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Sojo !!!!! great having you on our team. ty always
Thanks Thermo. for your honesty.. hard to argue with the news we have been getting from nwbo. ty for your support as well.
somebody is faking and somebody is taking
good to see you around. are you adding as well? I hope
lol. I bought today. added. .68. .68. .70. I guess we will see
so you think the roughly 770k in $ traded today is making this happen. I don't think so. buyers are ready.
Hi Sojo. any thoughts on todays action
Hi flipper why not just call les and ask why?
Hoff. You and a lot of others as well. Big Boys are watching
Hi Sojo its looks like its setting up for a 2 month play. we should know something from now to then.
Hi Sojo with all the positive news we have been getting plus the added revenue from sawston I would think we won't be down long. I feel large money is waiting for any raid on the stock price
Lykiri. could it be that a medical journal is adding this Information to its article ? rewriting what was ready for print
Sojo. as always I want to thank you for the knowledge
Hi Sojo. how do you view this ? Bullish
Are you the union rep. Speaking for all shareholders. Nobody is selling. 350k volume
Or eat a snickers
Thank you Sojo. The board is full of amazing people. What a team..
lol. Thank you. I prefer to keep that private but I will say even if you own 1 share you have done a great deed.
I have been through the run from 3-12$ and down to .17cents. adding all the way down There were days that knocked you to your knees especially for the ones holding large amount of shares. For me I found the strength to fight on thinking of all who suffered from this terrible disease and how I could be a part of helping this great cause. They would fight everyday just to see tomorrow I would do the same. Lets go NWBO. bring it home now.
same to you and all the longs who held what a story is about to be told
history being made, buy to the max
thank you Sojo.
Sojo, Hi so can we conclude that you are smiling we all should be happy......
Sojo, You are a true friend to all of us. hopefully one day soon we can put faces to all of us at the victory party
Delayed Effect of Dendritic Cells Vaccination on Survival in Glioblastoma: A Systematic Review and Meta-Analysis
Salvatore Cozzi 1, Masoumeh Najafi 2, Marzieh Gomar 3, Patrizia Ciammella 1, Cinzia Iotti 1, Corrado Iaccarino 4,5, Massimo Dominici 6, Giacomo Pavesi 4,5, Chiara Chiavelli 7, Ali Kazemian 3 and Amin Jahanbakhshi 8,*
Citation: Cozzi, S.; Najafi, M.; Gomar, M.; Ciammella, P.; Iotti, C.; Iaccarino, C.; Dominici, M.;
Pavesi, G.; Chiavelli, C.;
Kazemian, A.; et al. Delayed Effect of Dendritic Cells Vaccination on Survival in Glioblastoma: A Systematic Review and Meta-Analysis. Curr. Oncol. 2022, 29, 881–891. https://doi.org/10.3390/ curroncol29020075
Received: 6 December 2021 Accepted: 1 February 2022 Published: 4 February 2022
Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and institu- tional affiliations.
Copyright: © 2022 by the authors. Submitted for possible open access publication under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https://cre- ativecommons.org/licenses/by/4.0/).
1 Radiation Therapy Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; Salvatore.Cozzi@ausl.re.it (S.C.); Patrizia.ciammella@ausl.re.it (P.C.); cinzia.iotti@ausl.re.it (C.I.)
2 Skull Base Research Center, Rasool Akram Hospital, Iran University of Medical Sciences, Tehran 14535, Iran; najafi.mas@iums.ac.ir
3 Radiation Oncology Research Center, Iran Cancer Institute, Tehran University of Medical Sciences, Tehran 1416753955, Iran; m.gomar1365@gmail.com (M.G.); Kazemian@tums.ac.ir (A.K.)
4 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; corrado.iaccarino@unimore.it (C.I.); giacomo.pavesi@unimore.it (G.P.)
