Vaccines and immunomonitoring - OncologyPRO
Transcript of Vaccines and immunomonitoring - OncologyPRO
Vaccines
and
immunomonitoring
Radboud Institute for Molecular Life Sciences
Kalijn F. BolDepartment of Tumor Immunology & Medical Oncology
Radboud Institute for Molecular Life SciencesRadboudumc
Email: [email protected]
• Non antigen-specific immunotherapies– Non-specific immune stimulation (cytokines, BCG)– Immune checkpoint blockade
• Antigen-specific immunotherapies– Adoptive T cell transfer– Vaccination strategies
Cancer immunotherapies
Chen, Immunity 2013
The cancer-immunity cycle
Anti-CTLA4
Anti-PD-(L)1
Adoptive T cell therapy
Vaccines
Vaccination strategies
• Tumor cellsautologous / allogeneic
• Tumor antigenspeptides, proteins, RNA, DNA
• Antigen-presenting cellsantigen-loaded DCs
• Effector cellsautologous T cellsgenetically enginered T cells
Tumor cell
Tumor cells & tumor antigens
Tumor cells:
• self-antigens
• non-dividing (?)
Peptides/antigens:
• no danger signal/ costimulation
• Minimal toxicity
• Immunological responses
• Clinical responses in a minority of patients
Overall survival (months)41.1 (T-VEC) vs 21.5 (GM-CSF)IIIB-M1a
Overall survival (months)13.4 (T-VEC) vs 15.9 (GM-CSF)M1b-M1c
T-VEC in melanoma
Andtbacka, JCO 2015
Dendritic cell vaccination
Immature DC
Apheresis
Maturation factors
Monocytes
Mature DC
Growth factors
Monitoring
Vaccination with antigen
loaded autologous mature DCs
Control antigen
Tumor peptides
Dendritic cell vaccination
• Minimal toxicity
• Rarely auto-immunity
• Immunological responses
• Clinical responses in a minority of patients
need (and lots of possibilities) for optimization
APC takes up
the antigenRecombinant Prostatic Acid
Phosphatase (PAP) antigen
combines with resting antigen
presenting cell (APC)
Fully activated, the APC is
now sipuleucel-T
The precise mechanism of sipuleucel-T in prostate cancer has not been established.
Antigen is processed and presented
on surface of the APC
INFUSE PATIENT
T-cells proliferate
and attack
cancer cells
Sipuleucel-T
activates T-cells in
the body
“Dendritic cell” vaccine: Sipuleucel-T
+GM-CSF
Kantoff, NEJM 2010
Overall survival (months)21.7 (placebo) vs 25.8 (Sipuleucel-T)Benefit: 4.1 monthsHazard ratio: 0.78
Sipuleucel-T in prostate cancer
Adjuvant vaccination stage III melanoma
Median overall survival
DC 63.6 months n=78
Controls 31.0 months n=209
p = 0.018
Bol, OncoImmunol 2015Randomized phase III trial ongoing
Historical controls
Steps in immunomonitoring
�
Delivery of the vaccine
�Recruitment of effector cells
�
Activation of effector cells
�Emigration of activated cells
DC (blue) enter the T cell area
Section of human paraffin-embedded LN
Schuurhuis, CR 2003
Delivery of the vaccine
in vivoScintigraphy(111indium)
Steps in immunomonitoring
�
Delivery of the vaccine
�Recruitment of effector cells
�
Activation of effector cells
�Emigration of activated cells
✔
Recruitment of effector cells:Influx of effector cells after DC injectionVaccinated LN Control LN
volu
me
(mm
3 )
volu
me
(mm
3 )
�
Delivery of the vaccine
�Recruitment of effector cells
�
Activation of effector cells
�Emigration of activated cells
✔
✔
Steps in immunomonitoring
Increased [ 18F]FLT uptake in proliferating cells as early as 2 days after vaccination
CT
PET-CT
0
2
4
6
8
10
18F-FLT
(SU
Vm
ax)
Activation of effector T cells:T cell proliferation
Early processes in lymph nodes
�
Delivery of the vaccine
�Recruitment of effector cells
�
Activation of effector cells
�Emigration of activated cells
✔
✔
✔
Tumor
Blood
Skin test
• FACS analysis with tetrameric-MHC complexes
gp100-154
0.17
gp100-280
2.62
tyrosinase
0.02
control
0.02
CD8
Immigration of activated T cells:Tumor specific T cells in blood or skin tests
Many anti-tumor T cellsLow numbers of anti-tumor T cells
...
Immigration of activated T cells:Functionality in vivo
Stage IV melanoma patients
100
80
60
40
20
00 50 100 150
Follow up time (months)
Ov
era
ll S
urv
iva
l (%
) T cells, n=25
Absent T cells, n=52
p=0.055
Aarntzen, CR 2012
100
80
60
40
20
00 50 100 150
Follow up time (months)
Ov
era
ll S
urv
iva
l (%
) T cells, n=12
Absent T cells, n=65
p=0.001
Anti-tumor T cells present Functional T cells
Immigration of activated T cells:Correlation with survival
Early processes in lymph nodes
�
Delivery of the vaccine
�Recruitment of effector cells
�
Activation of effector cells
�Emigration of activated cells
✔
✔
✔
✔
Conclusion
• Cancer vaccines include many different approaches
• Immunological responses are often induced(more in patients with less tumor load)
• Cancer vaccines give little toxicity• Cancer vaccines have thus far shown limited
clinical efficacy• Cancer vaccines might be the ideal candidate
for combination treatment
Tumor Immunology, RIMLSTechniciansGerty SchreibeltJolanda de VriesCarl Figdor
Medical OncologyMartine BloemendalHarm WestdorpSteve BoudewijnsRutger KoornstraWinald Gerritsen
DermatologyMichelle van RossumWilmy van Meeteren
SurgeryHan BonenkampHans de WiltAnnelies Werner
PathologyWilleke Blokx
Clinical PharmacyJanine van der LindenAnna de Goede
EU
Acknowledgements
RadiologyErik AarntzenRoel Mus
HematologySandra Croockewit
Miltenyi BiotecKatia PetryGregor Winkels