Zie ook dit artikel: https://kanker-actueel.nl/immuuntherapie-met-het-vaccin-dcvax-geeft-uitstekende-resultaten-op-overall-overleving-bij-glioblastoma-multiforme-gegeven-bij-nieuwe-diagnose-na-operatie-blijkt-uit-fase-3-studie.html

Zie ook literatuurlijst niet-toxische middelen en behandelingen specifiek bij hersentumoren van arts-bioloog drs. Engelbert Valstar.

Zie ook dit artikel: 

https://kanker-actueel.nl/surviving-terminal-cancer-kunnen-overlevenden-van-een-hersentumor-helpen-kanker-te-overwinnen-drie-mannen-overwonnen-hun-hersentumor-gbm-en-2-ervan-zijn-al-15-en-20-jaar-vrij-van-kanker-met-eigen-cocktail-van-bewezen-niet-toxische-middelen-copy-1.html

en dit artikel: 

https://kanker-actueel.nl/NL/hersentumoren-man-38-jaar-blijft-na-operatie-al-ruim-twee-jaar-zonder-recidief-van-een-glioblastoma-door-standaard-behandeling-van-bestraling-en-temodal-met-aanvullend-onder-begeleiding-een-kytogeen-dieet-en-aanvullende-vitamines.html

En zie ook: 

https://kanker-actueel.nl/NL/utopie-of-uitdaging-immuuntherapie-als-eerste-keuze-bij-de-diagnose-van-kanker-concept-studieprotocollen.html  



8 december 2021: Bron:  2021; 16(3): e0247293. Published online 2021 Mar 10. The 2021 Society for Neuro-Oncology’s 26th Annual Scientific Meeting and Education Day, from November 18 – 21

Een kleine fase I/II studie bij totaal 14 patiënten met een recidief van een hersentumor van het type glioblastoma multiforme heeft veelbelovende resultaten laten zien voor een vorm van immuuntherapie met natural killercellen en opgekweekte autologe T-cellen verkregen uit bloed of uit de lymfeklieren van de patiënten zelf. (In het Engels heet dit: Autologous adoptive immune-cell therapy). (Zie ook deze studie uit 2004Autologous Natural Killer Cell Therapy for Human Recurrent Malignant Glioma)

Van de oorspronkelijk 16 geselecteerde patiënten bleven er 14 over voor de analyse van een open label fase I/II veiligheidstudie. Van die 14 patiënten overleden er 9 door progressie van hun ziekte tijdens de onderzoeksperiode, maar 5 patiënten overleefden langer dan 2 jaar. De mediane overall overleving was 22 maanden en progressievrije ziekte was mediaan 10 maanden. Belangrijk ook was dat ten gevolge van de autologe adoptieve immuuntherapie er slechts graad 1 en 2 bijwerkingen werden gezien die heel gemakkelijk waren te controleren. Alle patiënten hadden eerder standaard behandelingen gehad van chemo (temozolomide - temodal) en bestraling maar hadden ook allemaal een recidief gekregen. Bedenk dat de mediane overall overleving voor deze groep van patiënten slechts 4 maanden bedraagt historisch gezien. 

De gemiddelde leeftijd bij de diagnose in de GBM-groep met een aantoonbaar recidief en die met adoptie-immuuncellen werden behandeld, was 53 jaar (standaarddeviatie: 9,5, leeftijdsbereik: 27-69).
Van de 14 patiënten waren respectievelijk 42,9% en 57,1% man en vrouw.
De isocitraatdehydrogenase IDH1-mutatie, R132H, werd gedetecteerd bij één patiënt.
Adjuvante chemotherapie en radiotherapie werden gebruikt als palliatieve behandeling; gedetailleerde baseline-informatie en klinische kenmerken van de 14 patiënten worden gegeven in S2-tabel in  S1 File

De meest voorkomende bijwerkingen waren koorts, anorexia, opvliegers, koude rillingen, reactie op de injectieplaats en auto-immuunziekte. Zie Table 1  

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Of the 14 patients who received adoptive immune cell therapy, nine died during the study period. Five patients who had a durable response survived for at least 28 months and for a maximum of 76 months after tumor recurrence (Table 2 and S6 Fig in S1 File). There were no differences in terms of chemotherapy, re-irradiation, age-at-diagnosis of recurrent GBM, and sex between good and poor responders (Table 2). The median OS of adoptive-immune-cell-treated patients was 22.5 months (Fig 2A), and the median progression-free survival (PFS) was 10 months (Fig 2B). Five patients were alive for over 2 years and continued with activities of daily living. Four patients completed the adoptive immune-cell therapy (Fig 2C). One patient (A14) discontinued this therapy after the 11th expanded cell injection owing to our inability to obtain enough expanded immune cells over four attempts (S2 Table in S1 File). Adoptive immune-cell therapy was discontinued in nine patients because of tumor progression (S2 Table in S1 File).


