VACINAS CONTRA O CÂNCER

Ana Paula Lepique Laboratório de Imunomodulação

Departamento de Imunologia ICB – USP

alepique@icb.usp.br

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

WHY VACCINE?

- SPECIFICITY

- MEMORY

- MAY BE USED TOGETHER WITH OTHER ANTI-TUMOR STRATEGIES

ANTI-CANCER VACCINES

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

ANTI-TUMOR IMMUNE RESPONSES

TUMOR EVASION MECHANISMS: SUPRESSOR CYTOKINES, CHRONIC ANTIGENS (T CELL

EXHAUSTION, Treg, TAM, NAM, MDSC, LEUKOCYTOSIS

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

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

Immunomodulation – characterization of local and systemic tumor effects design of tools to interfere in tumor effects and increase vaccine efficacy

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

*

* *

*

*

*

INFLAMMATION X ANTIGEN PRESENTATION

DENDRITIC CELL

T CELL

HLA-I

HLA-II TCR

CD80 CD28

IL-12R STAT4

IFNg

IL-2/CD25

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

MHC-II DEPENDENT EFFECT

*

WARBURG EFFECT

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

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

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