5 Neurosurgery Division, University Hospital of Modena, 41125 Modena, Italy
6 Department of Medical and Surgical Sciences for Children & Adults, Division of Oncology,
University-Hospital of Modena and Reggio Emilia, 41121 Modena, Italy; massimo.dominici@unimore.it
7 Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences for Children & Adults,
Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy;
chiara.chiavelli@unimore.it
8 Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences,
Tehran 14535, Iran
* Correspondence: jahanbakhshi.a@iums.ac.ir; Tel.: +0098-912-190-2231
Abstract: Background: Dendritic cell vaccination (DCV) strategies, thanks to a complex immune response, may flare tumor regression and improve patients’ long-term survival. This meta-analysis aims to assess the efficacy of DCV for newly diagnosed glioblastoma patients in clinical trials. Meth- ods: The study databases, including PubMed, Web of Knowledge, Google Scholar, Scopus, and Cochrane, were searched by two blinded investigators considering eligible studies based on the following keywords: “glioblastoma multiforme”, “dendritic cell”, “vaccination”, “immunother- apy”, “immune system”, “immune response”, “chemotherapy”, “recurrence”, and “te- mozolomide”. Among the 157 screened, only 15 articles were eligible for the final analysis. Results: Regimens including DCV showed no effect on 6-month progression-free survival (PFS, HR = 1.385, 95% CI: 0.822–2.335, p = 0.673) or on 6-month overall survival (OS, HR = 1.408, 95% CI: 0.882–2.248, p = 0.754). In contrast, DCV led to significantly longer 1-year OS (HR = 1.936, 95% CI: 1.396–2.85, p = 0.001) and longer 2-year OS (HR = 3.670, 95% CI: 2.291–5.879, p = 0.001) versus control groups. Hence, introducing DCV could lead to increased 1 and 2-year survival of patients by 1.9 and 3.6 times, respectively. Conclusion: Antitumor regimens including DCV can effectively improve mid- term survival in patients suffering glioblastoma multiforme (GBM), but its impact emerges only after one year from vaccination. These data indicate the need for more time to achieve an anti-GBM immune response and suggest additional therapeutics, such as checkpoint inhibitors, to empower an earlier DCV action in patients affected by a very poor prognosis.
Keywords: glioblastoma; immunotherapy; dendritic cell vaccination; checkpoint inhibitor; survival
1. Introduction
Glioblastoma multiforme (GBM), the most common primary brain tumor, represents about half of the malignant glioma tumors in adults. The overall incidence of this tumor has been estimated to be 3.2 per hundred thousand populations with a median survival of 15 to 17 months [1]. The globally accepted therapeutic approach for GBM includes
Curr. Oncol. 2022, 29, 881–891. https://doi.org/10.3390/curroncol29020075 www.mdpi.com/journal/curroncol
Curr. Oncol. 2022, 29, 881–891 882
surgical resection, radiotherapy, and chemotherapy by temozolomide. However, its re- currence is very frequent, with a five-year survival rate of about 5% considering a maxi- mal surgical resection and adjuvant therapies being achievable [2–4]. This progressive and invasive behavior necessitates the development of novel treatments [5].
Tumor cells, especially in brain tumors, can evade the immune cells via different mechanisms, such as antigenic modulation, lowering immunogenicity, and immune sup- pression [6,7]. Immunotherapy is progressively becoming an effective approach for acti- vating the immune system to recognize and destroy tumor cells [8,9]. The application of immunotherapy for the treatment of different malignant tumors is discussed elsewhere, especially in metastatic settings [10–13]. However, immunotherapy in glioblastoma is much more challenging compared to other solid tumors because of its infiltrative nature and the complex structure of the blood–brain barrier in various parts of the tumor terri- tory. Some clinical trials have been performed to assess the efficacy and safety of immu- notherapy with different regimens. Overall, there are two main immunotherapy ap- proaches: passive immunotherapy (with the aim to activate the immune system by mon- oclonal antibodies and immune checkpoint modulators to confer antitumor response), and active immunotherapy or vaccination (by presenting tumor antigens that stimulate the immune system to produce an endogenous anti-tumor response, leading to the long- term recognition and destruction of the tumor cells) [14]. In the latter type, viral vectors and dendritic cells (DC) have been applied as stimulators and modulators [15]. DCs act as coordinators of the innate immune response by releasing activating cytokines for cyto- toxic lymphocytes and NK cells [16]. They present processed antigens to B and T lympho- cyte subsets, leading to activation and memory induction [17].
