CANCER

VACCINES
Dendritic Cell-Based Vaccines

KURT Bahoz, LUYCKX Margaux,

ROULTIAU Romain, JUVIGNE Rémi
 • Introduction
• Provenge (Sipuleucel-T)
PLAN
• Possible improvements
• Take Home Message

2
 CANCER VACCINES

= a type of immunotherapy in which the immune system is

boosted to recognize tumor-associated antigens and kill cancer cells

 Administered to cancer patients (therapeutic)

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 PROSTATE
CANCER

 Prostate Cancer

 Major health problem -> 25% of

cancer cases in men are prostate
cancer PROVENGE
 In 2010 : first dendritic cell vaccine
against protostat cancer called
Provenge or Sipuleucel-T was
approved by the FDA

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2020 Cancer incidence and mortality in EU-27 countries CATTANEO
 DENDRITIC
CELL BASED
VACCINE
1

 Customized vaccine
PA2024
 PAP : Prostate Acid Phosphatase
-> tumor associated antigen

 How does the vaccine work ?

 1. Leukapheresis from blood sample

5
Di Lorenzo, G., Buonerba, C. & Kantoff, P. (2011)
 DENDRITIC
CELL BASED
VACCINE

2
 How does the vaccine work ?
PA2024
 1. Leukapheresis from blood sample

q 2. DCs/APCs are cultured in vitro (+/- 2

days) -> selection with the CD54

6
• Hubert
Di ML, Haynes
Lorenzo, L, Parker
G., Buonerba, C.C, et al (2012)
& Kantoff, P. (2011)
 DENDRITIC
CELL BASED
VACCINE

 How does the vaccine work ?

PA2024
 1. Leukapheresis from blood sample
3
q 2. APCs are cultured in vitro (+/- 2
days) -> upregulation of CD54

q 3. Incubation of DCs
with recombinant protein PA2024

7
Di Lorenzo, G., Buonerba, C. & Kantoff, P. (2011)
 DENDRITIC
CELL BASED
VACCINE

 How does the vaccine work ?

 1. Leukapheresis from blood sample PA2024

q 2. APCs are cultured in vitro (+/-

2 days) -> upregulation of CD54

q 3. Incubation of DCs
with recombinant protein PA2024

q 4. Injection to patient -> Dcs

4
activate B&T-cells which attack prostate
cancer cells and antigens production
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• HubertDiML, Haynes
Lorenzo, L, ParkerC.C,&etKantoff,
G., Buonerba, al (2012)
P. (2011)
 DENDRITIC CELL
Signal 1
BASED VACCINE

 Interactions between DC & immune cells

 Mature DC active with CMH II and I

respectively TCD4 and TCD8 cells with
PAP antigen = signal 1

9
Drake CG. (2010)
 DENDRITIC CELL
BASED VACCINE

 Interactions between DC & immune cells

 Mature DC active with CMH II and I

respectively TCD4 and TCD8 cells with
PAP antigen = signal 1

q CD80 – CD28 activation = signal 2

CD80/86
CD28
Signal 2 10
Drake CG. (2010)
 DENDRITIC CELL
BASED VACCINE

Signal 3
 Interactions between DC & immune cells

 Mature DC active with CMH II and I

respectively TCD4 and TCD8 cells with
PAP antigen = signal 1

q CD80 – CD28 activation = signal 2

q Cytokine production : IFN-Y, TNF-α, IL5 Granzyme and perforin

– IL17, ...

