Download Prise en charge médicale des métastases cérébrales

Can cancer brain metastases
be treated using
humanized monoclonal antibodies:
a pilot pharmacological study
Guilhem BOUSQUET, Anne JANIN
University Paris VII, UMR_S1165
Brain metastases
• Most frequent brain tumors
• 15-40% patients with metastatic cancer –
even more in autopsy series
• Lung, breast, melanoma
• Low median survival
• Increased incidence in the last 10 years
because…
…of
• better control of localisations outside
the central nervous system
• an inadequate transfer through
the blood brain barrier (BBB)
of most chemotherapeutic agents
Blood Brain Barrier
• Tight continuous junctions
• Prevent the free paracellular diffusion
of water-soluble molecules, >150Da
• Murin models: BBB permeable,
but concentrations pharmacologically inactive
Reese, J Cell Biol 1967
Wilhelm, Acta Neurobiol Exp 2011
Lockman, Clin Cancer Res 2010
Brain metastases and breast cancer
• 5-15%
• Risk factors:
– Young age
– Black women
– Triple negative and HER2-overexpressed
phenotypes
• Median survival: less than 12 months
HER2 and brain metastases
• After treatments for localized breast cancer
– Meta-analysis on 6738 patients
– Trastuzumab-based chemotherapy
– RR of brain metastases=1.57
• In case of metastatic disease
– Incidence of brain metastases: 20-48%
Leyland-Jones, JCO 2009
Bria, Breast Cancer Res Treat 2008
Chemocurability …
From Swain SM et al. N Engl J Med 2015.
… with anti-HER2 antibodies
Brain metastases are challenging
our daily practice
Trastuzumab
• After intra-veinous injection
– Very low passage from blood to brain
– Ratio 300/1 à 1000/1
– 148 kDa
• After intra-thecal injection
– Proof of concept in case of carcinomatous
meningitidis
– Empirical doses ranging from 25 to 100mg
Pestalozzi, 2000
Stemmler, 2006
Mir, 2008
Trastuzumab
• After intra-veinous injection
– Very low passage from blood to brain
– Ratio 300/1 à 1000/1
– 148 kDa
• After intra-thecal injection
– Proof of concept in case of carcinomatous
meningitidis
– Empirical doses ranging from 25 to 100mg
Pestalozzi, 2000
Stemmler, 2006
Mir, 2008
A sequential pharmacological
pilot study
• 36-year-old woman
• HER2-overexpressing breast cancer
• Liver metastases, complete response under
trastuzumab treatment
• Resistant brain metastases
• Ventricular and lumbar reservoirs
• Intra-thecal injections of trastuzumab
Overexpression of HER2
Cerebellous metastasis
Treatments
Sampling
Pharmacology
Pre-C1
Pre-C7
Post-C10
Bousquet G, Darrouzain F, Janin A. J Clin Oncol 2015
A rapid clearance of the drug
from the cerebro-spinal fluid
• Cynomolgus monkeys
– Trastuzumab, lumbar catheter,
– 6 males and 6 females received weekly intrathecal
injections.
– A rapid decrease in CSF concentration of trastuzumab.
– A long terminal half-life of about 10 hours, independent
from the dose administered
• Phase I intra-thecal administration of rituximab
(anti-CD20)
– Rapid clearance from the CSF
Braen, Int J Toxicol 2010
Rubenstein, Blood 2013
• Receptors FcRn = efflux
• Rat model, after direct intra-cranial administration
of a monoclonal IgG1
Cooper, Brain Res 2013
Perspectives
• Chemical modification of the Fc fragment
• Engineered Fab fragment antibodies