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Programme d’Actions Intégrées de
Recherche en cancérologie pédiatrique
(PAIR Pédiatrie)
Maison de la Chimie - 13 avril 2016
Immunothérapie des cancers,
nouveaux concepts
Aurélien Marabelle, MD, PhD
Directeur Clinique du Programme d’Immunothérapie
DITEP, Pr JC Soria
INSERM 1015, Pr L Zitvogel
GUSTAVE ROUSSY
Qu’est ce que l’immunothérapie ?
Cytokines
Sang
Inné AdaptatifMoelle
Chemotherapy - 1930s Paul Ehrlich - alkylating agents
1943 nitrogen mustard - lymphoma
Surgery – 1890 Halsted performs first radical mastectomy
Radiotherapy – late 19th - Becquerel and Rontgen, Marie Curie
1898 radium identified, 1903 first successful cancer tx
Immunothérapies du Cancer
Shekarian T, Wittmann S, Caux C, Marabelle A. Paradigm shift in oncology: targeting the immune
system rather than cancer cells. Mutagenesis 2014
Cancer immunotherapy:
“the beginning of the end”
or “the end of the beginning” ?
Durant JR. N Engl J Med 1987; 316:939-41.
April 19, 2015
April 20, 2015
April 19, 2015
June 2, 2013
June 2, 2013
Nov 19, 2014
June 30, 2011
Nov 16, 2014
Aug 19, 2010
June 2, 2012
June 28, 2012
FOXP3
FOXP3
FOXP3
IMMUNO-
TOLERANCE
IMMUNO-
SURVEILLANCE
Tregs
Cancer Cells
DCs
TAMs
MDSCs
NKs
CD8+
T-cells
CD4+
T-cells
DCs
-
Adapté de Colombo MP, et al Nat Rev Cancer. 2007 Nov;7(11):880-7.
Le Système Immunitaire peut aussi
promouvoir le cancer !
Changement de Paradigme
Cellule
Tumorale
Paradigme Historique:
Cibler les Cellules Tumorales
Lymphocyte
Nouveau Paradigme:
Cibler les Cellules Immunitaires
Activation / Inhibition du Lymphocyte
Anticorps Immunomodulateurs
dirigés contre des “checkpoints” immunitaires
THERAPIES CIBLANT L’IMMUNITE
Hodi et al. Abstract #3008 ASCO 2008
Screening Week 12 Week 14 Week 72
Schadendorf D, J Clin Oncol 2015.
Anti-CTLA4
Before BRAFi After 15 weeks
of BRAFi
After 23 weeks
of BRAFi
Wagle N, et al.
JCO. 2011
Aug 1;29(22):3085-96
Chapman PB et al. N Engl J Med 2011;364:2507–16.
THERAPIES CIBLANT LA TUMEUR
Nouveaux Types de Réponses en Oncologie
Immune-Related Response Criteria
Bompaire et al Invest New drugs 2012
Nouvelles Toxicités en Oncologie
Hayden EC. Antibody alarm call rouses immune response to cancer. Nature. 2012 Jun 6;486(7401):16.
anti-PD-1 / anti-PD-L1 immunotherapy
Spectre d’Activité des Anti-PD-1/PD-L1
Marabelle A, Routy B, Michels J, Kroemer G, Zitvogel L. Prime time for Immune-Checkpoint Targeted
Therapy at ASCO 2015. Oncoimmunology 2016. in press.
AMM
AMM
Pembrolizumab Antitumor Activity
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
Melanoma1 (N=411)
KEYNOTE-001
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
NSCLC2 (N=262)
KEYNOTE-001
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
Gastric5 (N=39)
KEYNOTE-012
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
Urothelial4 (N=33)
KEYNOTE-012
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
H&N3 (N=61)
KEYNOTE-012
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
TNBC6 (N=32)
KEYNOTE-012
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
cHL7 (N=29)
KEYNOTE-013
1. Daud A et al. 2014 SMR; 2. Garon EB et al. ESMO 2014; 3. Chow LQ et al. ESMO 2014; 4. O’Donnell P et al. 2015 Genitourinary Cancers Symposium;
5. Muro K et al. 2015 Gastrointestinal Cancers Symposium; 6. Nanda R et al. SABCS 2014; 7. Moskowitz C et al. 2014 ASH Annual Meeting; 8. Alley EA et al. 2015 AACR.