Het volledige studierapport is gratis in te zien of te downloaden. Klik op de titel van het abstract. 

 2021; 16(3): e0247293.
Published online 2021 Mar 10. doi: 10.1371/journal.pone.0247293
PMCID: PMC7946298
PMID: 33690665

Autologous adoptive immune-cell therapy elicited a durable response with enhanced immune reaction signatures in patients with recurrent glioblastoma: An open label, phase I/IIa trial

Jaejoon LimConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationResourcesSoftwareSupervisionValidationVisualizationWriting – original draftWriting – review & editing,#1 YoungJoon ParkData curationFormal analysisMethodologySoftwareWriting – original draftWriting – review & editing,#1,2 Ju Won AhnData curationFormal analysisMethodologySoftware,1,2 JeongMin SimFormal analysisMethodologySoftware,2 Su Jung KangFormal analysisMethodology,2 Sojung HwangData curationFormal analysisInvestigationMethodologyResourcesValidation,1,3 Jin ChunData curationMethodology,3 Hyejeong ChoiData curationFormal analysisVisualization,4 Sang Heum KimFormal analysisMethodologyVisualization,4 Duk-Hee ChunData curationInvestigationMethodology,5 Kyoung Su SungWriting – review & editing,6 KyuBum KwackSupervision,2,* and Kyunggi ChoConceptualizationData curationFunding acquisitionInvestigationProject administrationResourcesValidationWriting – review & editing1,*
Antony Bayer, Editor

Abstract

Glioblastoma multiforme (GBM) is an aggressive malignancy classified by the World Health Organization as a grade IV glioma. Despite the availability of aggressive standard therapies, most patients experience recurrence, for which there are currently no effective treatments. We aimed to conduct a phase I/IIa clinical trial to investigate the safety and efficacy of adoptive, ex-vivo-expanded, and activated natural killer cells and T lymphocytes from peripheral blood mononuclear cells of patients with recurrent GBM. This study was a single-arm, open-label, investigator-initiated trial on 14 patients recruited between 2013 and 2017. The immune cells were administered via intravenous injection 24 times at 2-week intervals after surgical resection or biopsy. The safety and clinical efficacy of this therapy was examined by assessing adverse events and comparing 2-year overall survival (OS). Transcriptomic analysis of tumor tissues was performed using NanoString to identify the mechanism of therapeutic efficacy. No grade 4 or 5 severe adverse events were observed. The most common treatment-related adverse events were grade 1 or 2 in severity. The most severe adverse event was grade 3 fever. Median OS was 22.5 months, and the median progression-free survival was 10 months. Five patients were alive for over 2 years and showed durable response with enhanced immune reaction transcriptomic signatures without clinical decline until the last follow-up after completion of the therapy. In conclusion, autologous adoptive immune-cell therapy was safe and showed durable response in patients with enhanced immune reaction signatures. This therapy may be effective for recurrent GBM patients with high immune response in their tumor microenvironments. Trial registration:The Korea Clinical Research Information Service database: KCT0003815, Registered 18 April 2019, retrospectively registered.

Discussion

This study reports a phase I/IIa clinical trial on autologous, adoptive, expanded, and activated immune-cell therapy with high proportions of NK cells or T lymphocytes from PBMCs for patients with recurrent GBM. It adopted a single arm and open-labeled design to evaluate safety, efficacy, and mechanism of action of the adoptive immune-cell therapy.

