Riccardo Danielli
Medical Oncology and Immunotherapy, Department of Oncology University Hospital of Siena, Istituto Toscano Tumori
SIENA, ITALY
Immunotherapy and metronomic therapy
AIOM Meeting
Cancer metronomic therapy
February 26, 2016
Surgery
Radiotherapy
Chemotherapy
Immunotherapy
Evolving Therapeutic Options for
Cancer Treatment
Science, 2013
Science 2013
Adapted from: Cheng.G, et al. Cancer Immunol Immunother. 2013
IMMUNOLOGIC ROLE OF CHEMOTHERAPEUTIC AGENTS
Immune check-point(s) blockade-based
combinations/sequences holding the most promise for future development
• Vaccines
• Cytokines
• Tumor microenvironment modulating agents
• Selected chemotherapeutic agents
• Targeted therapies
• Epigenetic therapies
Heritable changes in gene expression not based
on modifications of the DNA sequence
EPIGENETICS
EPIGENETIC AND CANCER
DNA me th yla tion
Cancer development and progression
GLOBAL genomic DNA HYPOMETHYLATION
GENE-SPECIFIC promoter
HYPERMETHYLATION
DNA methylation
Histone modifications
MicroRNA gene silencing
EPIGENETIC MODIFICATIONS
PHARMACOLOGICALLY REVERSIBLE
DNMTs inhibitors (DNMTi)
HDAC inhibitors (HDACi)
Maio et al, unpublished
5-aza-2’deoxycytidine is devoid of antitumor activity ?
But low prolonged doses of 5-aza-2’deoxycytidine seems to be more active than high doses
Issa JP et al. Blood 2004 Kantarjian H. et al. Blood 2007
0,00E+00 5,00E‐04 1,00E‐03 1,50E‐03 2,00E‐03 2,50E‐03 3,00E‐03
NY‐ESO‐1/b‐actin molecules
melanoma cell lines
NY‐ESO‐1 expression
CTRL AZA 1µM DAC 1µM SGI 1µM
MODULATION OF NY‐ESO‐1 EXPRESSION IN HUMAN MELANOMA CELLS BY DHA
Maio unpublished
CTRL AZA 0.1µM AZA 0.5µM
HLA‐ABC (W6/32)
CTRL DAC 0.1µM DAC 0.5µM DAC 1µM DAC 5µM DAC 10µM
Mel 195 AZA
Mel 195 DAC
Ctrl SGI 0,1µM SGI 0,5µM SGI 1µM
Mel 195 SGI‐110
Ctrl SGI 0,1µM SGI 0,5µM SGI 1µM SGI 5µM
Ctrl SGI 0,1µM SGI 0,5µM SGI 1µM SGI 5µM SGI 10µM
Ctrl SGI 0,1µM SGI 0,5µM SGI 1µM SGI 5µM SGI 10µM
Mel 313 SGI‐110 Mel 313 DAC Mel 313 AZA
Mel 275 DAC
Mel 275 AZA
CTRLAZA 0.1µM AZA 0.5µM AZA 1µM
CTRL DAC 0.1µM DAC 0.5µM DAC 1µM DAC 5µM DAC 10µM
Ctrl SGI 0,1µM SGI 0,5µM SGI 1µM SGI 5µM SGI 10µM
Mel 275 SGI‐110
Maio unpublished
Dose-dependent induction of NY-ESO-1 expression in human melanoma cells by DHA
0,00E+00 2,00E‐04 4,00E‐04 6,00E‐04 8,00E‐04 1,00E‐03 1,20E‐03 1,40E‐03 1,60E‐03
0,00E+00 5,00E‐04 1,00E‐03 1,50E‐03 2,00E‐03 2,50E‐03 3,00E‐03
Maio unpublished
Dose-dependent induction of NY-ESO-1 expression in human melanoma cells by DHA
Modulation of CTA expression
in cancer cells of different histotype by DHA
‐ ++ +
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‐
0,0E+00 3,0E-04 6,0E-04 9,0E-04 1,2E-03
5 10 20 30
NY -ESO-1 mol/ -actin mol
Persistency of 5-AZA-CdR-induced CTA
expression in human melanoma xenografts
‐30
‐25
‐20
‐15
‐10
‐5 0 5
0 5 10 15 20 25 30
Re la ti ve LINE ‐1 meth yla tion (%)
Days
LINE‐1 methylation
‐16
‐14
‐12
‐10
‐8
‐6
‐4
‐2 0 2 4
0 5 10 15 20 25 30
‐18
‐16
‐14
‐12
‐10
‐8
‐6
‐4
‐2 0 2 4
0 5 10 15 20 25 30
Re la ti ve NY ‐ES O ‐1 meth yla tion (%) Re la ti ve MA GE ‐A1 meth yla tion (%)
NY‐ESO‐1 methylation MAGE‐A1 methylation
A. Covre et al., Semin Oncol 2015
Tumor immunomodulatory activity of DHA in vivo
Issa JP., Lancet Oncol 2015
BED: 60 mg/m 2 dailyx5
The BED defined as the smallest dose that achieves a
maximum global
hypomethylation in at least
three successive dose levels
NY‐ESO‐1 Induction (cut‐off ≥ 1E‐05) after SGI‐110 in AML and MDS patients
0,00E+00 1,00E‐04 2,00E‐04 3,00E‐04 4,00E‐04 5,00E‐04 6,00E‐04 7,00E‐04 8,00E‐04 9,00E‐04 1,00E‐03
0 5 10 15 20 25 30
NY‐ESO‐1/β‐actin molecules
days
A. Covre et al., Semin Oncol 2015
Maio M. et al., CCR 2015
Epigenetic Immunomodulation of Cancer cell
COMBOS
TUMOR
Epigenetic drugs
Modulate
Tumor immunogenicity and immune recognition HOST
Vaccine
Immunomodulating mAb
Improved the activity of host immune system
Epigenetic immuno‐sequencing
Antitumor activity of different schedules of 5 days DHA administration + α‐CTLA‐4 mAb in TS/A (breast) tumors
1 cycle
2 cycles
Covre A. AACR‐NCI‐EORTC October 18‐23, 2013, Boston MA
CTLA‐4 simul
bi‐weekly
Antitumor activity of bi‐weekly schedule of DHA + α‐CTLA‐4 mAb in TS/A (breast) tumors
Maio unpublished
Antitumor activity of SGI‐110 + α‐CTLA‐4 mAb in TS/A (breast) tumors
A. Covre et al., Semin Oncol 2015
84%
63%
MHC class I CD3
CTRL
mAb 9H10
DHA /mAb 9H10 DHA
CTRL
mAb 9H10
CD4
CD8 TUMOR
large intestine
dermis
liver
Kidney
NORMAL TISSUES CD3
IHC Analysis on tumor and normal tissues
A. Covre et al. OncoImmunol, 2015
BALB/c
Tu m o r vo lu m e cm
3Immune‐response contribution to the anti‐tumor activity
0,00 0,50 1,00 1,50 2,00 2,50 3,00
0 3 6 9 12 15 18 21 24 27 30 33 36
0,00 0,20 0,40 0,60 0,80 1,00 1,20 1,40 1,60
0 3 6 9 12 15 18
SCID Beige Athymic Nude
Tu m o r vo lu m e cm
3Tu m o r vo lu m e cm
30,00 0,20 0,40 0,60 0,80 1,00 1,20 1,40 1,60
0 3 6 9 12 15 18