Using dendritic cell vaccination (DCV) to induce tumor regression and improve pa- tients’ long-term survival has been demonstrated in several solid tumors [18]. Variability in DCV protocols includes different activation treatments, such as peptide, tumor antigen RNA, and whole tumor lysates, as well as combination therapy with immunomodulators [19]. Several studies have evaluated the treatment response to DCV in glioblastoma, but there are considerable inhomogeneities in the results. These variations in the results could be due to various methods in DCV preparations, concomitant treatments, or differences in patients’ disease status. In this study, we analyzed the available clinical trials and fo- cused on the time period in which the effect of DCV can become evident. We argue that a short life expectancy for glioblastoma may mask the effect of DCV. The results give us some explanation for such discrepancies in the outcomes of many clinical trials.
2. Materials and Methods
2.1. Study Selection
The present systematic review and meta-analysis followed the guidelines for the Pre- ferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) revised in 2015 [20] and was generated by the following question: what is the clinical impact of DCV on GBM patient survival? Registration in PROSPERO, by the time of completion of the work, was not a routine local research protocol. Therefore, we do not have a registration number, although our search shows there is no similar registered study in PROSPERO. Databases including Medline, Web of Knowledge, Google Scholar, Scopus, and Cochrane were searched by two blinded investigators for all eligible studies based on the considered keywords, including “glioblastoma multiforme”, “dendritic cell”, “vaccination”, “immu- notherapy”, “immune system”, “immune response”, “chemotherapy”, “recurrence”, and “temozolomide”. The inclusion and exclusion criteria were as follows: (1) prospective clinical trials (in different phases I/II/III) evaluating survival in patients suffering from newly diagnosed GBM and scheduling for dendritic cell vaccination with and without temozolomide chemotherapy; (2) studies published in the English language; (3) studies with unclear or irreproducible results (i.e., lack of clear outcomes or presence of errors in methodology and/or analyses) were all excluded; (4) lack of access to the manuscript’s full
Curr. Oncol. 2022, 29, 881–891 883
text was also considered an exclusion criterion, unless the abstracts had enough data for our analysis; (5) case reports, case series, and review papers were all excluded. As shown in the flow diagram of the study selection (Figure 1), 157 articles were initially collected by database searching. After removing 3 articles due to evidence of duplication, 154 rec- ords were primarily under-screened. Based on the mentioned criteria, 127 records were excluded, and the remaining 27 citations were assessed for further eligibility. Of those, 12 were also excluded due to the incompleteness of the data and contents. Finally, 15 articles were eligible for the final analysis [21–35] (Table 1).
Figure 1. The flowchart of screening the eligible studies. Table 1. Original data extracted from included studies.
Author, Year
Batich, 2017 [21]
Buchroithner, 2013 [23]
Buchroithner, 2018 [22]
Chang, 2011 [24]
Cho, 2012 [25] Jie, 2012 [26]
Trial Type of Phase Tumor
I ND a
II ND
II ND
I/II ND
II ND II ND
Sample Size
Case: 11
Control (historical): 23 Case: 19 Control (randomized): 21 Case: 34 Control (randomized): 42
Case: 17
Control (historical): 63
Case: 18
Control (randomized): 16 Case: 13 Control
Mean Male Age Gender
55 8 55 16
N/A N/A
54.6 29 54.0 22
45
42 N/A
52.1 8 55.8 8
40.2 10 43.1 9
Follow-Up DCV Regimen (Months)
Control Group
pp65 lysosome-associated membrane
60 60 glycoprotein mRNA-pulsed DCs
18 Not specified 18
Tumor lysate-charged autologous DCs
12 (Audencel) 12
Phagocytic DCs co-cultured with au-
tologous glioma cells treated by IFN-
60 gamma and heat-shock treatment and 60 then irradiated with 100 Gy
14–56
17–53 Whole-tumor lysate pulsed DCs 14
24 Autologous glioblastoma-DCs 22
Curr. Oncol. 2022, 29, 881–891
884
(randomized): 12
Case: 39
Control – 36
(historical): 80 Case: 117
52.2
(historical): 165
Case: 23 53 16
Control 55 48 60
(historical): 68 Case: 7
(GBM apoptosis induced by heat- shock)
Interferon-induced DCs
Not specified
Glioma lysate-pulsed DCs booster vac- cinations with either imiquimod or poly-ICLC adjuvant
Dendritic cell-based vaccine targeting cancer stem cells
Autologous DCs loaded with HLA- eluted peptides from cultured tumor cells or autologous tumor freeze-thaw lysate
DCs pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Ra2
Peripheral blood DCs
pulsed with autologous tumor lysate
DCs pulsed with glioblastoma stem cell lysates
Autologous DCs pulsed with autolo- gous tumor lysate
Leplina, 2007 [27]
Muller, 2015 [28] Prins, 2011 [29]
Vik-Mo, 2013 [30]
Wheeler, 2004 [32]
Wen, 2019 [31]
Yamanaka, 2005 [36]
Yao, 2018 [34]
Yu, 2004 [35]
Pilot ND
II ND
I ND
Pilot ND
I/II ND
II ND
I/II ND
II ND
I ND
43 46
36
30
58
24
48
39
48
12
60
51.0
Control – 36
57
Control – 24
(historical): 10
Case: 25
62
Control 54 16 48 (randomized): 13 56 4
Case: 75 57.4,
Control 57.5 44, 31 40 (randomized): 42
Case: 18
Control – 48
(historical): 27 Case: 22
Control 48, 50 13, 11 14 (Randomized): 21
46 10
Control 53 18 60
(historical): 26
50 56
Case: 14
a: Not defined.
