2 oktober 2017: Bron: Algemeen Dagblad

Wanneer bij mensen een beginnend melanoom wordt gevonden en deze kan worden weggehaald en daarna op de plaats van de operatie wordt een injectie gegeven met een zogeheten DNA mengsel (CpG-B) dat lijkt op een lichaamsvreemde bacteriënmix dan wordt veel vaker een recidief voorkomen dan als alleen een operatie wordt uitgevoerd plus een injectie met een zoutmengsel (placebogroep). De DNA injectie geeft een enorme boost aan het immuunsysteem dat doordoor voorkomt dat er een recidief ontstaat of verdere uitzaaiingen.

Bij tot nu toe 52 behandelde patienten, die ruim tien jaar geleden met een verdachte moedervlek naar de huisarts gingen werd een melanoom in een vroeg stadium ontdekt.
Dertig patiënten kregen de stof CpG-B ingespoten. Twee van hen kregen jaren later alsnog uitzaaiingen en overleden aan de ziekte (7 procent). Bij de patiënten uit de controlegroep die geen injectie kregen ontstond een recidief en zaaide de kanker bij 40 procent van de patiënten alsnog uit. Zes mensen overleden; drie werden opnieuw geopereerd. Dit meldt het Algemeen Dagblad d.d. 2 oktober 2017.

Immuuntherapie met CpG-B wordt wereldwijd al heel lang onderzocht. Zoek in pubmed op CpG-B en je krijgt een aantal hits. De studie die nu wordt aangehaald van onderzoeker en medisch bioloog Tanja de Gruijl begon al in 2003 en werd gesloten voor patienten in 2007. En is in 2015 al gepresenteerd op het CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference

The researchers found that after a median follow-up of 76.5 months, two of the 30 patients assigned CpG-B and nine of the 22 patients assigned placebo had experienced melanoma recurrence.

Hier een beeld van twee patienten met elkaar vergeleken: (tekst gaat verder onder grafiek)

Fig. 4

An external file that holds a picture, illustration, etc.
Object name is 262_2016_1811_Fig4_HTML.jpg

MAA-specific CD8+ T cells in the SLN. a MAA-specific tetramer+CD8+ T cell rates in the SLN of HLA-A2+ saline-administered patients are shown for tumor-negative and tumor-positive SLNs. Each dot represents one melanoma-specific tetramer-binding CD8+ population. The cutoff threshold set for positive tetramer responses is shown as a dashed line. b MAA-specific tetramer+CD8+ T cell rates in tumor-negative SLNs for all three groups. Below both graphs response numbers relative to evaluated numbers of patients and epitopes are shown. *p < 0.05

En toen al zei Tanja de Gruijl:

"Our results imply that local conditioning of the melanoma excision site by simple intradermal administration of an immune-stimulatory compound like CpG-B can lead to boosting of a systemic antimelanoma immune response that affords protection against recurrences in the long term, with minimal transient side effects," said de Gruijl. "We plan to conduct a large, randomized phase III clinical trial of intradermal CpG-B versus saline to confirm our findings of prolonged long-term recurrence-free survival."

According to de Gruijl, the major limitations of the study are that the data are the combined results of two phase II clinical trials with low numbers of enrolled patients and that different CpG-B doses were used in the two clinical trials. The low patient numbers mean that a large, randomized phase III clinical trial is needed to confirm the current promising findings, she added.

Nu twee jaar later worden alsnog in Nederland  de resultaten naar buiten gebracht. Met in het AD een herhaalde opmerking van Tanja de Gruijl uit 2015 maar nu in een Nederlandse krant: 

,,De verschillen zijn nogal overweldigend. Het lijkt erop dat een simpel spuitje veel ellende kan voorkomen. Maar let op: voor het op de markt komt, zullen we een vervolgstudie met een groter aantal patiënten moeten doen", zegt onderzoeker en medisch bioloog Tanja de Gruijl.

Waarom wordt dit nu pas allemaal naar buiten gebracht? En waarom moet dit nog eens tien jaar duren? Hebben ze geld nodig in het VUmc? Of is dit onderdeel van het lobbywerk om de EMA naar Amsterdam te krijgen? 