The most important consideration in immune-cell treatment is immunological reaction with severe adverse effects. In this study, most of the patients experienced adverse effects of grades 1 and 2 related to the adoptive immune-cell therapy without any severe immunological rejection (Table 2 and S5 Table in S1 File), which manifests as a cytokine storm [,]. The most frequent events were mild immune-related symptoms, such as fever, hot flushes, chills, injection-site reaction, and gastrointestinal symptoms, such as anorexia, nausea, and constipation (Table 2). The hematological symptoms related to the immune-cells therapy were mild and reversed with conventional treatment. The most severe adverse effect related to this adoptive immune-cell therapy was a grade 3 fever, which resolved without any complication (Table 2 and S5 Table in S1 File). During adoptive immune-cell therapy, severe adverse events of grades 4 and 5 occurred 6 times. Leukocytopenia occurred 3 times, and thrombocytopenia occurred once. These events were related to the salvage chemotherapy as they occurred after administration of the chemo-drug, ACNU or BCNU, they were treated with medication and transfusion. Other severe adverse events occurred in the poor response group and were related to tumor progression. Hydrocephalus and severe brain swelling occurred in one case. Taken together, these results suggest that this adoptive immune-cell therapy is safe.

An anticancer therapeutic agent must prolong the patient’s survival and slow the progression of tumor. In the case of GBM, standard treatment using temozolomide and radiation extends the mean OS by approximately 4 months [,]. However, this is much lower than the OS observed for other cancers, and extension of OS is extremely rare in recurrent GBM. Recurrent GBM is associated with an OS of 6–8 months despite the administration of adjuvant treatment [,,]. The median OS of adoptive immune-cell-treated patients was 22.5 months, and the median PFS was 10 months. Five patients survived for more than 2 years after the recurrence of GBM. Although this trial was conducted in a small number of patients (14), prolonged OS and PFS are important indicators of efficacy. These results indicate that adoptive immune-cell therapy could be used to treat GBM; however, they will have to be validated in clinical trials on a large number of patients.

Recently, clinical trials have been conducted using several immune cells or neoadjuvant immune check point inhibitors and have shown durable responses with OS of over 2 years in some recurrent GBM patients [,]. In this study, 5 patients showed a good response with OS of more than 2 years (Fig 2C). Four patients presented a durable response to the adoptive immune-cell therapy, without progression, and with a fuzzy pattern of enhancement or a “soap bubble or Swiss cheese appearance” with cystic changes on MRI (S6-S8 Figs in S1 File and Fig 2D). The fuzzy, enhanced lesions increased gradually during therapy, followed by a time-dependent decrease after the therapy. A thickened pattern of enhancement was observed for up to 14 months after the first adoptive immune-cell therapy session, after which the degree of enhancement decreased. This response was considered to indicate pseudoprogression with high immune reaction. Patients who did not respond to the adoptive immune-cell therapy presented a thick pattern of gadolinium enhancement or progression of ventricle wall enhancement (S9 and S11 Figs in S1 File). It is not clear whether the thickened pattern of enhancement was pseudoprogression or radiation necrosis [,]. Except A13 patient, all of the participants received re-irradiation therapy as salvage treatment before the administration of the adoptive immune-cell therapy (S2 Table in S1 File). These MRI signatures, which may be pseudoprogression or radiation necrosis, were continuously observed in good responders for at least 1 year. Compared to other modes of immunotherapy, immune cells were transferred many times (maximum of 24) to recurrent GBM patients in this study. Long-term-immune boosting effects were observed in the MRI signatures, indicating a durable immune effect and longer survival.

We performed NanoString transcriptomic analysis to elucidate the mechanism of action of the adoptive immune-cell therapy used in this study. Our results demonstrated that immune-related genes were associated with a protective effect in terms of PFS or were up-regulated in good responders (Fig 3, S13 and S14 Figs, and S7 Table in S1 File). In addition, four annotated terms including “Immune Cell Localization to Tumors”, “Recognition of Cancer Cells by T-cells”, “Myeloid Cell Activity”, and “Common Signaling Pathways” were able to discriminate between good and poor responders (Fig 3). Hyper-immunoactivity was detected in good responders. Recently, analysis of omics data was able to establish a subtype of GBM with high resolution []. The subtypes, classified based on multi-omics, were proneural, neural, classical, and mesenchymal. Several previous studies have reported that the mesenchymal subtype GBM is characterized by a higher degree of immune cell infiltration than the other subtypes, and it is considered more suitable to immunotherapy []. Using public GBM transcriptomic data from TCGA, all genes that were significantly associated with a protective effect for PFS or those that were upregulated in good responders, were found to be overexpressed in the mesenchymal hyper-enriched cluster (S15 Fig in S1 File). This indicates that this immune cell therapy may be efficacious in patients with an immune-response tumor type, such as those with mesenchymal subtype GBM from the TCGA dataset. A vaccination clinical trial using dendritic cells has also reported that the mesenchymal type GBM showed a good prognosis [].

