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Nuevas Herramientas de Inmunoterapia del Cancer
Javier BrionesServicio Hematología
Hospital Santa Creu i Sant PauBarcelona
• Citoquinas
• Virus Oncolíticos
• Inmunoterapia celular T
IL-2• T cell growth factor• Enhances NK cytolitic
activity• Increases Ab production• TREG development
Clinical Trials with IL-2: AML
M. Buyse. Blood 2011
M. Buyse. Blood 2011
Survival after IL-2 maintenance
Immunotherapy with Cytokine-induced Killer Cells (CIK)
• CIK: CD3+ CD56+ NKG2D+• HLA-independent cell killing• Cultured with IL-2, anti-CD3
+ INFg (28d)• 18 pts: 3 AML, 2 ALL, 2 MDS,
5 NHL, 1 HL, 2 CLL, 3 MM• Relapsed after AlloSCT
IL-15
• Essential for NK cell development
• Activation of CD8+ T cells• Expansion of memory
CD8+ T cells
0
20
40
60
80
100
30:1 15:1 5:1 1:1
E:T Ratio
% A
DC
C ControlRituxIL-15R/IL-15
P < 0.001
IL-15 Enhancement of Rituximab-mediated ADCC of Lymphoma
Moga et al. Exp Hem 2011
0 10 20 30 40
IL-15
CpG ODN A
CpG ODN Cont
% lysis
P= 0.01
0
10
20
30
40
50
40:1 20:1 10:1
IL15-R NK +
IL15-R NK -
Clinical Trials with IL-15
ALT-803 in Patients With Relapse/Refractory IndolentNon-Hodgkin Lymphoma (iNHL) in Conjunction With Rituximab
A Study of ALT-803 in Patients With Relapsed or Refractory Multiple Myeloma
IL-15 Super Agonist ALT-803 to Treat Relapse Of Hematologic Malignancy After Allogeneic SCT
Subcutaneous Recombinant Human IL-15 and Alemtuzumab for People With Refractory or Relapsed Chronic and Acute Adult T-cell Leukemia (ATL)
IL-21
• Proliferation of Naive T cells• Expansion of CD8+ T cells
(coop. with IL-7/15)• Apoptosis of B cell lymphoma
– DLBCL– Mantle cell
• Clinical trial (20 NHL pts)– 11 SLL/CLL, 9 Follicular– IL-21 weekly x 4 + rituximab
• OR 42%: 3 CRs, 5 PRsLossos. Blood 2015Timmerman. Clin Can Res. 2012
• Citoquinas
• Virus Oncolíticos
• Inmunoterapia celular T
Gene Therapy with Self-Replicating Viruses (ONYX)
RbRAS
12S
13S
E1A E1B
Síntesis de DNA viralp53
p53E4orf6
55k
Apoptosis
19k
Homólogo bcl-2
Bloqueo del ciclo celular
p21
bax
Bartlett. Mol Cancer 2013
Modification Virus
Genetic deletions AdenovirusHerpes simplex virusVaccinia virusInfluenza virus
Use of tissue- or tumor-specific promoters
AdenovirusHerpes simplex virus
Gene replacement Polio virus
Citokines GM-CSF, IL12, CD40L
Adenovirus Herpessimplex
virus
Vaccinia virus
Influenza virus
Polio virus
• Citoquinas
• Virus Oncolíticos
• Inmunoterapia celular T
Adoptive Immunotherapy with Tumor-Infiltrating Lymphocytes (TILs)
Rosenberg and Restifo. Science. 2015
TILs for Myeloma (MILs)
Borrello. Sci Transl Med. 2016
Neoantigens-Tumor-specific T cells: towards “True” Personalized Medicine
Rosenberg. Nat Biotech. 2014
Genetic Modification of T cells
Restifo et al. Nat Rev Immunol. 2012
T cell Receptor VH/VL (scFv)a b
g ee
z
d
zCD3
TCR signaling
+
CAR
scFv
Chimeric Antigen Receptor (CAR) T cells
Kershaw et al. Nat Rev Cancer. 2013
T cell Receptor Costimulation
CAR Design Evolution
Maus et al. Annu Rev Immunol. 2014Brenner et al. Annu Rev Immunol. 2015
CD19 CAR T cell Trials: Summary of Clinical Results
DLBCL B-ALL CLL
Overall Response 80% 90-95% 57-90%
Complete Response
40-57% 70-90% 22-40%
PFS (@ 1 y) 50% 40-50% 50-100%
Clinical Complications following CAR-T
• Neurological symptomsØ Cytokine release/macrophage activation syndrome
Ø Fever, constitutional symptomsØHypotensionØHypoxia, lung distress
Lee et al. Blood. 2014
Moving Beyond CAR19
Klebanoff et al. Nat Med. 2016
Target Antigen DiseaseCD22 ALL
CD19/CD22 ALL
CD123 (IL-3 R) AMLCD33 AMLLewis Y AMLFolate Receptor b AML
FLT3 AML
New Targets for CAR T cells Immunotherapy for Hematological Malignancies
New Targets for CAR T cells Immunotherapy for Hematological Malignancies
Target Antigen DiseaseROR1g Mantle cell, CLL
CD30 Hodgkin
k light chain B cell NHL
New Targets for CAR T cells Immunotherapy for Hematological Malignancies
Target Antigen DiseaseBCMA Myeloma
CS1 Myeloma
CD138 Myeloma
CD19 Myeloma
CAR Design Evolution: “Towards 4th Generation” ( “CAR T 2.0”)
• Increase tumor specificity– Bivalent CARs
• Increase safety (On-target/Off-tumor toxicities)
– Inhibitory CARs– CAR-depleting elements
• Increase antitumor efficacy– Cytokine production– Harnessing costimulation– Blocking inhibition
IL-12
IL-15