A Fantástica História da Imunoterapia do Câncer

Daniel Tabak

Centro de Tratamento Oncológico (CENTRON-RJ)

Diretor Centro de Transplante de Medula Óssea(INCA)1987-2004

Membro Titular,Academia Nacional de Medicina

Conflitos de Interesse

• Palestrante: Roche, Jannsen, Abbvie

• Consultoria científica : Roche, Janssen, Abbvie

A Fantástica História da Imunoterapia do Câncer

D'où venons-nous? Que sommes-nous? Où allons-nous?Paul Gauguin, 1897

ASCO 2017

2002

Demócrito (470-360 AC)

Jackson,R. Canadian Med Assoc.Journal, 1974,111,8271265 DC

Infecção e câncer

Gordon, S Eur. J. Immunol 2008

• Elie Metchnikof (1845-1916)

• Prêmio Nobel de Medicina em 1908

• Descreveu a fagocitose (imunidade inata)

1908

Paul Ehlich magischen kugeln,1890

“Imunização”

“Nature often gives us hints

to he profoundest secrets”

William B Coley,MD (1862-1936)

1888

John D Rockfeller,Jr e Elizabeth Dashiell

Coley,WB Am.J.Med.Sciences, May 1893

Mr. Fred Stein

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William Coley

James Ewing

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Hospital of Special Surgery (150 anos em 2015)

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MSKCC

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Helen Coley Nauts (1907-2001)

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1928Zbar,B JNCI 1970

1928

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• 7/10 pacientes apresentaram resposta (redução ou

erradicação do tumor)

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Anticorpos Monoclonais

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1979

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1979

1979

A Saga da Patente dos Anticorpos Monoclonais

1979

A Saga da Patente dos Anticorpos Monoclonais

1979

A Saga da Patente dos Anticorpos Monoclonais

1979

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Ciclo Imunidade - Câncer

Célula

Apresentadora de

Antígenos

SIPULEUCEL-T

Figure 1

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SCIENCE * VOL. 271 * 22 MARCH 1996

Figure 1

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PD-1 necessário para auto-tolerância

Ribas A Science 2018

RCC

Jama Oncology, 25/7/2019

Jama Oncology, 25/7/2019

Jama Oncology, 25/7/2019

Nobel Prize Medicine and Physiology 2018

Slide 27

Presented By Timothy Chan at 2017 ASCO-SITC Clinical Immuno-Oncology Symposium

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Science 8/6/2017

Science 8/6/2017

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fócit

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Rosenberg,S,Science,2015

Slide 7

Slide 8

Zelig Eshhar, Weizmann Institute,Israel

CAR T cell

84

CAR T CellsT cell

Viral DNA

Insertion

Tumor cell

Expression of

CAR

CAR T cells

multiply and

release cytokines

Tumor cell

apoptosis

CAR enables T cell to

recognize tumor cell

antigen

Antigen

Slide created by E Squared Communications

ASBMT2019

Emily’s story: Relapsed/refractory pediatric B-cell ALL

Tisagenlecleucel produz respostas em 81% na LLA-B pediátrica refratária e SLP 50% em 1 ano

ASBMT2019ASBMT2019

ASBMT2019ASBMT2019

Efficacy of 3 CAR T-cell products for Diffuse Large B-cell Lymphoma

Presented By Jeremy Abramson at 2019 ASCO Annual Meeting

Juna C ,Science 2018

Toxicidade de Células CAR-T

2002

Demócrito (470-360 ac)

Juna C ,Science 2018

Toxicidade de Células CAR-T

June, C ICML, Lugano 2019

June, C Science 2018

Slide 2

Slide 4

Brown CE et al. NEJM 2016

Brown CE et al. NEJM 2016

Mesothelin is a target antigen for solid tumors

Presented By Prasad Adusumilli at 2019 ASCO Annual Meeting

Regional delivery of mesothelin-targeted CAR T cells for pleural cancers: safety and preliminary efficacy in combination with anti-PD-1 agent

Presented By Prasad Adusumilli at 2019 ASCO Annual Meeting

Slide 16

Presented By Prasad Adusumilli at 2019 ASCO Annual Meeting

Limitações do uso de células CAR-T

• Capacidade de coletar e produzir o produto em pacientes

altamente tratados

• Disfunção das células T relacionadas à doença e terapia anterior

• Tempo de manufatura em portadores de linfoma

• Custo

Uma das respostas pode ser células CAR-T alogênicas...

NewScientist,2015

NewScientist,2015

Qasim W et al Science Transl Med 2017

NewScientist,2015ASH 2018

ASBMT2019

ASBMT2019

Model T Car 1920

Armored CARs

Presented By Jeremy Abramson at 2019 ASCO Annual Meeting

Armored CARs can enhance expansion <br />and persistence in vivo

IL-12 secreting anti-MUC-16ecto CAR T-cells Improves T-cell activation, expansion and ovarian tumor killing

Presented By Jeremy Abramson at 2019 ASCO Annual Meeting

2002

Demócrito (470-360 ac)

ASH,2017

Sivan A. Science 2015

Hampton, T Jama 2018

Science,2018

Jobin C. Science 2018

Antibiotics prescription decreases progression-free survival (PFS) and overall survival (OS) in patients with advanced cancers treated with PD1/PDL1 immune checkpoint inhibitors

Slide 4

NYT,1975

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Mecanismos de Ação dos Vírus Oncolíticos

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Após injeção intratumoral

de metástase cutânea

Primary overall survival (OS) from OPTiM, a randomized phase 3 trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of unresected stage IIIB/C and IV melanoma

Presented By Howard Kaufman at 2014 ASCO Annual Meeting

Slide 8

Presented By Howard Kaufman at 2014 ASCO Annual Meeting

Slide 13

Presented By Howard Kaufman at 2014 ASCO Annual Meeting

Time to Response And Duration of Response

Presented By Howard Kaufman at 2016 ASCO Annual Meeting

Slide 19

28/10/2015

May 15,2016

ASCO2016

ASCO2016

2018

Cell,2017

Cell,2017

Cell,2017

2002

Demócrito (470-360 ac)

2002

Vírus MARABÁ (1983)

• Rabdovírus

• Associado à vesiculo estomatite

• Transmitido por moscas da areia

• Induz IFN após a infecção

• Pequena auto-imunidade pré-existente e pós exposição

• Prolifera exclusivamente no citoplasma (baixa genotoxicidade)

Marabá: vocábulo indígena (mayrabá) que significa filho do

estrangeiro com índia ou fruto da índia com o branco Wikipedia

2018

2018

2002

2002

CD3

CD3

The Lancet 2001https://www.sciencephoto.com

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Slide 32

November 2018

ICML-Lugano-2019

ICML-Lugano-2019

Forbes N .Nature Reviews Cancer 2010

Imunoterapia e Nanotecnologia

Chowdhury S et al. Nature Medicine May 2019

Chowdhury S et al. Nature Medicine May 2019

A Fantástica História da Imunoterapia do Câncer

D'où venons-nous? Que sommes-nous? Où allons-nous?Paul Gauguin, 1897

A revolution in cancer care<br />>2000 immunotherapy agents in development

Tang Ann Oncol 2018

Uma Revolução no Tratamento do Câncer

> 2000 agentes imunológicos em desenvolvimento

"Before Alamein we never had a victory. After Alamein we never had a defeat.”(1942)Após a vitória em El Alamein,1942

Linfócitos T

CâncerCélula Dendrítica

Macrófago

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