2.2. Data Extraction and Quality Assessment
The data collection was independently performed by two unblinded reviewers on structured collection forms. We resolved disagreements by consensus or by involving a third person. The study quality was evaluated based on the following criteria: (1) the sys- tematic review and meta-analysis based on the questions primarily described and formu- lated; (2) inclusion and exclusion criteria predefined in the studies as eligibility criteria; (3) searching the literature performed on a systematic and comprehensive approach; (4) to minimize the bias, the full texts of the article were dually reviewed; (5) the quality of the included studies was rated independently by the reviewers for appraising internal validity; (6) the studies’ characteristics and findings were comprehensively listed; (7) the publication and risk of bias were listed; and (8) heterogeneity was also assessed. The nine- star Newcastle–Ottawa Scale (NOS) scoring system was employed to assess the method- ological quality of all eligible studies. In this quality assessment technique, each study was assessed qualitatively for three criteria: the selection of the study groups, the comparabil- ity of the study groups, and the ascertainment of the outcome. The studies awarded 7 stars or more were deemed to be of high quality. Any disagreement was resolved by discussion in the whole study team. The endpoints of this meta-analysis are overall survival, pro- gression-free survival, and toxicity associated with dendritic cell vaccination. Mid-term survival is considered outcomes encountered less than one year after treatment.
2.3. Statistical Analyses
The dichotomous variables are reported as proportions and percentages. The pooled likelihood of improving the survival of patients on different regimens was assessed and presented by the hazard ratio (HR) and 95% confidence interval (CI) as summary statistics.
Curr. Oncol. 2022, 29, 881–891 885
The fixed effects or random effects (in the case of significant heterogeneity across the data) models were used to obtained pooled dichotomous data using the mean difference (MD) followed by reporting 95% CIs and its corresponding p values. Cochrane’s Q test was used to determine the statistical heterogeneity. This test was complemented with the I2 statistic, which quantifies the proportion of total variation across studies that is due to heterogene- ity rather than chance. Publication bias was assessed by the rank correlation test and also confirmed by funnel plot analysis. The reported values were two-tailed, and the hypoth- esis testing results were considered statistically significant at p = 0.05. Statistical analysis was performed using the Comprehensive Meta-Analysis (CMA) software version 3.0 (Bi- ostat, Englewood, NJ, USA).
3. Results
Study characteristics: In total, 15 clinical trials in the different phases (2 studies as first-in-man, 3 in phase I, 3 in phase I/II, and 7 in phase II), consisting of 452 cases and 629 controls, were included in our analysis. Regarding the GBM population included in the studies, all studies included only the cases with newly diagnosed GBM.
The quality assessment showed a NOS score of 7 or higher for all studies, indicating the presence of high methodological quality (Figure 2).
Figure 2. The quality assessment of the studies according to the nine-star Newcastle–Ottawa Scale (NOS) scoring system.