-100
-80
-60
-40
-20
0
20
40
60
80
100
ChangeFromBaselinein
TumorSize,%
Mesothelioma7 (N=25)
KEYNOTE-028
Mais les réponses tumorales aux
immunothérapies sont durables
JCO, April 20, 2015.
Durabilité des réponses tumorales des CBNPC sous nivomulab (anti-PD-1, BMS)
Immune-Targeted mAbs provide Survival Benefits
Motzer RJ, et al. NEJM 2015.
nivolumab
docetaxel
Non Sq NSCLC
Borghaei H, et al. NEJM 2015.
Nivolumab
(BMS)
Pembrolizumab
(MSD)
Atezolizumab
(Roche/Genentech)
Durvalumab
(AZ/Medimmune)
Avelumab
(Pfizer)
Anti-PD-1 Anti-PD-L1
Approved
Ipilimumab
(BMS)
Tremelimumab
(AZ)
Anti-CTLA-4
Approved
Know your Immune Checkpoint Antibodies
What is the Future of Oncology ?
Chemotherapy + PD-1/PD-L1 Blockade in 1st
line NSCLC
Giaccone et al, ESMO 2015
The Future of Oncology ?
Larkin J, et al. N Engl J Med 2015.
Anti-CTLA4
Anti-PD-1
Anti-PD-1 + Anti-CTLA4
AGONISTIC ANTAGONISTIC
This is just the beginning
But also Target Innate Immune Cells!
DCs
αCD40
TAMs
αCSF1R
αCD47
NK Cells
αKIR
αCD137
αNKG2A
The Future is Bright
Bi
Spe
Oncolytic
Virus
Cancer
Vaccines
CAR
T-cells
Oral Immuno
Modulator
30
25 mg
BID
50 mg
BID
100 mg
BID
300 mg
BID
Off study
treatment
Epacadostat + pembrolizumab in Metastatic Melanoma
(Incyte, NCT02178722)
Gangadhar et al. SITC 2015. Abstract #07
ORR = 58% (11/19)
Lenalidomide + aPD-1 in Multiple Myeloma
ORR = 76%
(13/17)
San Miguel et al, ASH 2015
The Future is Bright
Bi
Spe
Oncolytic
Virus
Cancer
Vaccines
CAR
T-cells
IDO inhibitors
T-VEC EMA approval
Q4 2015
in situ immunization
T-VEC + anti-PD-1 in Melanoma
-100
-75
-50
25
50
-25
0
75
100
ORR = 56% (9/16)
PercentageChangefromBaseline
Stage IV M1c (N=7)
Stage IV M1b (N=2)
Stage IV M1a (N=1)
Stage IIIc (N=5)
Stage IIIb (N=1)
All 16 patients were followed at least 12 weeks from the first dose of pembrolizumab and must have had an evaluable
response. Stable disease must be > 77 days to be considered evaluable.
34Long G V et al, SMR congress 2015, San Franisco, USA
The Future is Bright
Bi
Spe
Oncolytic
Virus
Cancer
Vaccines
CAR
T-cells
IDO inhibitors
T-CELL CAR T-CELL
Nature Reviews Cancer, 13, 525–541 (2013)
Adoptive T-cell Therapy
N Engl J Med. 2014 Oct 16;371(16):1507-17
The Future is Bright
Bi
Spe
Oncolytic
Virus
Cancer
Vaccines
CAR
T-cells
IDO inhibitors
Blinatumomab EMA approval
Q4 2015
Bispecific T-cell Engaging mAbs
Blinatumomab on Chemotherapy-Refractory MRD in B-
ALL
Blinatumomab in ALL & NHL
The Future is Bright
Bi
Spe
Oncolytic
Virus
Cancer
Vaccines
CAR
T-cells
IDO inhibitors
T-VEC EMA approval
Q4 2015
Blinatumomab EMA approval
Q4 2015
aPD-1/aPD-L1
aOX40
aCD137
aGITR
aKIR
IDOi
Oncolytic
Virus
Vaccines
TLR ago
RIG ago
STING ago
CHEMOTHERAPY
RADIOTHERAPY
TKI
TCE
BiSpe
mAbs
2016 : Combinaisons!