Drake CG. (2010) 11

 DENDRITIC CELL
BASED VACCINE

 CD4 activates B Cell

• CD40L – CD40
• CD28-CD86
• IL6 -> differenciation
• IL4 -> proliferation

q Antibodies production
Varricchi G, Harker J, Borriello F, et al (2016)

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 Immune Responses at any Post-
Baseline
: Control group : Sipuleucel-T group

PROVENGE

P O S T- T R E AT M E N T
IMMUNE RESPONSE

Sheikh NA, Petrylak D, Kantoff PW et al (2013)

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mCRPC: metastatic castration resistance prostate cancer
 PROVENGE

P O S T- T R E AT M E N T I M M U N E R E S P O N S E

• Neoadjuvant therapy on non-

metastatic prostate cancer patients

• ≥ 3 fold increase in mean cells/area

at the tumor interface for total T
Lawrence Fong, Peter Carroll, Vivian Weinberg, Stephen Chan, Jera Lewis, John Corman, Christopher
L. Amling, Robert A. Stephenson, Jeffrey Simko, Nadeem A. Sheikh, Robert B. Sims, Mark W.
cells, CD4+FOXP3- helper T cells,
and CD8+ cytotoxic T cells.
Frohlich, Eric J. Small July 17, 2014.

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RP : Radical prostatectomy
 PROVENGE
P O S T- T R E AT M E N T I M M U N E R E S P O N S E

• Significant correlation between OS and immune

responders or non-responders to Sipuleucel-T
• Robust post-treatment antibody
response detected till at least 26 weeks
• IgM switch to IgG 6 weeks after the last
infusion

Immunologic memory
Sheikh NA, Petrylak D, Kantoff PW et al (2013)
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 C H E MO -
V S I MMU N O -
THERAPY

• Long-term OS benefit

• No reduction of the tumor size

a) no therapy
b) Chemotherapy • Antigen-specific immune response
c) Immunotherapy takes time

Peter F. Mulders,Maria De Santis, Thomas Powles, Karim Fizazi. 30 May • Nonpathogenic increase in size
2015
(leukocytes Infiltration)
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 EARLIER
USE OF SIPULEUCEL-T
THERAPY

• Allow more time for the

immune response to develop
OS increased

e) Late stage
d) Early stage • APC activation and eosinophil
counts are greater in early stage

Peter F. Mulders,Maria De Santis, Thomas Powles, Karim Fizazi. 30 May

2015

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 FDA AND EMA APPROVAL

• Based on three randomized phase III

studies
(NCT00005947, 01133704 and 00065442)

• Adverse effects mild to moderate

(typically chills, fever, fatigue, nausea,
and/or headache) resolved within 1–2 days

• Huber et al. concerns

Small EJ, Schellhammer PF, Higano CS et al

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(2006)
 PROVENGE IS STILL APPROVED BY
THE FDA BUT ...

 Provenge is no longer available on

the market

• Less efficient than competitors

• Prostvac : median survival

(months) : 9.9

• Costs much more than M/A Bavarian Nordic Prosvact 9.9 months

 Dendreon went bankrupt and was bought by Valeant

Pharmaceuticals in 2015 who stopped marketing the drug
Provenge
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Speights, K. (2016)
 LIMITATIONS

Downregulation of
Limited migration
tumor-associated Immunosuppressive
of DCs to lymph
antigens and MHC microenvironment
nodes
on tumor cells

Only a small proportion of patients can benefit from this therapy

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 HOW TO BOOST THE VACCINE?

Use of Transgelin-2

Combined therapy

Nanoparticles

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 THE USE OF TRANSGELIN-2 TO IMPROVE IMMUNE RESPONSE

• Actin-binding protein involved in filopodes

initiation and elongation = phagocytic behaviour of macrophages...
• ...but also in dendritic cells maturation:
Ø DCs Tagln 2 -/- can not control the growth and metastasis of a
B16F10 tumor (=melanoma)
in mice and show impaired migration into the lymph node

Kim, HR., Park, JS., Park, JH. et al. (2021)

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 THE USE OF TRANSGELIN-2 TO IMPROVE IMMUNE
RESPONSE

• Use of a cell-permeable Tagln-2 recombined with a PTD (=protein transduction

domain) and mutated on the ubiquitination site (=improve its stability) called
dU-TG2P
• Can potentiate DC-based cancer immunotherapy, allowing a decrease of
metastatic nodules, an improving of the OS,...

