Workpackage 7 SIMULATOR ASSESSMENT: PRECLINICAL TESTS PierLuigi Lollini University of Bologna UniBO,

1
Workpackage 7 SIMULATOR ASSESSMENTPRECLINICAL
TESTSPier-Luigi LolliniUniversity of Bologna
(UniBO),Bologna, Italywww.lollini.it
2
TUMOR IMMUNOLOGY
The immune system recognizes and kills tumor cells
Apply to cancer patients
Does immunity prevent cancer?
Cancer immunotherapy
Cancer immunoprevention
Antibodies
Cytokines immune stimulants
Therapeutic vaccines
Antibodies
Cytokines immune stimulants
Prophylactic vaccines
3
HER-2/neu TRANSGENIC MICE AND THE TRIPLEX VACCINE
J. Exp. Med. 194 1195, 2001 Cancer Res. 64
4001, 2004 Hum. Gene Ther., 2009
BALB/c (H-2d) FVB (H-2q)
4
PREVENTION OF MAMMARY CARCINOMAJ. Exp. Med. 194
1195, 2001 Cancer Res., 67 11037, 2007
5
FINDING THE OPTIMAL/MINIMALVACCINATION SCHEDULE
Redundant?
Insufficient
6
VACCINATION PROTOCOLS
7
KAPLAN-MEIER SURVIVAL CURVES
8
IN SILICO vs IN VIVO CURVES
9
TUMOR MULTIPLICITY
10
IMMUNE MONITORING AND BIO-BANKING

• Leukocytes count and cytofluorometric evaluation
  of antibodies, T (CD3, CD4, CD8), B and NK cells
  were performed at various time-points
• Biological samples were collected from all
  experimental groups
• More than 800 serum samples collected throghout
  the experiment, stored frozen. Available for
  antibody (e.g. isotype) or cytokine
  determinations
• At necropsy
• mammary carcinomas, split into three parts
  frozen, formalin-fixed, frozen for
  immunohistochemistry
• lungs, fixed for metastasis evaluation

11
ANTI-VACCINE ANTIBODIES

• To prevent mammary carcinoma, vaccine-elicited
  antibodies MUST
• Reach threshold 1 as early as possible
• Stay above threshold 2 for the entire lifespan of
  the mouse
• Low antibody level at 9 weeks of age predicts
  failure (i.e. tumor onset) at 6-12 months of age

12
CONCLUSIONS

• The Genetic and Heuristic vaccination schedules
  resulted in a tumor-free survival shorter than
  the Chronic, and similar to the Early
  schedule.Predicted efficacy of the Genetic and
  Heuristic schedules was overestimated.
• Analysis of tumor multiplicity showed
• That the Genetic schedule indeed prevented more
  tumors than the Heuristic and Early schedules
• A better agreement with the predicted efficacy of
  the Genetic and Heuristic schedules
• Antibody response correlated with protection from
  tumor onset and predicted tumor-free survival

13
FEEDBACK FOR SIMULATOR DESIGN AND IMPROVEMENT

• Improve simulation of precocious vaccine-induced
  immune responses to better reflect experimental
  findings
• Intensity of early vaccinations should be added
  to the constraints of the genetic algorithm
• Use data from the current experiment for a second
  round of simulator tuning
• All simulations of immune responses in
  adult/elderly hosts should consider aging of the
  immune system