aCTLA4
Asgharzadeh., et al. Journal of Clinical Oncology. 2012
Tumor Associated Macrophages
in High-Risk Neuroblastoma
CD163+IHCstaining
Macrophages
Good Prognosis
Neuroblastoma
Bad Prognosis
Neuroblastoma
Stage IV, MYCN NA, >18months
Yu, A. L. et al. (2010). Anti-GD2 antibody with GM-CSF, interleukin-2, and
isotretinoin for Neuroblastoma. The New England Journal of Medicine,
363(14), 1324–34.
Rationnel pour l’Immunotherapie
des Neuroblastomes
Impact Pronostic des Isoformes NKp30
dans les NB de Haut Risque
Semeraro M, et al. Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma
patients. Sci Transl Med 2015;7:283ra55.
Niveaux d’Expression Variables du CMH I
dans les Cancers Pédiatriques
Haworth KB, et al. Characterization of MHC Class I and β-2-Microglobulin Expression in Pediatric
Solid Malignancies to Guide Selection of Immune-Based Therapeutic Trials. Pediatr Blood Cancer
2016;63:618–26.
Challenge #1: How do we overcome resistance to
immunotherapy?
Ott et al. Pembrolizumab in SCLC. WCLC 2015
Challenge #2: Immune Toxicity
7.7%
18.6%
39.6%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
nivolumab ipilimumab nivo+ipi
Grade 3-4 Adverse Events with anti-CTLA4 + anti-PD-1
Grade 3-4
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and
Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015.
Challenge #3: Financial Toxicity
Nature. 2013 May 30;497(7451)
Immunotherapy's cancer remit widens. Ledford H.
ipilimumab
On treatment
Off treatment
First response
Ongoing
response
0 8 16 24 32 40 48 64 72 8056
Time (weeks)
NIVOLUMAB+IPILIMUMAB
Time to and Durability of Response in Patients Who Discontinued Due to Toxicity
The Good News:
We Might Not Need To Treat for Long
Larkin et al. Abstract Number 3303. ESMO 2015.
Institut national du cancer ● 52, avenue André Morizet ● 92513 Boulogne-Billancourt Cedex ● France ● Tél. +33 (0) 1 41 10 50 00 ● e-cancer.fr
plus d’informations sur
e-cancer.fr
Kluger HM. Safety and
activity of pembrolizumab
in melanoma patients with
untreated brain metastases.
J Clin Oncol 2015;33:abstr
9009.
Goldberg SB. Activity and
safety of pembrolizumab in
patients with metastatic
NSCLC with untreated brain
metastases. J Clin Oncol
2015;33:abstr 8035.
Activity of anti-PD-1 against Brain Mets
in situ immunization
William Coley
Streptococcus pyogenes
“…on May 2, 1891,
I inoculated a case of sarcoma”
“At the end of two
weeks, the tumor had
disappeared”
Copyright © 2012 American Medical Association. All
rights reserved.
Treatment of Lymphangiomas With OK-432 (Picibanil) Sclerotherapy: A Prospective
Multi-institutional Trial
Arch Otolaryngol Head Neck Surg. 2002;128(10):1137-1144. doi:10.1001/archotol.128.10.1137
Patient 3 with a stage I lymphangioma of the left side of the neck. Photographs taken before (A) and after (B) a single injection demonstrate a
complete response to OK-432 treatment.
