Vaccines

and

immunomonitoring

Radboud Institute for Molecular Life Sciences

Kalijn F. BolDepartment of Tumor Immunology & Medical Oncology

Radboud Institute for Molecular Life SciencesRadboudumc

Email: Kalijn.Bol@radboudumc.nl

No disclosures

• 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

Tumor cell recognition

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

T-VEC: oncolytic virus

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

Activation of effector T cells:Interaction with CD8+ T cells

CD4 CD8

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

CD25CD69

Verdijk, CCR 2009Schuurhuis, CR 2003

Activation of effector T cells:T cell activation

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

Immigration of activated T cells:Testing functionality in vitro

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

The future ….

Personalized vaccinese.g. usage of neoantigens

Off-the-shelf product

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