Voor het oorspronkelijke studierapport verwijs ik naar de twee fase II studies: Arming the Melanoma Sentinel Lymph Node through Local Administration of CpG-B and GM-CSF: Recruitment and Activation of BDCA3/CD141+ Dendritic Cells and Enhanced Cross-Presentation

en deze studie: Local delivery of CpG-B and GM-CSF induces concerted activation of effector and regulatory T cells in the human melanoma sentinel lymph node

Hieronder de referentielijsten behorend bij deze studies:

referentielijst behorend bij Local delivery of CpG-B and GM-CSF induces concerted activation of effector and regulatory T cells in the human melanoma sentinel lymph node

References

1. Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet. 2005;365:687–701. doi: 10.1016/S0140-6736(05)70937-5. [PubMed] [Cross Ref]
2. Romero P, Dunbar PR, Valmori D, Pittet M, Ogg GS, Rimoldi D, Chen JL, Liénard D, Cerottini JC, Cerundolo V. Ex vivo staining of metastatic lymph nodes by class I major histocompatibility complex tetramers reveals high numbers of antigen-experienced tumor-specific cytolytic T lymphocytes. J Exp Med. 1998;188:1641–1650. doi: 10.1084/jem.188.9.1641. [PMC free article] [PubMed] [Cross Ref]
3. Munn DH, Mellor AL. The tumor-draining lymph node as an immune-privileged site. Immunol Rev. 2006;213:146–158. doi: 10.1111/j.1600-065X.2006.00444.x. [PubMed] [Cross Ref]
4. Grotz TE, Mansfield AS, Jakub JW, Markovic SN. Regional lymphatic immunity in melanoma. Melanoma Res. 2012;22:9–18. doi: 10.1097/CMR.0b013e32834e1f33. [PubMed] [Cross Ref]
5. Gabrilovich D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol. 2004;4:941–952. doi: 10.1038/nri1498. [PubMed] [Cross Ref]
6. Cochran AJ, Huang RR, Lee J, Itakura E, Leong SP, Essner R. Tumour-induced immune modulation of sentinel lymph nodes. Nat Rev Immunol. 2006;6:659–670. doi: 10.1038/nri1919. [PubMed] [Cross Ref]
7. Molenkamp BG, van Leeuwen PAM, van den Eertwegh AJM, Sluijter BJR, Scheper RJ, Meijer S, de Gruijl TD. Immunomodulation of the melanoma sentinel lymph node: a novel adjuvant therapeutic option. Immunobiology. 2006;211:651–661. doi: 10.1016/j.imbio.2006.06.009. [PubMed] [Cross Ref]
8. Vuylsteke RJCL, van Leeuwen PAM, Meijer S, Wijnands PGJT, Statius Muller MG, Busch DH, Scheper RJ, de Gruijl TD. Sampling tumor-draining lymph nodes for phenotypic and functional analysis of dendritic cells and T cells. Am J Pathol. 2002;161:19–26. doi: 10.1016/S0002-9440(10)64152-1. [PMC free article] [PubMed] [Cross Ref]
9. Elliott B, Cook MG, John RJ, Powell BW, Pandha H, Dalgleish AG. Successful live cell harvest from bisected sentinel lymph nodes research report. J Immunol Methods. 2004;291:71–78. doi: 10.1016/j.jim.2004.04.025. [PubMed] [Cross Ref]
10. Molenkamp BG, van Leeuwen PAM, Meijer S, Sluijter BJR, Wijnands PGJT, Baars A, van den Eertwegh AJM, Scheper RJ, de Gruijl TD. Intradermal CpG-B activates both plasmacytoid and myeloid dendritic cells in the sentinel lymph node of melanoma patients. Clin Cancer Res. 2007;13:2961–2969. doi: 10.1158/1078-0432.CCR-07-0050. [PubMed] [Cross Ref]
11. Molenkamp BG, Sluijter BJR, van Leeuwen PAM, Santegoets SJAM, Meijer S, Wijnands PGJT, Haanen JBAG, van den Eertwegh AJM, Scheper RJ, de Gruijl TD. Local administration of PF-3512676 CpG-B instigates tumor-specific CD8+ T-cell reactivity in melanoma patients. Clin Cancer Res. 2008;14:4532–4542. doi: 10.1158/1078-0432.CCR-07-4711. [PubMed] [Cross Ref]
12. Vuylsteke RJCL, Molenkamp BG, van Leeuwen PAM, Meijer S, Wijnands PGJT, Haanen JBAG, Scheper RJ, de Gruijl TD. Tumor-specific CD8+ T cell reactivity in the sentinel lymph node of GM-CSF-treated stage I melanoma patients is associated with high myeloid dendritic cell content. Clin Cancer Res. 2006;12:2826–2833. doi: 10.1158/1078-0432.CCR-05-2431. [PubMed] [Cross Ref]