Figure Legend:

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Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle

  • 1. Programme d’Actions Intégrées de Recherche en cancérologie pédiatrique (PAIR Pédiatrie) Maison de la Chimie - 13 avril 2016
  • 2. Immunothérapie des cancers, nouveaux concepts Aurélien Marabelle, MD, PhD Directeur Clinique du Programme d’Immunothérapie DITEP, Pr JC Soria INSERM 1015, Pr L Zitvogel GUSTAVE ROUSSY
  • 3. Qu’est ce que l’immunothérapie ? Cytokines Sang Inné AdaptatifMoelle
  • 4. Chemotherapy - 1930s Paul Ehrlich - alkylating agents 1943 nitrogen mustard - lymphoma Surgery – 1890 Halsted performs first radical mastectomy Radiotherapy – late 19th - Becquerel and Rontgen, Marie Curie 1898 radium identified, 1903 first successful cancer tx
  • 5. Immunothérapies du Cancer Shekarian T, Wittmann S, Caux C, Marabelle A. Paradigm shift in oncology: targeting the immune system rather than cancer cells. Mutagenesis 2014
  • 6. Cancer immunotherapy: “the beginning of the end” or “the end of the beginning” ? Durant JR. N Engl J Med 1987; 316:939-41.
  • 7. April 19, 2015 April 20, 2015 April 19, 2015 June 2, 2013 June 2, 2013 Nov 19, 2014 June 30, 2011 Nov 16, 2014 Aug 19, 2010 June 2, 2012 June 28, 2012
  • 8.
  • 9. FOXP3 FOXP3 FOXP3 IMMUNO- TOLERANCE IMMUNO- SURVEILLANCE Tregs Cancer Cells DCs TAMs MDSCs NKs CD8+ T-cells CD4+ T-cells DCs - Adapté de Colombo MP, et al Nat Rev Cancer. 2007 Nov;7(11):880-7. Le Système Immunitaire peut aussi promouvoir le cancer !
  • 10. Changement de Paradigme Cellule Tumorale Paradigme Historique: Cibler les Cellules Tumorales Lymphocyte Nouveau Paradigme: Cibler les Cellules Immunitaires
  • 11. Activation / Inhibition du Lymphocyte
  • 12. Anticorps Immunomodulateurs dirigés contre des “checkpoints” immunitaires
  • 13. THERAPIES CIBLANT L’IMMUNITE Hodi et al. Abstract #3008 ASCO 2008 Screening Week 12 Week 14 Week 72 Schadendorf D, J Clin Oncol 2015. Anti-CTLA4
  • 14. Before BRAFi After 15 weeks of BRAFi After 23 weeks of BRAFi Wagle N, et al. JCO. 2011 Aug 1;29(22):3085-96 Chapman PB et al. N Engl J Med 2011;364:2507–16. THERAPIES CIBLANT LA TUMEUR
  • 15. Nouveaux Types de Réponses en Oncologie Immune-Related Response Criteria
  • 16. Bompaire et al Invest New drugs 2012 Nouvelles Toxicités en Oncologie
  • 17. Hayden EC. Antibody alarm call rouses immune response to cancer. Nature. 2012 Jun 6;486(7401):16. anti-PD-1 / anti-PD-L1 immunotherapy
  • 18. Spectre d’Activité des Anti-PD-1/PD-L1 Marabelle A, Routy B, Michels J, Kroemer G, Zitvogel L. Prime time for Immune-Checkpoint Targeted Therapy at ASCO 2015. Oncoimmunology 2016. in press. AMM AMM
  • 19. Pembrolizumab Antitumor Activity -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% Melanoma1 (N=411) KEYNOTE-001 -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% NSCLC2 (N=262) KEYNOTE-001 -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% Gastric5 (N=39) KEYNOTE-012 -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% Urothelial4 (N=33) KEYNOTE-012 -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% H&N3 (N=61) KEYNOTE-012 -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% TNBC6 (N=32) KEYNOTE-012 -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% cHL7 (N=29) KEYNOTE-013 1. Daud A et al. 2014 SMR; 2. Garon EB et al. ESMO 2014; 3. Chow LQ et al. ESMO 2014; 4. O’Donnell P et al. 2015 Genitourinary Cancers Symposium; 5. Muro K et al. 2015 Gastrointestinal Cancers Symposium; 6. Nanda R et al. SABCS 2014; 7. Moskowitz C et al. 2014 ASH Annual Meeting; 8. Alley EA et al. 2015 AACR. -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% Mesothelioma7 (N=25) KEYNOTE-028
  • 20. Mais les réponses tumorales aux immunothérapies sont durables JCO, April 20, 2015. Durabilité des réponses tumorales des CBNPC sous nivomulab (anti-PD-1, BMS)
  • 21. Immune-Targeted mAbs provide Survival Benefits Motzer RJ, et al. NEJM 2015. nivolumab docetaxel Non Sq NSCLC Borghaei H, et al. NEJM 2015.