Efficacy outcomes: Among the 15 studies, 15 assessed the overall survival (OS) and progression-free survival (PFS), 12 determined the median OS time (months), 4 assessed the median PFS time (month), 6 assessed the mid-term PFS, and 12 assessed the mid-term OS. The OS and the PFS were significantly different between patients who received the DCV and those who did not. In this regard, using the DCV led to significantly longer OS (weighted mean differences of 5.775, 95% CI: 3.901–7.649, p < 0.001), and also longer PFS (weighted mean differences of 1.598, 95% CI: 1.204–1.933, p < 0.014). DCV could lead to increased OS and PFS by 5.7 and 1.5 times, respectively. The heterogeneity across the studies in OS and PFS measurements was significantly relevant, with I2 values of 91.564 to 92.325, respectively. In terms of comparing the mid-term survival of patients receiving
Curr. Oncol. 2022, 29, 881–891
886
therapeutic regimens with and without considering DCV, we observed no difference be- tween the two groups 6-month PFS (HR = 1.385, 95% CI: 0.822–2.335, p = 0.673) and also 6-month OS (HR = 1.408, 95% CI: 0.882–2.248, p = 0.754); however, DCV led to significantly longer 1-year OS (HR = 1.936, 95% CI: 1.396–2.85, p = 0.001) and longer 2-year OS (HR = 3.670, 95% CI: 2.291–5.879, p = 0.001). Hence, introducing the DCV could lead to increased 1- and 2-year survival of patients by 1.9 and 3.6 times, respectively (Figure 3).
Figure 3. The pooled analysis of the efficacy of dendritic cell vaccination on mid-term survival (A: 6-month PFS, B: 6-month OS, C: 12-month OS, D: 24-month OS).
Safety outcomes: No side effects were reported following DCV protocols, and drug- related complications were tolerable and reversible (Table 2).
Table 2. The outcome of the dendritic cell vaccination strategy.
Author, Year
Batich, 2017 [21]
Buchroithner, 2013 [23]
Buchroithner, 2018 [22]
Chang, 2011 [24]
Cho, 2012 [25] Jie, 2012 [26]
Number
Case: 11 Control: 23 Case: 19 Control: 21
Case: 34 Control: 42
Case: 17 Control: 63
Case: 18 Control: 16 Case: 13
Median Median 6-Month 6-Month OS PFS PFS OS
12-Month 24-Month OS OS
Toxicity
No adverse events No adverse events
- Thrombopenia (n = 7)
- lymphopenia (n = 1)
- leucopenia (n = 2)
- rash (n = 2)
- fatigue (n = 3)
- headache (n = 2)
- nausea (n = 1)
- Lymphopenia (n = 17)
- serum AST/ALT elevations (n = 8) - seizures (n= 3)
- hydrocephalus (n = 1)
- abnormal liver function (n = 1)
- mild lymphopenia (n = 1)
- fever (n = 2)
41.1 19.2 14.6 12.7
18.8 18.9
17.3 12.7
ND: 31.9 ND: 15.0 ND: 17.0
25.3 8.0
100 78.3
66.7 71.4
100
100 ND: 92.3
100 100 95.7 52.2 89.0 62.0
85.1 64.7 81.0 55.6
88.9 ND: 88.9 75.0 ND: 75.0 92.3 ND: 69.2
72.7 17.4
41.2 11.1
ND: 44.4 ND: 18.8 ND: 7.7
ND: 8.5 ND: 8.0
Curr. Oncol. 2022, 29, 881–891
887
Leplina, 2007 [27]
Muller, 2015 [28] Prins, 2011 [29]
Vik-Mo, 2013 [30] Wheeler, 2004 [32]
Wen, 2019 [31]
Yamanaka, 2005 [36]
Yao, 2018 [34] Yu, 2004 [35]
52.5 81.3 52.3 76.3 43.6
Control: 12
Case: 39 Control: 80 Case: 117 Control: 165 Case: 9 Control: 82
Case: 7 Control: 10
Case: 13 Control: 13
Case: 75 Control: 42
Case: 18 Control: 27 Case: 22 Control: 21 Case: 14 Control: 26
ND: 10.5
31.4 15.9
MD: 17 MD: 15
MD: 17.3 MD: 10.7 33.2 7.5
ND: 91.7 100
ND: 41.7
74.4
ND: 0.0
35.9 27.5
55.6 24.4
71.4 30.0
53.8 15.4
22.2 3.7
42.9 7.7
- red papules (n = 1) No adverse events
No adverse events No adverse events
- Fatigue (n = 7)
- anorexia (n = 5)
- focal epileptic seizures (n = 1)
No adverse events
- Nervous system disorder (n = 4) - fatigue (n = 3)
- musculoskeletal disorder (n = 1) - blood disorders (n = 6)
- infections (2)
- metabolic disorders (n = 9)
- skin disorders (n = 8)
No adverse events - fever (n = 1)
- erythema (n = 1) No adverse events
100 100 80 100
88.9 70.7
MD: 11.2 MD: 9.0
69.1 60.4
77.2 66.7
100 58.7 100 80.0
100 92.3 100 61.5
88.6 61.1 88.6 59.3
100 78.6 57.7 26.9
Publication bias: The heterogeneity across the studies in assessing the efficacy of DCV on mid-term survival was insignificant, with I2 values ranging from 0.0 to 0.39, and Egger test excluded non- significant publication bias in the analyses.
