THERAPEUTIC CANCER VACCINES Cancer Immunology and Immunotherapy Center St. Savas Cancer Hospital.

THERAPEUTIC CANCER VACCINESTHERAPEUTIC CANCER VACCINES

Cancer Immunology and Immunotherapy CenterSt. Savas Cancer Hospital

To activate T cell responses against TAAsTo activate T cell responses against TAAsthat are of sufficient magnitude to eliminatethat are of sufficient magnitude to eliminate

tumor and prevent its recurrencetumor and prevent its recurrence

Why we vaccinate against cancer? Why we vaccinate against cancer?

Cancer immunoediting reoccurs during immunotherapiesCancer immunoediting reoccurs during immunotherapies

vacstart

vacend

Generate IR

Equilibrium

Anti-tumor response

Reduced tumor growth ratesReduced tumor growth rates

Increased OSIncreased OS

Escape(recurrences)

M e m o r yM e m o r y

Anti-tumor response

Elimination

tumortumorburdenburden conventional therapyconventional therapy

Cytotoxicgranules

Tumor cells can be recognized and destroyed by CD8Tumor cells can be recognized and destroyed by CD8++ T cells, T cells,thus a therapeutic vaccine needs to activate T cells recognizing tumor antigensthus a therapeutic vaccine needs to activate T cells recognizing tumor antigens

FasLFasL FasFas

perforin

CD8CD8++ tumortumor

1. Low numbers2. Low activation3. Short-lived immunity4. Wrong patient selection

Poor clinicaloutcome

How can we change this?How can we change this?

• Optimize vaccination methods

to yield highly activated tumor

specific CTLs in high numbers

and of long-lasting anti-tumor activity

• Combinatorial treatmentsImmune suppression

• Tregs, MDSCs, enzymes/cytokines etc.

Cytotoxicgranules

TumorTumor cellscells cancan bebe recognizedrecognized andand destroyeddestroyed byby CD8CD8++ T T cellscells,,thusthus a a therapeutictherapeutic vaccinevaccine needsneeds toto activateactivate T T cellscells recognizingrecognizing tumortumor antigensantigens

FasLFasL FasFas

perforin

CD8CD8++ tumortumor

1. Low numbers2. Low avidity3. Short-lived immunity

Poor clinicaloutcome

• Vaccinating patients with low tumor volume

Optimizing therapeutic cancer vaccinesOptimizing therapeutic cancer vaccines

tumorantigen

adjuvant vehicle

Multiple CTL peptidesfrom various tumor Ag restricted by various alleles.Helper peptides also needed

Viral vectorsDCs ?

Why helper peptides?Why helper peptides?

• CD8+ induction phase and CD8+ T cell memory

• Effector phase of CD8+ T cell at the tumor site

How to produce polyvalent vaccinesHow to produce polyvalent vaccines

1. Synthetic long peptides encompassing CTL + TH epitopes

2. Mixtures of synthetic peptides representing immunogenic CTL + TH epitopes

3. Recombinant proteins

Synthetic long peptides encompassing CTL + TH epitopes

HER-2 (776-790) is a promiscuous helper peptide that containsHER-2 (776-790) is a promiscuous helper peptide that contains multiple HLA-DR-specific binding motifs multiple HLA-DR-specific binding motifs

776 GVGSPYVSRLLGICL 790

DRB1*0101, DRB1*1501, DRB1*0404, DRB1*0401, DRB1*1101, DRB1*1302,DRB1*0701, DRB1*0802, DRB1*0901, DRB4*0101, DRB5*0101

Functional assaysDR1(High), DR3(Low), DR4(Intermediate-High), DR7(High), DR8(High), DR15(High), DR13(High), DR51(Low), DR52(Low), DR53(High)

Sotiriadou NN et al. 2001 Brit. J Cancer 85(10):1527 Salazar, LG et al. 2003 Clin Cancer Res 9:5559 http://www.syfpeithi.de

A2.1

A11, A3 A24

Syfpeithi

Syfpeithi

HER-2(776-790) is immunogenic in vivo and has antitumor activityHER-2(776-790) is immunogenic in vivo and has antitumor activity(Voutsas I et al, IJC, 2007,121:2031; Gritzapis AD et al, (Voutsas I et al, IJC, 2007,121:2031; Gritzapis AD et al, Cancer Res. 2006Cancer Res. 2006, , 66:545266:5452; Gritzapis AD et al, Cancer Res, 2010, ; Gritzapis AD et al, Cancer Res, 2010, 70:268670:2686))

Ii-key/HER-2(776-790) hybrid (AE37) is more immunogenic than native HER-2(776-790)Ii-key/HER-2(776-790) hybrid (AE37) is more immunogenic than native HER-2(776-790)(Voutsas I et al, IJC, 2007,121:2031;(Voutsas I et al, IJC, 2007,121:2031; Gillogly ME et al, Gillogly ME et al, CIICII,, 2004 2004,,53:49053:490 )