  • 23. What is the Future of Oncology ?
  • 24. Chemotherapy + PD-1/PD-L1 Blockade in 1st line NSCLC Giaccone et al, ESMO 2015
  • 25. The Future of Oncology ?
  • 26. Larkin J, et al. N Engl J Med 2015. Anti-CTLA4 Anti-PD-1 Anti-PD-1 + Anti-CTLA4
  • 27. AGONISTIC ANTAGONISTIC This is just the beginning
  • 28. But also Target Innate Immune Cells! DCs αCD40 TAMs αCSF1R αCD47 NK Cells αKIR αCD137 αNKG2A
  • 29. The Future is Bright Bi Spe Oncolytic Virus Cancer Vaccines CAR T-cells Oral Immuno Modulator
  • 30. 30 25 mg BID 50 mg BID 100 mg BID 300 mg BID Off study treatment Epacadostat + pembrolizumab in Metastatic Melanoma (Incyte, NCT02178722) Gangadhar et al. SITC 2015. Abstract #07 ORR = 58% (11/19)
  • 31. Lenalidomide + aPD-1 in Multiple Myeloma ORR = 76% (13/17) San Miguel et al, ASH 2015
  • 32. The Future is Bright Bi Spe Oncolytic Virus Cancer Vaccines CAR T-cells IDO inhibitors T-VEC EMA approval Q4 2015
  • 34. T-VEC + anti-PD-1 in Melanoma -100 -75 -50 25 50 -25 0 75 100 ORR = 56% (9/16) PercentageChangefromBaseline Stage IV M1c (N=7) Stage IV M1b (N=2) Stage IV M1a (N=1) Stage IIIc (N=5) Stage IIIb (N=1) All 16 patients were followed at least 12 weeks from the first dose of pembrolizumab and must have had an evaluable response. Stable disease must be > 77 days to be considered evaluable. 34Long G V et al, SMR congress 2015, San Franisco, USA
  • 35. The Future is Bright Bi Spe Oncolytic Virus Cancer Vaccines CAR T-cells IDO inhibitors
  • 36. T-CELL CAR T-CELL Nature Reviews Cancer, 13, 525–541 (2013) Adoptive T-cell Therapy
  • 37. N Engl J Med. 2014 Oct 16;371(16):1507-17
  • 38. The Future is Bright Bi Spe Oncolytic Virus Cancer Vaccines CAR T-cells IDO inhibitors Blinatumomab EMA approval Q4 2015
  • 40. Blinatumomab on Chemotherapy-Refractory MRD in B- ALL Blinatumomab in ALL & NHL
  • 41. The Future is Bright Bi Spe Oncolytic Virus Cancer Vaccines CAR T-cells IDO inhibitors T-VEC EMA approval Q4 2015 Blinatumomab EMA approval Q4 2015
  • 42. aPD-1/aPD-L1 aOX40 aCD137 aGITR aKIR IDOi Oncolytic Virus Vaccines TLR ago RIG ago STING ago CHEMOTHERAPY RADIOTHERAPY TKI TCE BiSpe mAbs 2016 : Combinaisons! aCTLA4
  • 43.
