after gross total resection in glioblastoma.