A2.1/DR1/neuT+

TUBO.A2

HER-2(435-443)HER-2(435-443)+ HER-2(776-790)

HER-2(435-443)

0 25 50 75 1251000

50

100

150

200

250

Days

Tu

mo

r si

ze (

mm

2)

2

HER-2(435-443) + HER-2(776-790)

00

50

100

150

200

250

DaysT

um

or

size

(m

m)

25 50 75 125100 150 175 200

rechallengeTUBO.A2

APC

APC+HER-2(776-790)

APC+HER-2(776-790)+aDR

ELISPOT-IFNγ

020406080100120140160180200

no

IFN

γ sp

ots

(5x1

05 C

D4+

ce

lls)

cpm

Proliferation

0

4000

8000

12000

16000

20000

0

10

20

30

40

50

60

70

20:1 10:1 5:1

% s

peci

fic

51C

r re

leas

e

CD8+

CD8+ + HER-2 CD4+

CD8+ + Ii-key/HER-2 CD4+

E:T ratio

Activates CD4+ T cellsin DR4-transgenic animals

Days

Tu

mor

siz

e (m

m2 )

Cytotoxicity

CD8+

CD8+ + HER-2 CD4+

CD8+ + Ii-key/HER-2 CD4+

Vaccinating with Ii-key/HER-2(776-790)Vaccinating with Ii-key/HER-2(776-790)(AE37)(AE37)

HER-2/neuHER-2/neu++ prostate cancer patients. prostate cancer patients.A phase I studyA phase I study

Vaccination scheduleVaccination schedule(Perez SA et al. Clin Cancer Res 2010, 16(13):3495)(Perez SA et al. Clin Cancer Res 2010, 16(13):3495)

Vac(id): 0.5 ml HER-2(776-790) (500 μg)+GM-CSF (60 μg) x 2

Pre-DTH

Vac1+

BD

BD: blood drawingDR: dermal reaction

months0 1 2 3 4 5 6

Post-DTH

→2d (DR) →2d (DR) →2d (DR) →2d (DR) →2d (DR) →2d (DR)

Vac2+

BD

Vac3+

BD

Vac4+

BD

Vac5+

BD

Vac6+

BD

vac DTH

12Longterm

Durable immunity inducedDurable immunity inducedby the Ii-key/HER-2(776-790) vaccineby the Ii-key/HER-2(776-790) vaccine

pat

ien

ts w

ith

res

pon

se (

%)

IFN

γ sp

ecif

ic s

pot

s/10

6 PB

MC

HER-2(776-790)

100

80

60

40

20

Immunological responses and toxicityImmunological responses and toxicity

Toxicity

T cell subset responses

23

0

5

10

15

20

25

No

of

res

po

ns

es

ICSCD4+γ+

orCD8+γ+

DTH γ+ ICS vs

DTH

Assay

23 23

19

Correlation between in vitro and in vivo immunologicalCorrelation between in vitro and in vivo immunologicalresponses in prostate cancer patients immunized responses in prostate cancer patients immunized

with Ii-key/HER-2(776-790)with Ii-key/HER-2(776-790)

Biological and immunological parameters Biological and immunological parameters pre vac, post vac, and at long termpre vac, post vac, and at long term

Other trials using AE37Other trials using AE37

1. Phase I, NN, disease-free breast cancer patients(completed standard therapies) (Holmes JP et al. JCO 2008, 26:3426)

2. Phase II, randomized, single-blinded, NP, NN (at high risk for recurrence),disease free breast cancer patients (Peoples GE)

3. Phase II, randomized, single-blinded, non-metastatic, castrate resistantprostate cancer patients in combination with anti-androgen treatment(preparing)

HPV-E6 1 325019

65418055

957110985

12091140109

158127

Vaccine composition

HPV-E7 1 355622

7743

9864

Adjuvant: Montanide ISA-51

Vaccination against HPV-16 oncoproteinsVaccination against HPV-16 oncoproteinsfor vulvar intraepithelial neoplasia for vulvar intraepithelial neoplasia

(Dutch Cancer Society, Leiden University) (Kenter GG et al, N Engl J Med 2008 361:1838)

Vaccine schedule

vaccinations q3w x 3-4 Each vaccine consisted of: 3.9 mg of peptide (total 0.3mg x 13) in 2.8 ml PBS

Kenter GG et al, N Engl J Med 2008;361:1838

Clinical Results at 24 mo after vaccination

Complete responses: 9/30Partial responses: 6/30

Correlation between immunologic and clinical responsesCorrelation between immunologic and clinical responses(Kenter GG et al, N Engl J Med 2009 361;19)(Kenter GG et al, N Engl J Med 2009 361;19)

