Marianna Nuti
Dipartimento di Medicina Sperimentale, UP Terapie Cellulari Policlinico Umberto I,
BIOMARKERS : tra promesse e speranze
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
What have we learned this year from the laboratory?
• Forget the single biomarker…..
• Different biomarkers could be significant during treatment to make clinical decisions
• Tumor microenvironment and microbioma the BIG issues
• Increasing number of small clinical trials ”proof of concept”with translational end points
• Immunomonitoring of pts blood samples is increasing
Looking for biomarkers……..
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Baseline lymphopenia should not be used as exclusion criteria in ICI early clinical trials
Sun R et al, EJC 2017
Baseline “old” biomarkers: LDH
revised immune role
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Marabelle, A ESMO 2017
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Champiat S et al. Clin Cancer Res 2017
Hyperprogressive disease: new pattern of progression
in cancer pts treated by anti-PD-1/PD-L1
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
LDH an immunosuppressive molecule targeting MSDC, VEGF and the TME
Seth P, et al. Cancer Res 2017
Hyperprogressive disease mediate by ICI
• IFN-gamma induces PD-L1 and can initiate a “diabolical circuit” leading to rapid tumor progression
• PD-L1 can be modulated in several cells immune and TME
• Activation of TIL could trigger local inflammation, angiogenesis, tissue remodeling,metabolism
modification (LDH)
• PD1/PD-L1 blockade can affect alternative signaling networks in the tumor favouring tumor progression
Possible suggestions: Switch to PD-L1 treatment, anti-IDO,
Other anti-immunosuppressive molecules
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Not all patients with an immunological response to pembro (anti-PD1) have clinical benefit
Anti-PD1 response is associated to the exspansion of a SIGNIFICANT NUMBER OF SPECIFIC T CELLS
Huang,AC et al, Nature 2017
Anti-PD1 response is associated to the exspansion of a SIGNIFICANT NUMBER OF SPECIFIC T CELLS
• Most pts demonstrated immunological response ( CD8 T ex cells Ki67 pos)
• Clinical failure due to:
1.Inability to induce immune reinvigoration
2.Imbalance between T cell reinvigoration and tumor burden
• Magnitude of reinvigoration of circulating T ex cells in relation to tumor burden correlates with clinical response
29 pts stage IV melanoma with prior anti-CTLA4 treatment
treated with PEMBRO
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Partial responders….stable disease…
•Pts that should be characterized further. Should they receive another immunotherapy (combined/alternate) such as anti immunosuppression or immune
activation?
•Is timing an important factor? (before balance tips dramatically vs immunosuppression)
•Should we design studies to investigate in the
laboratory this set of pts?
Targeting TME and vascular network to allow
lymphocyte trafficking
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
CD4+ and ICI regulate vascular normalization in tumors
De Palma M, Immunity 2017; Tian L ,Nature 2017
Pazopanib exerts a potent immunopriming effect on DCs by downregulating β-catenin pathway
pErk 1,2
NF-κb (p50) β-catenin
Immature DCs Mature DCs
Pazopanib CD14+
HLA-DR CD40 CCR7 CD40 PD-L1
T cell proliferation
IL-10 IL-12
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Beta-catenin signaling in DCs induces immune tolerance
Suryawanshi A et al. Frontiers in immunology 2016
Immunomonitoring of mRCC patients
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Zizzari,I unpublished
Radiotherapy before Pazopanib changes immune
repertoire in mRCC patient
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Longitudinal immunomonitoring of pts during cancer therapies
• Time points have to adapt to the different therapies and do not necessarily match to clinical outcome (PD1 early changes, TKI and chemo later)
• The immune fitness of the patient must be studied starting at diagnosis
• New methodologies are coming to make the immunoassays easier and quicker
• Oncologists should try to include immunological
parameters into clinical practice
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Added value of peripheral blood biomarkers: Take home message from initial immunomonitoring studies (….real life)
• Chance to monitor at different time points treatment induced changes
• Peripheral blood biomarkers: a partial and dinamic picture strongly
indicative of tumor immune scenario. Modifications of the repertoire /function of circulating immune cells is an early event ( earlier than tumor response)
• Circulating cytokine and chemokine can anticipate the changes in target populations, can be alert of manifest immunesuppressive status, are indicators of activated recirculation and/or cross-talk of immune cells
• All data should have a longitudinal setting per patient
• We need to learn from our patients:….longsurvivors, excellent responders, off-label etc…
• Novel “mentality” in designing treatment protocols and clinical
trials…Immunomonitoring guided trials
IPILIMUMAB : novel mechanisms of immune interaction
Must remember that all these “drugs”
are antibodies……the example of ipi
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Michielin O, ESMO 2017
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Michielin O, ESMO 2017
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
Traditional biomarker concept
Presented By Michael Postow at 2017 ASCO Annual Meeting
Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010
