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TRANSCRIPT
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São Paulo 20-03-2019
Martín Bonamino
Instituto Nacional de Câncer (INCA)
FIOCRUZ
Imunoterapia do câncer
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Funções do Sistema Imune
• Detectar disturbios na fisiologia celular e de tecidos
• Eliminar o agente causal
• Re-estabelecer a homeostasia tecidual
• Exemplos: dano tecidual, infecções, célulastumorais
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Componentes do Sistema Imune
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Células da imunidade inata - ativação
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Resposta imune
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Ativação de linfócitos T
T Limphocyte
APC/
Target cell
Multiple signals required
T lymphocyte activation
Janeway`s Immunobiology – 9th edition
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Nature Reviews Immunology 3, 984-993 (December 2003) | doi:10.1038/nri1246
Ativação de linfócitos T
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Ag+
CD4+Foxp3-
Tn
Effector T cell Regulatory T cell
Adaptive Natural
+IL-4
Th2
IL-4
IL-5
IL-13
GATA-3
+IL-6
+TGF-
Th17
IL-17
RORt
Th1
IFN-
T-bet
+IFN-
+IL-12
Th9
IL-9
PU.1
+IL-4
+TGF-
Tfh
Contact
Bcl-6
c-Maf
+IL-6
+IL-21
+IL-27
Tp
CD4+Foxp3+
nTreg
Contact
Foxp3
iTreg
TGF-
Foxp3
+IL-2
+TGF-
Foxp3-
IL-10
+IL-10
Dr. João Viola – slide do autor
Diferenciação de linfócitos T
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Há tumores que nunca vemos?
Células transformadas sãoeliminadas por mecanismos de
imunovigilância
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O que é enxergado pelo sistema imune?
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Células Natural Killer - ativação
https://commons.wikimedia.org/wiki/File:Antibody-dependent_cell-mediated_cytotoxicity.png
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Resposta de linfócitos T contra tumores
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Resposta de linfócitos T contra tumores
Pré-requisitos:
-Antígeno-Ativação da imunidade inata
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http://www.invivogen.com/review-damp
Ativação endógena da imunidade inata
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Adaptado de Zitvogel et al, Nat Rev Immunol 2008
Estresse celular e ativação do sistema imune- Estresse pelo microambiente- Morte celular imunogênica- Estresse induzido pela terapia
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Estresse Celular e Ativação de APCs
Zitvogel et al, Nat Rev Immunol 2008
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Proteínas mutadas são reconhecidaspela imunidade adaptativa
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Estresse Celular e Ativação de APCs
Zitvogel et al, Nat Rev Immunol 2008
Lymph node – Antigen Presentation
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Mutações vs resposta imune – o que é reconhecido pelos linfócitos?
O que é realmente visto pelos linfócitos T?
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Mellman, Coukos e Dranoff Nature (2011) 480:480
Resposta Imune contra Tumores
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Adaptado de Zitvogel et al, Nat Rev Immunol 2008
Estresse celular→ ativação e recrutamento de leucócitos→modulação do microambiente
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Como são os tumores que vemos?
DOI: 10.1158/0008-5472.CAN-11-4094 Published July 2012
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→ O câncer não é um processo autônomo de células
“O câncer é uma doença do tecido, em
particular, de um tecido que chamamos
tumor.”
Weinberg, The Biology of Cancer (2007)
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Schreiber et al. Science 2011
Teoria dos 3 “Es” do câncer
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Um zoom na ativação de linfócitos T
Chave para as novas imunoterapias
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Nature Reviews Immunology 3, 984-993 (December 2003) | doi:10.1038/nri1246
Ativação de Linfócitos T
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Ativação de Linfócitos T
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Freeman G J et al. J Exp Med 2006;203:2223-2227
Exaustão
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AS NOVAS IMUNOTERAPIAS
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Receptores Inibitórios
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Bloqueio de CTLA-4
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T Cell Activation by TCR and Co-stimulation Through CD28
Dendritic
cell T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
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CTLA4 Receptors Are Up-Regulated Following T-Cell Activation
Dendritic
cell T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
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Dendritic
cell T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
CTLA4 Negatively ModulatesT-Cell Activation
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Dendritic
cell T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
Blocking Antibodies to CTLA4 Allow Positive Signaling from Costimulatory Molecules to T Cells
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734-1736.
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Adapted from ASCO 2008 meeting. Suzanne Louise Topalian, MD
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Ipilimumab Improves Overall Survival compared to control
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What mediates anti-CTLA4-induced durable tumor regressions?