Significant decrease of
tumor size and weight
Kim, HR., Park, JS., Park, JH. et al.
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(2021)
 COMBINED THERAPY:
A PROMISING PHASE-2 TRIAL (SOV02)

• Standard treatment (= platinum-based chemotherapy + gemcitabine)

VS
Standard treatment + DCVAC/OvCa (= DCs exposed ex vivo to pressure-killed
tumor cells) can produce a polyclonal T cells response

Reduce the risk of immune evasion via Ag loss

• With DCVAC/OvCa= DCs vaccine (combined with 2nd
line chemotherapy) in advanced ovarian cancer

Cibula D, Rob L, et al. 2021

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 COMBINED THERAPY:
A PROMISING PHASE-2 TRIAL (SOV02)
• In 2018 a significant increase of the OS was observed in the vaccine group!

Combined therapy
VS
Standard treatment

Cibula D, Rob L, et al. 2021 25

 PREPARATION OF MINI DC

BMDC= Bone-Marrow derived Dendritic Cells

PLGA = Poly(Lactic-co-Glycolic Acid)

MHC
CD86
CD40

26
Shanshan Cheng, et
al (2020)
 ADVANTAGES OF MINI DC

High LN trafficking Low LN trafficking

Long shelf-life Short shelf-life
Insusceptible to metabolic Susceptible to metabolic
constraints constraints

27
Shanshan Cheng, et
al (2020)
 MINI DC

increased proportion of CD8+ T cells, as well as an increased

They observed an
concentration of pro-inflammatory cytokines (IFNγ and TNF α)
Female C57BL/6 mice

CONTROLS 28
Shanshan Cheng, et
 MINI DC

BMDC and mini DC

were found to delay
tumor growth
compared to control

29
Shanshan Cheng, et
al (2020)
 TAKE HOME MESSAGE

TUMOR-
PROMISING
SPECIFIC RECENT
STRATEGY
RESPONSE

IMPROVEMEN
LIMITATIONS
TS

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THANK YOU FOR YOU
ATTENTION!