13. Vuylsteke RJCL, Molenkamp BG, Gietema HA, van Leeuwen PAM, Wijnands PGJT, Vos W, van Diest PJ, Scheper RJ, Meijer S, de Gruijl TD. Local administration of granulocyte/macrophage colony-stimulating factor increases the number and activation state of dendritic cells in the sentinel lymph node of early-stage melanoma. Cancer Res. 2004;64:8456–8460. doi: 10.1158/0008-5472.CAN-03-3251. [PubMed] [Cross Ref]
14. Lou Y, Liu C, Kim GJ, Liu YJ, Hwu P, Wang G. Plasmacytoid dendritic cells synergize with myeloid dendritic cells in the induction of antigen-specific antitumor immune responses. J Immunol. 2007;178:1534–1541. doi: 10.4049/jimmunol.178.3.1534. [PubMed] [Cross Ref]
15. Sandler AD, Chihara H, Kobayashi G, Zhu X, Miller MA, Scott DL, Krieg AM. CpG oligonucleotides enhance the tumor antigen-specific immune response of a granulocyte macrophage colony-stimulating factor-based vaccine strategy in neuroblastoma. Cancer Res. 2003;63:394–399. [PubMed]
16. Tarhini AA, Leng S, Moschos SJ, Yin Y, Sander C, Lin Y, Gooding WE, Kirkwood JM. Safety and immunogenicity of vaccination with MART-1 (26–35, 27L), gp100 (209–217, 210 M), and tyrosinase (368–376, 370D) in adjuvant with PF-3512676 and GM-CSF in metastatic melanoma. J Immunother. 2012;35:359–366. doi: 10.1097/CJI.0b013e31825481fe. [PMC free article] [PubMed] [Cross Ref]
17. Sluijter BJ, van den Hout MF, Koster BD, van Leeuwen PA, Schneiders FL, van de Ven R, Molenkamp BG, Vosslamber S, Verweij CL, van den Tol MP, van den Eertwegh AJ, Scheper RJ, de Gruijl TD. Arming the melanoma SLN through local administration of CpG-B and GM-CSF: recruitment and activation of BDCA3/CD141 + DC and enhanced cross-presentation. Cancer Immunol Res. 2015;3(5):495–505. doi: 10.1158/2326-6066.CIR-14-0165. [PubMed] [Cross Ref]
18. van der Veen H, Hoekstra OS, Paul MA, Cuesta MA, Meijer S. Gamma probe-guided sentinel node biopsy to select patients with melanoma for lymphadenectomy. Br J Surg. 1994;81:1769–1770. doi: 10.1002/bjs.1800811220. [PubMed] [Cross Ref]
19. Schneiders FL, de Bruin RC, Santegoets SJAM, Bonneville M, Scotet E, Scheper RJ, Verheul HM, de Gruijl TD, van der Vliet HJ. Activated iNKT cells promote Vgamma9Vdelta2-T cell anti-tumor effector functions through the production of TNF-alpha. Clin Immunol. 2012;142:194–200. doi: 10.1016/j.clim.2011.10.006. [PubMed] [Cross Ref]
20. Tran DQ, Andersson J, Hardwick D, Bebris L, Illei GG, Shevach EM. Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I/II (CD121a/CD121b) on activated human FOXP3 + regulatory T cells allows for their purification from expansion cultures. Blood. 2009;113:5125–5133. doi: 10.1182/blood-2009-01-199950. [PMC free article] [PubMed] [Cross Ref]
21. Venken K, Thewissen M, Hellings N, Somers V, Hensen K, Rummens JL, Stinissen P. A CFSE based assay for measuring CD4 + CD25 + regulatory T cell mediated suppression of auto-antigen specific and polyclonal T cell responses. J Immunol Methods. 2007;322:1–11. doi: 10.1016/j.jim.2007.01.025. [PubMed] [Cross Ref]
22. Sluijter BJ, van den Hout MF, Stam AG, Lougheed SM, Suhoski MM, van den Eertwegh AJ, van den Tol MP, van Leeuwen PAM, Meijer S, Scheper RJ, June CH, de Gruijl TD, Santegoets SJAM. 4-1BB-mediated expansion affords superior detection of in vivo primed effector memory CD8+ T cells from melanoma sentinel lymph nodes. Clin Immunol. 2010;137:221–233. doi: 10.1016/j.clim.2010.07.009. [PubMed] [Cross Ref]
23. Sun J, Tang DN, Fu T, Sharma P. Identification of human regulatory T cells in the setting of T-cell activation and anti-CTLA-4 immunotherapy on the basis of expression of latency-associated peptide. Cancer Discov. 2012;2:122–130. doi: 10.1158/2159-8290.CD-11-0236. [PubMed] [Cross Ref]
24. Willimsky G, Blankenstein T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature. 2005;437:141–146. doi: 10.1038/nature03954. [PubMed] [Cross Ref]
25. Kim PS, Ahmed R. Features of responding T cells in cancer and chronic infection. Curr Opin Immunol. 2010;22:223–230. doi: 10.1016/j.coi.2010.02.005. [PMC free article] [PubMed] [Cross Ref]