4. Discussion
It can be inferred from many animal and human studies that the immune system can help shape the future of cancer treatment by recognizing malignant cells and destroying them efficiently. In fact, this tumor suppression role is mediated by both the cellular and humoral antitumor immune response, especially by CD8+ cytotoxic T lymphocytes [37]. Pathologically, T cells in cancer patients have been revealed to exhibit reactivity against tumor biochemical particles, including peptides and proteins derived from the tumor tis- sue that are sourced by occurring mutations on embryonic genes related to tumor growth and differentiation [38,39]. These potentials can provide new insights into developing therapeutic agents, such as creating vaccines for inhibiting cancer progression and im- proving patients’ survival. Immunotherapy for GBM comprises various methods, includ- ing peptide and dendritic cell vaccines, checkpoint inhibitors, chimeric antigen receptor (CAR) T-cells, and oncolytic virotherapy [40]. Initially, vaccines originated from autolo- gous tumor cells, tumor antigen peptides, or cell lysates generating promising immune responses [41]. However, by applying such methods, no specific immune antitumor re- sponse was achieved. In recent decades, one of the major discoveries in tumor immuno- therapy has been to prove the critical role of specialized antigen-presenting cells, like the DC in the creation of cell-mediated immune responses by the production of cancer-spe- cific vaccines [42]. The DCV against GBM has garnered special attention. Extensive clinical trials have been designed and conducted to prove its effectiveness and safety, but some have been met with conflicting results. In the present study, we aimed to summarize and interpret the results of these studies in order to reach a credible consensus. Hence, we systematically reviewed 15 clinical trials assessing the DCV efficacy on GBM patients’ sur- vival to ultimately reveal its significant efficacy in improving mid-term OS and OFS in patients with GBM. In other words, the introduction of DCV could effectively prolong patients’ survival and, therefore, inhibit the tumor progression/recurrence. However, two important points are worth considering. The DCV treatment regimen is apparently inca- pable of generating a clinical measurable response in the short term, with no significant
Curr. Oncol. 2022, 29, 881–891 888
effect on patients’ survival at 6 months. However, after a longer observation time (more than one year), the DCV shows its inhibitory effect on tumor progression.
In a meta-analysis performed by Vatu et al., the DCV resulted in improvements in OS and PFS (35% and 41%, respectively) and it was superior to viral therapy (four clinical trials on herpes simplex virus thymidine kinase/ganciclovir gene therapy were included) in both outcome measures. However, they did not analyze the results at different follow- up times. While there is only a 40% overlap in the final analyzed studies, our work in- cludes 50% more patients in the case group [43]. Another meta-analysis performed by Artene et al. did not observe a significant improvement in OS and PFS by viral therapy, but they found a statistically significant improvement of OS by DCV in both primary and recurrent high-grade glioma. However, despite a trend toward an improvement in PFS, it did not reach a significant threshold. They analyzed 8 studies, including 104 patients in the experimental arm [44]. Cao et al. also found a significantly better outcome in terms of both OS and PFS after antigen-pulsed DC treatment at 1, 1.5, 2, 3, and 4-year time points. Their study included nine clinical trials, six of which are also included in our study [45].