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 BIBLIOGRAPHY

• Fong L, Weinberg V, Chan S et al (2012) Neoadjuvant sipuleucel-T in localised prostate cancer: effects on immune cells within the prostate tumour microenvironment. European Society for Medical Oncology (ESMO) Congress, Vienna, Austria,
September 28–October 2, 2012. Poster No. 939
• Sheikh NA, Petrylak D, Kantoff PW et al (2013) Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer. Cancer Immunol Immunother 62:137–147
• Liu YT, Sun ZJ. Turning cold tumors into hot tumors by improving T-cell infiltration. Theranostics 2021; 11(11):5365-5386. doi:10.7150/thno.58390
• Simon, Sonja,Utikal, Jochen,Umansky, Viktor.2019/05/01.Opposing roles of eosinophils in cancer.68.10.1007/s00262-018-2255-4.Cancer Immunology, Immunotherapy.
• Mulders PF, De Santis M, Powles T, Fizazi K. Targeted treatment of metastatic castration-resistant prostate cancer with sipuleucel-T immunotherapy. Cancer Immunol Immunother. 2015 Jun;64(6):655-63. doi: 10.1007/s00262-015-1707-3. Epub 2015
May 30. PMID: 26025563; PMCID: PMC4456994.
• Small EJ, Schellhammer PF, Higano CS et al (2006) Placebocontrolled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089–3094
• Cibula D, Rob L et al. Dendritic cell-based immunotherapy (DCVAC/OvCa) combined with second-line chemotherapy in platinum-sensitive ovarian cancer (SOV02): A randomized, open-label, phase 2 trial. Gynecol Oncol 2021; 162(3):652-660.
• Kim, HR., Park, JS., Park, JH. et al. Cell-permeable transgelin-2 as a potent therapeutic for dendritic cell-based cancer immunotherapy. J Hematol Oncol 14, 43 (2021).
• Cheng, S., Xu, C., Jin, Y., Li, Y., Zhong, C., Ma, J., Yang, J., Zhang, N., Li, Y., Wang, C., Yang, Z., & Wang, Y. (2020). Artificial Mini Dendritic Cells Boost T Cell–Based Immunotherapy for Ovarian Cancer. Advanced Science, 7(7), 1903301–n/a.
https://doi.org/10.1002/advs.201903301
• Bol, K. ., Schreibelt, G., Gerritsen, W. ., Vries, I. J. M. de, & Figdor, C. . (2016). Dendritic Cell-Based Immunotherapy: State of the Art and Beyond. Clinical Cancer Research, 22(8), 1897–1906. https://doi.org/10.1158/1078-0432.CCR-15-1399
• Santos, P. M., & Butterfield, L. H. (2018). Dendritic Cell-Based Cancer Vaccines. The Journal of Immunology (1950), 200(2), 443–449. https://doi.org/10.4049/jimmunol.1701024
• Zhao, Y., Guo, Y., & Tang, L. (2018). Engineering cancer vaccines using stimuli-responsive biomaterials. Nano Research, 11(10), 5355–5371. https://doi.org/10.1007/s12274-018-2162-1
• Kudrin, A. (2012). Overview of cancer vaccines: Considerations for development. Human Vaccines & Immunotherapeutics, 8(9), 1335–1353. https://doi.org/10.4161/hv.20518
• Anassi, E., & Ndefo, U. A. (2011). Sipuleucel-T (provenge) injection: the first immunotherapy agent (vaccine) for hormone-refractory prostate cancer. P&T (Lawrenceville, N.J.), 36(4), 197–202.
• Marie L. Huber, Laura Haynes, Chris Parker, Peter Iversen, Critique interdisciplinaire de Sipuleucel-T comme immunothérapie dans le cancer de la prostate résistant à la castration, JNCI : Journal of the National Cancer Institute , Volume 104, Numéro 4,
22 février 2012, Pages 273 –279, https://doi.org/10.1093/jnci/djr514
• Gulley, J. ., Madan, R. ., Pachynski, R., Mulders, P. F. ., Sheikh, N. ., Trager, J., & ke, C. . (2017). Role of Antigen Spread and Distinctive Characteristics of Immunotherapy in Cancer Treatment. JNCI : Journal of the National Cancer Institute, 109(4),
djw261–. https://doi.org/10.1093/jnci/djw261
• 5 Most Expensive Medicare Drugs -- and Which Companies Are Getting Rich From Them Speights https://www.fool.com/investing/2016/11/20/5-most-expensive-medicare-drugs-and-which-companie.aspx

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 Eosinophils
• Key immune cell types
(APCs, T, and B
cells) contribute to the OS
benefit

• Transient increase in +/- 30%

of the patients from week 6 to
week 14 after treatment

• May be involved in antitumor

immune response by
interactions with the others
immune cells.

•Elevated eosinophil
Sonja.C.S.Simon, Jochen Utikal, Viktor Umansky (2019) counts is correlated with OS
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IMMUNOSURVEILLANCE

Yuan-Tong Liu1, Zhi-Jun Sun 2021

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METHOD (SLIDE 32)

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 TUMOR-SPECIFIC IMMUNE RESPONSE

36
Shanshan Cheng, et
al (2020)
 MINI DC

They determined that the immune response observed was tumor-specific

Ratio effector cells : target

Shanshan Cheng, et cells 37
al (2020)
MINI DENDRITIC CELLS

Higher
percentage of
CD8+ T cells
after mini DC
vaccination

Lower
percentage
of Tregs
after mini
DC
vaccinatio
38

n
 COMBINED THERAPY:
A PROMISING PHASE-2 TRIAL (SOV02)
• Increase of the frequencies of MAGE-A1/NYESO-1 specific
CD4+ cells in the vaccine compared to treatment impact
on T CD8+ cytotoxic response

(Results for the MAGE-A1 Ag)

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CYTOKINES
FUNCTION

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