Brown:
CD8+ T
cells
Blue:
melanoma2005Durable
response
> 5 years
Treatment with anti-CTLA4
antibodies
The great majority of responses last years without relapses:
- Longest responder: Ongoing since May 2001
- Response rate: ~10%
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Metastatic Melanoma Response to Ipilimumab
Before Ipilimumab
04/22/11
After Ipilimumab
08/05/11
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Bloqueio de PD1
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Células tumorais são capazes de inibir linfócitos efetores infiltrantes
http://www.bmsimmunooncology.com/tumor-immunosuppression.aspx
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Receptores inibitórios
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Revigorando células T exaustas
Freeman G J et al. J Exp Med 2006;203:2223-2227
© 2006 Rockefeller University Press
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Expressão de PD-1L por células tumorais e/ou microambiente
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Esforços para personalização das imunoterapias
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Expressão de PD-1L por células tumorais e/ou microambiente
Marcação periférica Marcação difusa
HPV-Associated Head and Neck Squamous Cell Carcinoma
Lyford-Pike et al. CanRes 2013
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Esforços para predizer a resposta aos ICBs
Abordagens Reducionistas (ex. IHQ para PD-L1)
Abordagens Holisticas – Estudos mecanísticos
Abordagens Reducionistas→ novos marcadores e algoritmos
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Abordagem ultra - holística
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Carga de Mutações e Resposta
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Nature, v.547, p165
Vacinas com Peptídeos de Neoantígenos(medicina ultra personalizada)
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Vacinas, Vírusoncolíticos,Ativadores da imunidade inata
Bloqueio de checkpoint Imunológico
Barros et al, 2018, adaptado de Mellman, Coukos e Dranoff Nature (2011) 480:480
Quimioterapia,Radioterapia
Interferências na resposta antitumoral
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Imunoterapias alvejando o microambiente
DOI: 10.1158/0008-5472.CAN-11-4094 Published July 2012
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Alteração do micro-ambiente
N Engl J Med 2008; 358:2704-15
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Uso do sistema imune para tratamento do câncer – uma história revisitada
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Uso do sistema imune para tratamento do câncer – uma história revisitada
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Células da imunidade inata - ativação
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BCG
Mycobacterium bovis atenuado – vacina para tuberculose
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Imiquimod
• 1º ligante de TLR consolidado na clínica
• Tratamento tópico de tumores cutâneos
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Neville JA et al. (2007) Management of nonmelanoma skin cancer in 2007 Nat ClinPract Oncol 4: 462–469 doi:10.1038/ncponc0883
Figure 6 Treatment of a basal-cell carcinoma with imiquimod
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Vírus Oncolítico
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Fármacos antitumorais tambémpodem ter efeito imunológico
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Zitvogel et al, Nat Rev Immunol 2008
Estresse celular e sinalização imune
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Modulação do microambiente tumoral baseada emquimioterapia
Kersten et al, Frontiers in Immunol 2015
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Klemm and Joyce, Trends in Cell Biol 2015
Modulação do microambiente tumoral baseada emterapia alvo
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IL-2
IFN
IL-15
IL-21
Peptide
vaccine
DC vaccine
Genetic
vaccine
OX40
CD137
CD40
PD1CTLA4
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Blocking the Inhibiting
(Checkpoints)
Regulação da célula T
Turning up the activating
Mellman I et al. Nature 2011;480: 480-489.
Reprinted by permission from Macmillan Publishers
Ltd: Nature. Mellman I et al. Nature 2011;480:480.
Materiais destinados exclusivamente a profissionais de saúde habilitados a prescrever e/ou dispensar medicamentos. Novembro/2016
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Imunoterapias celulares
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IL-2
IFN
IL-15
IL-21
Peptide
vaccine
DC vaccine
Genetic
vaccine
OX40
CD137
CD40
PD1CTLA4
T cell cloningTCR or CAR
genetic engineering
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Microambiente tumoral
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78
Tumor Infiltrating Lymphocytes
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Immunotherapy
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Rosenberg and Dudley, Curr Opin Immunol 2009
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Rosenberg and Dudley, Curr Opin Immunol 2009
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ACT: Transferência adotiva de células
NMA: Não Mieloablativo
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E quando não há resposta antitumoral prévia?
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E quando não há resposta antitumoral prévia?
Truques para “enganar" células T
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Anticorpos Bi-específicos
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Weidle et al, Cancer Gen Proteom 2013
mAbs: estruturas e alternativas
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Frankel and Baeuerle, Curr Opin Chem Biol 2013
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IL-2
IFN
IL-15
IL-21
Peptide
vaccine
DC vaccine
Genetic
vaccine
T cell cloningTCR or CAR
genetic engineering
OX40
CD137
CD40
PD1CTLA4
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Redirecionamento genético de linfócitos como terapia
Receptores Quiméricos da Antígenos - CARs
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CD19 – an ideal cell therapy target
• CD19 expression is restricted to B cells and possibly follicular dendriticcells
• CD19 is not expressed on pluripotent bone marrow stem cells
• CD19 is expressed on the surface of most B cell malignancies
• Antibodies against CD19 inhibit growth of tumor cells
Adapted from Brentjens and Sadelain, slide from the authors
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Kochenderfer et al, Blood 2010
NHL – B cells
CAR 19-28z
Clinical trials - 2nd generation CAR
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Porter DL, et al. N Engl J Med 2011Kalos M, et al. Sci Transl Med 2011
CLL-B
CAR 19-BBz
10e7 cells
Clinical trials - 2nd generation CAR
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US$ 475.000/paciente
US$ 295.000/paciente
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Dezembro 2013
Imunoterapias aprovadas pelo FDA até 2019
- Anticorpos de bloqueio de checkpoint imunológico(CTLA-4, PD-1, PD-L1)
- Compostos químicos estimuladores do sistema imune
- Vacinas de ativação de células dendríticas (PSMA)
- Vírus Oncolíticos
- CAR-T (CD19) para LLA-B e linfoma B
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Vacinas, Vírusoncolíticos,Ativadoresda imunidadeinata
Bloqueio de checkpoint Imunológico
Transferência adotiva de linfócitos(CARs, TILs)
Adaptado de Barros et al, 2018, baseado em Mellman, Coukos e Dranoff Nature (2011) 480:480
Quimioterapia,Radioterapia
Interferências na resposta antitumoral
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Schmid et al. JOncology 2010
Ambiente pró-inflamatório
Ambiente regulatório pró-reparo
Macrophagepolariza6on