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