26. Moseman EA, Liang X, Dawson AJ, Panoskaltsis-Mortari A, Krieg AM, Liu YJ, Blazar BR, Chen W. Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4 + CD25 + regulatory T cells. J Immunol. 2004;173:4433–4442. doi: 10.4049/jimmunol.173.7.4433. [PubMed] [Cross Ref]
27. Kortylewski M, Kujawski M, Herrmann A, Yang C, Wang L, Liu Y, Salcedo R, Yu H. Toll-like receptor 9 activation of signal transducer and activator of transcription 3 constrains its agonist-based immunotherapy. Cancer Res. 2009;69:2497–2505. doi: 10.1158/0008-5472.CAN-08-3031. [PMC free article] [PubMed] [Cross Ref]
28. Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol. 2008;181:5396–5404. doi: 10.4049/jimmunol.181.8.5396. [PMC free article] [PubMed] [Cross Ref]
29. Jung YJ, Seoh JY. Feedback loop of immune regulation by CD4 + CD25 + Treg. Immunobiology. 2009;214:291–302. doi: 10.1016/j.imbio.2008.09.004. [PubMed] [Cross Ref]
30. Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood. 2002;99:3493–3499. doi: 10.1182/blood.V99.10.3493. [PubMed] [Cross Ref]
31. Weiner HL. Induction and mechanism of action of transforming growth factor-β-secreting Th3 regulatory cells. Immunol Rev. 2001;182:207–214. doi: 10.1034/j.1600-065X.2001.1820117.x. [PubMed] [Cross Ref]
32. Andersson J, Tran DQ, Pesu M, Davidson TS, Ramsey H, O’Shea JJ, Shevach EM. CD4 + FoxP3 + regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. J Exp Med. 2008;205:1975–1981. doi: 10.1084/jem.20080308. [PMC free article] [PubMed] [Cross Ref]
33. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–787. doi: 10.1016/j.cell.2008.05.009. [PubMed] [Cross Ref]
34. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006;212:28–50. doi: 10.1111/j.0105-2896.2006.00420.x. [PubMed] [Cross Ref]
35. Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal Malefyt R, Roncarolo MG. IFN-α and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol. 2001;166:5530–5539. doi: 10.4049/jimmunol.166.9.5530. [PubMed] [Cross Ref]
36. Puccetti P, Grohmann U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-ĸB activation. Nat Rev Immunol. 2007;7:817–823. doi: 10.1038/nri2163. [PubMed] [Cross Ref]
37. Neeland MR, Elhay MJ, Nathanielsz J, Meeusen EN, de Veer MJ. Incorporation of CpG into a liposomal vaccine formulation increases the maturation of antigen-loaded dendritic cells and monocytes to improve local and systemic immunity. J Immunol. 2014;192:3666–3675. doi: 10.4049/jimmunol.1303014. [PubMed] [Cross Ref]
38. Moretta L, Ferlazzo G, Bottino C, Vitale M, Pende D, Mingari MC, Moretta A. Effector and regulatory events during natural killer-dendritic cell interactions. Immunol Rev. 2006;214:219–228. doi: 10.1111/j.1600-065X.2006.00450.x. [PubMed] [Cross Ref]
39. Kawarada Y, Ganss R, Garbi N, Sacher T, Arnold B, Hämmerling GJ. NK- and CD8+ T cell-mediated eradication of established tumors by peritumoral injection of CpG-containing oligodeoxynucleotides. J Immunol. 2001;167:5247–5253. doi: 10.4049/jimmunol.167.9.5247. [PubMed] [Cross Ref]
40. Liu C, Lou Y, Lizee G, Qin H, Liu S, Rabinovich B, Kim GJ, Wang YH, Ye Y, Sikora AG, Overwijk WW, Liu YJ, Wang G, Hwu P. Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest. 2008;118:1165–1175. [PMC free article] [PubMed]
41. Pashenkov M, Goëss G, Wagner C, Hörmann M, Jandl T, Moser A, Britten CM, Smolle J, Koller S, Mauch C, Tantcheva-Poor I, Grabbe S, Loquai C, Esser S, Franckson T, Schneeberger A, Haarmann C, Krieg AM, Stingl G, Wagner SN. Phase II Trial of a toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma. J Clin Oncol. 2006;24:5716–5724. doi: 10.1200/JCO.2006.07.9129. [PubMed] [Cross Ref]
42. Zanoni I, Foti M, Ricciardi-Castagnoli P, Granucci F. TLR-dependent activation stimuli associated with Th1 responses confer NK cell stimulatory capacity to mouse dendritic cells. J Immunol. 2005;175:286–292. doi: 10.4049/jimmunol.175.1.286. [PubMed] [Cross Ref]
43. Chapman PB, D’Angelo SP, Wolchok JD. Rapid eradication of a bulky melanoma mass with one dose of immunotherapy. N Engl J Med. 2015;372(21):2073–2074. doi: 10.1056/NEJMc1501894. [PubMed] [Cross Ref]

