biotecnologia no combate ao câncer - ufrj - início · para combate ao câncer ... terapia celular...
TRANSCRIPT
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)
Challenges and Solutions in Cancer Research and Treatment Club Med Mangaratiba, Rio de Janeiro, Brazil April 27-30, 2014