It can be hypothesized that the DCV would require more time to be effective against GBM, so that a more articulated immune response, including a combination of cellular and humoral immunity, could be established. Interestingly, Rangel-Reyes et al. have shown this delay in a mathematical model for dendritic cell treatment. They evaluated common obstacles, such as immunosuppression and poor transfer to lymph nodes, that reduce the effect of the DCV and entered them into a mathematical model, and showed that time can be considered in the model as the gestation time or transport delay of the DCV [46]. In addition, the DCV may have less effect on more invasive glioblastomas. Thus, its effect cannot be detected in a short time, during which these patients could die. In this particular setting, the potential to activate an immune response combining cell therapy with additional immuno-oncology tools, like checkpoint inhibitors (CPI), may generate a faster immune response. There are several clinical trials, such as NCT04201873 (using pembrolizumab) and NCT03014804 (using nivolumab), designed to investigate the efficacy of combined treatment with DCV and CPI. Moreover, one can find case presenta- tions that report a good outcome for such a combination therapy [47]. However, more studies are needed to prove its safety and efficacy.
There are some limitations to the current study. The small number of clinical studies and patients enrolled in the meta-analysis, evaluation of newly diagnosed respectable GBM, differences in patients’ characteristics between these studies, differences in DCV preparation protocols, and variations in concomitant administered therapeutics, may have affected the final analysis. It should be noted that, as shown in Table 1, many studies integrated into this meta-analysis are of a non-randomized or historical type. This may reduce the statistical significance of the analysis.
5. Conclusions
Among the different modalities for immunotherapy in glioblastoma, dendritic cell vaccination has gathered considerable attention after some encouraging reports that have shown acceptable levels of efficacy and safety. In the present review, we found that the effect of the DCV needs a minimum 6-month period to become significant—a finding that can be explained by mathematical models and pathophysiology. This vital outcome may explain some of the conflict between different clinical trials. We suggest a revision in the design of future clinical trials to include patients with longer expected survival periods, and also consider the incorporation of combination immunotherapies to boost the effect of the DCV. Nevertheless, the limitations of our work should be taken into account, in- cluding the limited number of studies and the fact that it may not be generalizable to re- current glioblastoma and other high-grade gliomas.
Author Contributions: Conceptualization, A.J. and M.N.; methodology, M.G.; software, M.G.; val- idation, P.C., C.I. (Cinzia Iotti), and C.C.; formal analysis, M.G.; writing—original draft preparation,
Curr. Oncol. 2022, 29, 881–891 889
References
M.N. and A.J.; writing—review and editing, C.I. (Corrado Iaccarino), M.D. and G.P.; supervision, A.K.; project administration, S.C., M.N. and A.J. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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Sojo !!! yes I do. many years waiting . I have a feeling next spike could be the big one. could make the spike to 2.50 look small
Conclusions
Among the different modalities for immunotherapy in glioblastoma, dendritic cell vaccination has gathered considerable attention after some encouraging reports that have shown acceptable levels of efficacy and safety. In the present review, we found that the effect of the DCV needs a minimum 6-month period to become significant—a finding that can be explained by mathematical models and pathophysiology. This vital outcome may explain some of the conflict between different clinical trials. We suggest a revision in the design of future clinical trials to include patients with longer expected survival periods, and also consider the incorporation of combination immunotherapies to boost the effect of the DCV. Nevertheless, the limitations of our work should be taken into account, in- cluding the limited number of studies and the fact that it may not be generalizable to re- current glioblastoma and other high-grade gliomas.
New SAP now has rGBM as the first secondary endpoint, an even larger market than nGBM! Did $NWBO just more than double their potential market cap for #DCVax-L? This doesn't even take into consideration other solid tumor cancers! #glioblastoma $mrk $bmy
Directed gene therapy taking place at Ohio State could prove to be the breakthrough researchers have been working toward for decades
Author: Kelli Trinoskey
Topics:
Research Research Innovations
February 04, 2022
Doctor performing AADC infusionDecades of research into gene therapy, where new genetic material replaces a faulty gene or adds a new gene to cure disease, has reached a pivotal point in the ability to address untreatable or incompletely treated neurological diseases. Many first-in-human trials, which bridge advances in basic science to the practical, translational application of that knowledge, are now underway at Ohio State.
