Biotecnologia no

combate ao câncer

Martin Bonamino

I SBERJ – 09-2013

Microambiente tumoral

Biotecnologia como abordagem

para combate ao câncer

• Bloqueio de fatores estimuladores

• Anticorpos Monoclonais específicos para o tumor

• Anticorpos Monoclonais imuno-moduladores

• Terapia celular/gênica

Scott et al, Nat Rev Cancer 2012

Weidle et al, Cancer Gen Proteom 2013

mAbs: estruturas e alternativas

Anticorpos Monoclonais: tumor como alvo

Rituximab – mAb quimérico anti CD20 - IgG

Rituximab – mAb quimérico anti CD20 - IgG

Cetuximab – mAb quimérico anti EGFR – IgG1

Panitumumab – mAb humanizado anti EGFR – IgG2

Scott et al, Nat Rev Cancer 2012

Scott et al, Nat Rev Cancer 2012

Anticorpos Monoclonais: sistema imune como alvo

Bloqueio de CTLA-4

Adapted from ASCO 2008 meeting. Suzanne Louise Topalian, MD

T Cell Activation by TCR and

Co-stimulation Through CD28

Dendritic

cell T cell

MHC

B7

TCR

CD28

Antigen

CTLA4

CTLA4 Receptors Are Up-Regulated Following

T-Cell Activation

Dendritic

cell T cell

MHC

B7

TCR

CD28

Antigen

CTLA4

Dendritic

cell T cell

MHC

B7

TCR

CD28

Antigen

CTLA4

CTLA4 Negatively Modulates

T-Cell Activation

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.

Survival Rate Ipi + gp100 N=403 Ipi + pbo

N=137 gp100 + pbo

N=136

1 year 44% 46% 25%

2 year 22% 24% 14%

Ipilimumab Improves Overall Survival

compared to control

Ipi + gp100 (A)

Ipi alone (B)

gp100 alone (C)

1 2 3 4 Years

What mediates anti-CTLA4-induced durable tumor regressions?

Brown:

CD8+ T

cells

Blue:

melanoma 2005 Durable

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%

Metastatic Melanoma Response to Ipilimumab

Before Ipilimumab

04/22/11

After Ipilimumab

08/05/11

Years

Immunotherapy

Pe

rce

nt

ali

ve

1 2 3 0

Targeted therapy

Pe

rce

nt

ali

ve

1 2 3 0 Years

Immunotherapy vs targeted therapy for melanoma

Bloqueio de PD1

Células tumorais são capazes de matar

linfócitos efetores infiltrantes

http://www.bmsimmunooncology.com/tumor-immunosuppression.aspx

Expressão de PD-1L por células tumorais

Marcação periférica Marcação difusa

HPV-Associated Head and Neck Squamous Cell Carcinoma

Lyford-Pike et al. CanRes 2013

Enhancing Immune Responsiveness

PD1 Ab (MDX1106)

Phase I, single dose,

Tolerable, responses in

Colon, Lung, MM, RCC

Brahmer, ASCO 2008

PDL1 Ab

Phase I trial ongoing

PD1 Ab Phase 1,

multi dose, tolerable,

PRs in RCC, MM and

Lung, Sznol, ASCO 2010

Durable partial regression of metastatic

kidney cancer following 3 doses of

anti-PD-1 (10 mg/kg)

01/15/08, pre-Rx 07/22/08 04/22/08

72 year old male with RCC metastatic to lung, LN, muscle,

bone, pancreas. Prior therapies included HDAC inhibitor,

sunitinib, and sorafenib.

Brahmer et al., JCO 2010

33

Percent Change in Tumor Burden in RCC Patients

*Patients treated with the 10 mg/kg dose †Upper horizontal line denotes no change; lower horizontal line denotes 30%

decrease (RECIST threshold for PR).

Abbreviations: PR = partial response; RCC = renal cell carcinoma; RECIST = Response Evaluation Criteria in Solid Tumors

Outros alvos de intervenção

Kwek et al, Nat Rev Cancer 2012

Anticorpos Bi-específicos

Frankel and Baeuerle, Curr Opin Chem Biol 2013

IL-2

IFN

IL-15

IL-21

Peptide vaccine

DC vaccine

Genetic vaccine

OX40

CD137

CD40

PD1 CTLA4

T cell cloning TCR or CAR

genetic engineering

Terapia celular

39

Tumor Infiltrating Lymphocytes

Immunotherapy

Rosenberg and Dudley, Curr Opin Immunol 2009

Rosenberg and Dudley, Curr Opin Immunol 2009

ACT: Transferência adotiva de células

NMA: Não Mieloablativo

Terapia gênica

Transferência gênica de TCR

Receptores Quiméricos de Antígenos (CARs)

Redirecting lymphocyte specificity for tumor elimination

Chimeric Antigen Receptor (CAR)

Adapted from Pule et al, 2003

MHC-independent antigen

recognition;

High affinity for the antigen;

Independent of patient-

derived TILs

Multiple signals required

T lymphocyte activation

Acuto et al., 2003

Chimeric Antigen Receptor (CAR)

1st generation

2nd generation

3rd generation

Chimeric Antigen Receptor (CAR)

Clinical trials – 1st generation CAR

Nature Medicine, 2008

Sadelain et al, Cancer Disc 2013

Kochenderfer et al, Blood 2010

NHL – B cells

CAR 19-28z

Clinical trials - 2nd generation CAR

Porter DL, et al. N Engl J Med 2011 Kalos M, et al. Sci Transl Med 2011

CLL-B

CAR 19-BBz

Clinical trials - 2nd generation CAR

10e7 cels

Grupp, et al. N Engl J Med 2013

Sleeping Beauty Transposon

Chicaybam et al, 2013

Sleeping Beauty Transposon

Chicaybam et al, 2013

Strategies to circumvent adverse effects

Chicaybam et al, 2011

a)

b) d)

c)

mbonamino@inca.gov.br

Challenges and Solutions in Cancer Research and Treatment Club Med Mangaratiba, Rio de Janeiro, Brazil April 27-30, 2014