In the present study, ex-vivo-expanded and activated immune cells were administered by intravenous injection. Therefore, trafficking and transport of the immune cells to the tumor microenvironment are very important. Several previous studies revealed that the BBB is destroyed to different levels in patients with GBM, allowing immune cell trafficking [,]. In this study, using transcriptomic analysis, we elucidated the mechanism of action of this immune cell therapy and found a component involving the movement of immune cells to the tumor in order to maximize their tumor-killing ability. Several chemokines, including CCL4CCL3L1, and CCL20, were upregulated in good responders or were associated with a protective effect for PFS. Several studies have reported that the in vitro activation of NK cells with IL-2 leads to the production of CCR2, CCR4, CCR5, and CCR8 []. Notably, these NK cells demonstrate high chemo-attractive responses with various chemokines including CCL4 [,]. Tumor tissues with increased level of these chemokines may have an enhanced ability to attract immune cells, which would move towards such tumor cells after administration. In the poor responders, although many immune cells were administered, the immune cells could not move toward the tumor microenvironment as the chemotactic signal was weak. Radiologically, an encouraging aspect about our results is pseudoprogression. The iRANO criteria suggest that pseudoprogression, in the MR scan after immunotherapy, could be considered a therapeutic response with immune infiltration []. As a result, in the MRI, long-lasting pseudoprogression was detected in only four good responders (S6-S8 Figs in S1 File and Fig 2D) with no additional tumor progression, but not in poor responders (S9 Fig in S1 File). These results suggest that immune cells administered to good responders would reach the tumor site via chemotaxis as a result of the immune response in the cancer microenvironment.

Consequently, in good responders with mesenchymal subtype, immune cells might have reached the brain. Immunohistochemical stain demonstrated that the CD3, CD8 or CD16 positive cells were significantly more infiltrated in tissue during adoptive immune cell therapy compared with pre-Tx in A1 patient with a good response (S1-S16 Figs and supplemental data in S1 File). Furthermore, by presenting long-lasting pseudoprogression, which is considered a treatment response to immunotherapy, good responders could present a long survival benefit. However, we were not able to experimentally determine whether NK cells actually exert anticancer effects among the expanded immune cell populations from PBMCs. In addition, as this was a clinical phase I/IIa trial on the safety and minimal efficacy, sufficient statistical power was not obtained due to the small number of patients. Therefore, further evaluation is needed through phase II clinical trials in the future.

Conclusions

Autologous adoptive immune-cell therapy was safe and showed good clinical outcome. This therapy demonstrated durable responses in five patients without severe adverse effects, and transcriptomic analysis showed that the good responders had enhanced immune response signatures. Therefore, this adoptive immune-cell therapy may be effective in a group of recurrent GBM patients with enhanced immune signatures, such as those with mesenchymal subtype.

Acknowledgments

Expanded and activated immune cells were manufactured by the Immunotherapy Development Team at CHA Biotech. Some of the results of this study were presented at the 2019 Congress of Neurological Surgeons Annual Meeting. The authors thank Dr. Sohyun Hwang, Jinhyung Heo, Haeyoun Kang, Ah-Young Kwon, Hee Jung An and Prof. Michael Lim for the review and comment about the manuscript.

Funding Statement

This research was supported by grants of Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Korea government (MSIT) (Grant No. 2018R1C1B5086460) and the Industrial Technology Innovation Program through the Ministry of Trade, Industry and Energy (Korea), funded by the Ministry of Trade, Industry and Energy, Republic of Korea (Grant No. 10067378). 1.Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Korea government (MSIT) Award Number: 2018R1C1B5086460 Recipient: Jaejoon Lim Role: Study design, Data collection and analysis, Decision to publish, Preparation of the manuscript 2. The Industrial Technology Innovation Program through the Ministry of Trade, Industry and Energy (Korea), funded by the Ministry of Trade, Industry and Energy, Republic of Korea Award Number: 10067378 Recipient: kyunggi Cho Role: Study design, Data collection and analysis, Decision to publish, Preparation of the manuscript.

Data Availability

NanoString data have been uploaded to GEO dataset in NCBI (GSE142693).

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