referentielijst behorend bij Arming the Melanoma Sentinel Lymph Node through Local Administration of CpG-B and GM-CSF: Recruitment and Activation of BDCA3/CD141+ Dendritic Cells and Enhanced Cross-Presentation

References

  1. 1.
  2. 2.
  3. 3.
  4. 4.
  5. 5.
  6. 6.
  7. 7.
  8. 8.
  9. 9.
  10. 10.
  11. 11.
  12. 12.
  13. 13.
  14. 14.
  15. 15.
  16. 16.
  17. 17.
  18. 18.
  19. 19.
  20. 20.
  21. 21.
  22. 22.
  23. 23.
  24. 24.
  25. 25.
  26. 26.
  27. 27.
  28. 28.
  29. 29.
  30. 30.
  31. 31.
  32. 32.
  33. 33.
  34. 34.
  35. 35.
  36. 36.
  37. 37.
  38. 38.
  39. 39.
  40. 40.
  41. 41.
  42. 42.
  43. 43.
  44. 44.
  45. 45.
  46. 46.
  47. 47.
  48. 48.
  49. 49.
  50. 50.

Plaats een reactie ...

Reageer op "Immuuntherapie met DNA injectie van bacterien look-a-like (CpG-B) bij beginnende melanomen geeft uitstekende resultaten in voorkomen van recidief door boost in activering van immuunsysteem"


Gerelateerde artikelen
 

Gerelateerde artikelen

Archief nieuwsberichten over >> Kankerpatiënten met een laag >> Nederlandse filmpremière >> Wim Hof die wereldberoemd >> Retour Hemel: documentaire >> Kankerpil - AOH1996, van professor >> Patienten met zeldzame vormen >> Sterkere MRI-scanner met nieuw >> Er dreigt een wereldwijde >> 34 procent van alle kankerpatienten >>