  • 44. Asgharzadeh., et al. Journal of Clinical Oncology. 2012 Tumor Associated Macrophages in High-Risk Neuroblastoma CD163+IHCstaining Macrophages Good Prognosis Neuroblastoma Bad Prognosis Neuroblastoma Stage IV, MYCN NA, >18months
  • 45.
  • 46.
  • 47. Yu, A. L. et al. (2010). Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for Neuroblastoma. The New England Journal of Medicine, 363(14), 1324–34. Rationnel pour l’Immunotherapie des Neuroblastomes
  • 48. Impact Pronostic des Isoformes NKp30 dans les NB de Haut Risque Semeraro M, et al. Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients. Sci Transl Med 2015;7:283ra55.
  • 49. Niveaux d’Expression Variables du CMH I dans les Cancers Pédiatriques Haworth KB, et al. Characterization of MHC Class I and β-2-Microglobulin Expression in Pediatric Solid Malignancies to Guide Selection of Immune-Based Therapeutic Trials. Pediatr Blood Cancer 2016;63:618–26.
  • 50. Challenge #1: How do we overcome resistance to immunotherapy? Ott et al. Pembrolizumab in SCLC. WCLC 2015
  • 51. Challenge #2: Immune Toxicity 7.7% 18.6% 39.6% 0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% 35.0% 40.0% 45.0% nivolumab ipilimumab nivo+ipi Grade 3-4 Adverse Events with anti-CTLA4 + anti-PD-1 Grade 3-4 Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015.
  • 52. Challenge #3: Financial Toxicity Nature. 2013 May 30;497(7451) Immunotherapy's cancer remit widens. Ledford H. ipilimumab
  • 53. On treatment Off treatment First response Ongoing response 0 8 16 24 32 40 48 64 72 8056 Time (weeks) NIVOLUMAB+IPILIMUMAB Time to and Durability of Response in Patients Who Discontinued Due to Toxicity The Good News: We Might Not Need To Treat for Long Larkin et al. Abstract Number 3303. ESMO 2015.
  • 54. Institut national du cancer ● 52, avenue André Morizet ● 92513 Boulogne-Billancourt Cedex ● France ● Tél. +33 (0) 1 41 10 50 00 ● e-cancer.fr plus d’informations sur e-cancer.fr
  • 55. Kluger HM. Safety and activity of pembrolizumab in melanoma patients with untreated brain metastases. J Clin Oncol 2015;33:abstr 9009. Goldberg SB. Activity and safety of pembrolizumab in patients with metastatic NSCLC with untreated brain metastases. J Clin Oncol 2015;33:abstr 8035. Activity of anti-PD-1 against Brain Mets
  • 57. William Coley Streptococcus pyogenes “…on May 2, 1891, I inoculated a case of sarcoma” “At the end of two weeks, the tumor had disappeared”
  • 58.
  • 59. Copyright © 2012 American Medical Association. All rights reserved. Treatment of Lymphangiomas With OK-432 (Picibanil) Sclerotherapy: A Prospective Multi-institutional Trial Arch Otolaryngol Head Neck Surg. 2002;128(10):1137-1144. doi:10.1001/archotol.128.10.1137 Patient 3 with a stage I lymphangioma of the left side of the neck. Photographs taken before (A) and after (B) a single injection demonstrate a complete response to OK-432 treatment. Figure Legend:

Editor's Notes

  1. > Over the last decade, a tremendous amount of data has been published on how cancers generate immune tolerance. > We know now that within the tumor micro-environment, there are subsets of myeloid cells, which, together with the Tumor cells, sustain the development of a type of lymphocytes, called regulatory T-cells or Tregs. These Tregs are a subset of CD4+ T-cells identified by the expression of a transcription factor called FOXP3 and have the ability to inhibit specifically the immune response directed against the tumor. In order to treat cancers, people have been focusing so far on the tumor cells. A paradigm shift is happening today in cancer therapy where instead of targeting the tumor cells, new molecules are designed to target the immune system in order to break the cancer tolerance and stimulate the anti-tumor immune response.
  2. Interestingly, it has also been shown recently that inflammatory cells of the myeloid lineage are of bad prognosis in NB.