vacinas contra o cÂncer - abc · vacinas contra o cÂncer ana paula lepique laboratório de...
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VACINAS CONTRA O CÂNCER
Ana Paula Lepique Laboratório de Imunomodulação
Departamento de Imunologia ICB – USP
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23803 papers in PudMed 1369 clinical trials registered at NIH
- prostate - lung
- mesotheliomas - -multiple mieloma
-pancreas - -lynphoma - melanoma
- head and neck - breast
- hepatocarcinoma - ovary
- intestine - glioma
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WHY VACCINE?
- SPECIFICITY
- MEMORY
- MAY BE USED TOGETHER WITH OTHER ANTI-TUMOR STRATEGIES
ANTI-CANCER VACCINES
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TUMOR ANTIGENS
Gonzalez-Angulo A M et al. Clin Cancer Res 2004;10:6215.
p53 expression in breast tumor BRC/ABL mutation in CML
Cai A et al. Clin Cancer Res 2012;18:5761.
Cancer/testis antigens
Simpson A et al. Nat Rev 2005;5:615.
Viral antigens
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ANTI-TUMOR IMMUNE RESPONSES
TUMOR EVASION MECHANISMS: SUPRESSOR CYTOKINES, CHRONIC ANTIGENS (T CELL
EXHAUSTION, Treg, TAM, NAM, MDSC, LEUKOCYTOSIS
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IMMUNOTHERAPY
- non-specific: cytokines – IL-2, IL-12 (is back on the game),
GM-CSF
anti-CTLA-4/anti-PD-1/PD-1L
Imiquimod – ativação da resposta inata
-Prophylatic vaccines–HPV. HBC
- Therapuetic vaccines – several strategies
-Adoptive cell transfer: activated lymphocytes, antigen
loaded mature DCs
-Antibodies: antibody mediated citotoxicity
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One should consider: Antigen - DNA x peptides (proteins): low immunogenicity (virus like particles – prophylatic vaccines) Vectors – possible to “decorate” with adjuvants (the same can be done with naked DNA) adenovirus, lentivirus, Listeria anti-vector immune responses may be a problem Adjuvants – inflammation is necessary for efficient antigen presentation restricted use due to adverse effects Patient conditions – leukocytosis, regulatory T cells, metastasis immunossupression
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Immunomodulation – characterization of local and systemic tumor effects design of tools to interfere in tumor effects and increase vaccine efficacy
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DC BASED IMMUNIZATION
Ativação de
células T
específicas
Ativação de
células T
espcíficas
Vacina com DC
pulsadas com
antígeno
Vacina com DC
transfectada com
DNA
Plasmídeo codificante do
Ag tumoral
DCs pulsadas com antígeno
tumoral
DCs transfectadas com plasmídeo que codifica Ag
tumoral
APC apresenta antígeno tumoral
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*
* *
*
*
*
INFLAMMATION X ANTIGEN PRESENTATION
DENDRITIC CELL
T CELL
HLA-I
HLA-II TCR
CD80 CD28
IL-12R STAT4
IFNg
IL-2/CD25
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p=0.049
p=0.049
p=0.0015
p=0.02
p=0.0001
p=0.0033
B CELL ACTIVATION EX VIVO MAY BE AN EFFICIENT APC
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MHC-II DEPENDENT EFFECT
*
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WARBURG EFFECT
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STAT3 total
Erk-P
Erk total
AKT total
STAT3-P
AKT-P
CREB-P
CREB total
ATF1-P
A
phospho
total
Akt
NFkB
CD45
CD45+
12%
CD45-
CD45- CD45+ B
LOCAL TUMOR EFFECTS – CELL SIGNALING
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0
1
2
3
4
5
6
7
8
9
10
rapamycin 3BrPA R+3BRPA control
% o
f to
tal c
ells
total inflammatory infiltrate
0
100
200
300
400
500
600
0 2 4 6 8
tum
or
volu
me
(mm
3)
days after initiating treatment
control
3-BrPA
Rapamycin
3BrPA/Rap
-0,1
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
%CD4 %CD8
% o
f to
tal
tum
or
cell
s
Tumor infiltrate
control
3BrPA
Rapamycin
3Br+Rap
0
5
10
15
20
25
Rapamycin 3BrPA R+BrPA control
iNO
S in
du
ctio
n (
LPS,
IFN
gam
a
stim
ula
ted
/co
ntr
ol)
METABOLIC INHIBITORS BLOCK TUMOR GROWTH AND ENHANCES ANTI-TUMOR CD8 RESPONSES
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CONCLUSIONS
ANTI-CANCER VACCINES ARE CHALLENGING HOWEVER, UNDERSTANDING IMMUNE RESPONSES, EVASION MECHANISMS, AND TUMOR SYSTEMIC EFFECTS WE MAY BE ABLE TO DESIGN EFFICIENT ANTI-TUMOR VACCINES