“We have a large portfolio of active, and soon-to-be active, first-in-human gene trials of direct infusion for gene therapy and treatment of Parkinson’s, Alzheimer’s and Huntington’s diseases as well as AADC deficiency and multiple system atrophy,” says Russell Lonser, MD.
Lonser, who serves as chair of the Department of Neurological Surgery at The Ohio State University College of Medicine and as co-director of the Ohio State Neurological Institute, says funding from the National Institutes of Health will ensure that Ohio State is a dominant player in directing gene therapy in the future.
The Human Genome Project formed the basis for the understanding that genes are made up of DNA, and they play an essential role in determining the function of each cell in the body. Living beings are made up of 30 million codes of DNA. If even one of these codes is damaged, a genetic alteration may occur, causing a genetic disease which is often debilitating and life-threatening.
Lonser and Krystof Bankiewicz, MD, professor of Neurological Surgery at the Ohio State College of Medicine, are already quite well known among patients and peers for their novel delivery of gene therapy in targeted brain structures of patients. They developed a technique where they monitor the direct infusion of genetic material into the brain using real-time MRI imaging so they can perfectly target an area to affect a cure.
They used this technique to infuse a viral vector that carries a gene that makes the missing enzyme that produces dopamine and serotonin in the central nervous systems of children suffering from aromatic L-amino acid decarboxylase (AADC) deficiency, a rare deadly, neurodevelopmental disorder. Children with AADC lack muscle control, and are usually unable to speak, feed themselves or even hold up their heads. They also suffer from seizure-like episodes called oculogyric crises, that can last for hours.
When Lonser and Bankiewicz surgically infuse this functioning gene into the specific site in the brain, the brain integrates the gene into its circuitry, which is comprised of a cluster of neurons. These neurons receive electrochemical information that the circuit then modifies and transmits to other circuits in the brain that need this modified genetic material to function properly. MRI imaging allows the team to see the process take place during surgery and then see it further play out by improved functioning in patients.
“Remarkably, the seizure-like episodes are the first symptom to disappear after gene therapy surgery, and they never return,” Bankiewicz says. “In the months that follow, many patients experience life-changing improvements. Not only do they begin laughing and have improved mood, but many are able to begin speaking and even walking.”
Early data has shown that the results and improvements in motor functioning are not waning as time passes. Further, by targeting a specific brain site and manipulating only the circuits in the brain that are diseased, versus treating the entire brain, patients do not suffer side effects on other bodily systems.
“This work provides a framework for the treatment of other human nervous system genetic diseases. It’s our hope that this will be first of many ultra-rare and other neurologic disorders that will be treated with gene therapy in a similar manner,” Bankiewicz says.
The findings described in the AADC study are the culmination of decades of work by teams from multiple academic institutions, including University of California San Francisco, Washington University in St. Louis, Medical Neurogenetics Laboratory in Atlanta, St. Louis Children’s Hospital and Nationwide Children’s Hospital in Columbus, Ohio. The research was supported by the National Institute of Neurological Disorders and Stroke and foundational grants, including the AADC Research Trust, the Pediatric Neurotransmitter Disease Association and funding from The Ohio State University.
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Fasten your seatbelts and shorts should BRACE FOR IMPACT! $NWBO GETTING CLOSE!
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$nwbo is an existential threat to Big Cancer. Hundreds of Billions at stake if "most cancers." Cofer Black was a wise choice. If #Jane for eg. is a front for a foreign BP Cayman client, he is the one guy able to find out. If true, Damages could be worth more than $mrk BO.
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COMBINATIONS OF CHECKPOINT INHIBITORS AND THERAPEUTICS TO TREAT CANCER NWB1155367 Printer Friendly Version
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Examiner Name: CANELLA, KAREN A Location: What is a Location? ELECTRONIC
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Title of Invention: COMBINATIONS OF CHECKPOINT INHIBITORS AND THERAPEUTICS TO TREAT CANCER
Sojo/Judge. what do you see ? interesting moves
My condolences Gary.
TDD I see a future for you as the head PR man. You have talent my man... Great work.
Bravo !!!! DD. great work..
I agree 100 pct. Maybe DD can