Multi-peptide vaccination with IMA 901 in advanced RCCMulti-peptide vaccination with IMA 901 in advanced RCC(Immatics Biotech, GmbH) (Walter S et al. Nat. Med. 2012;18:1254)(Immatics Biotech, GmbH) (Walter S et al. Nat. Med. 2012;18:1254)

A therapeutic cancer vaccine consisting of 10 synthetic tumor-associated CTL peptides,identified by:

• isolating HLA-peptide complexes from primary RCC specimens

• determining their sequences by MS

• selection based on over-expression of their encoding genes

• immunogenicity tests

Plus a TH (Pan DR class II) peptide

Study designStudy design

Patients withAdvanced RCC

(n=68)

Randomization1

1

cyclo+IMA901+GM-CSF (i.d)

placebo+IMA901+GM-CSF (i.d)

17 vaccinations over 9 months

Immune response and clinical outcomeImmune response and clinical outcome((Walter S et al. Nat. Med. 2012;18:1254Walter S et al. Nat. Med. 2012;18:1254))

Cyclo+IMA-treated patientstotal patients

Cyclo+IMA

IMA

Phase III study – IMPRINT Phase III study – IMPRINT (Rini B et al. ASCO 2011)(Rini B et al. ASCO 2011)

IIMA 901 MA 901 MMulti-ulti-PPeptide vaccine eptide vaccine RRandomized andomized INTINTernational ernational

Advanced/Metastatic RCC

STRATIFICATION• Risk (low vs intermediate)• Region (European vs US)• Nephrectomy (yes vs no)

Randomization

Cyclo + IMA901 + sunitinib Sunitinib

Cyclo: 300 ng/m2

IMA901: 10 vaccinations over 4 monthsSunitinib: 5 cycles

3 2

Sunitinib 1st cycle

PRIMARY ENDPOINT• OS

SECONDARY ENDPOINTS• PFS-Safety• Immunomonitoring

Recruiting

330 patientsEnd of enrolment: 2nd half 2012





soluble PulsedDCs

Recombinantviruses

MAGE-A3 plus AS15 immunostimulant (TLR-L) in patients with NSCLC MAGE-A3 plus AS15 immunostimulant (TLR-L) in patients with NSCLC (Pujol J-L et al. JCO 2012;30(15):7013(Pujol J-L et al. JCO 2012;30(15):7013

(suppl. May20); ASCO Annual Meeting Proceedings)(suppl. May20); ASCO Annual Meeting Proceedings)

NSCLC• stage IB (T2N0) and stage II (T1-2N1), T3N0)• MAGE-A3 by qPCR• Complete resection• Recovered (DS 0-1)

Stratified• Stage IB vs II• Squamous vs non-squamous• LN sampling vs dissection

R1

2

MAGE-A3Administration 300 μg im.• Induction q3wx5• Maintenance q3wx8• Total 27 months

PlaceboSame schedule

Double-blindn=122

HR=0.73one-sided logrank test p=0.093

Impact of predictive gene signature on disease-free survivalImpact of predictive gene signature on disease-free survival

DFS: Interval from the date of surgical resection to the date of recurrence OR death,irrespective of cause of deathHR: Hazard ratio calculated by Cox analysis

Total population



Gene signature negative Gene signature positive

Active immunization toward the MAGE-A3 antigen in patientsActive immunization toward the MAGE-A3 antigen in patientswith metastatic melanoma with metastatic melanoma (Kruit W et al. ASCO 2011, JCO 2011;29(15):8535 (May 20 Suppl.))(Kruit W et al. ASCO 2011, JCO 2011;29(15):8535 (May 20 Suppl.))

Open-labeled/non-controlled

MAGE-A3+, unresectable stage III-IV M1acutaneous Melanoma

Rn=36 n=36

MAGE-A3administration 300 mg imq3wx5→q3mx24 max

+ +

TLR-4L TLR-4L+

TLR-9L

=AS02B=AS15

CR n=0 n=3PR n=1 n=1IR 21% 69%Med OS 19 months 33 months

3 6 9 12 15 18 21 24 27 30

Time (months)

DF

S

HR=0.31

Efficacy of MAGE-A3 in metastatic melanoma is associated Efficacy of MAGE-A3 in metastatic melanoma is associated to immune microenvironmentto immune microenvironment

GS(+) (n=21):10.3 monthsGS(-) (n=14):2.3 months

Phase III study – MAGRIT (Vansteenkiste J. et al. ASCO 2007) Phase III study – MAGRIT (Vansteenkiste J. et al. ASCO 2007) MMAGE-A3 as AGE-A3 as AAdjuvant Non-Small Cell Lundjuvant Non-Small Cell LunGG Cance CanceRR

IImmunommunoTTherapyherapy

Resectable NSCLC

Surgery

Pathological stage IB, II, IIIA

No chemo Up to 4 cycles ofplatinum-based chemo

Randomization Randomization

MAGE-A3 + AS15 placebo MAGE-A3 + AS15 placebo

2,270 patients double-blind, randomized trial

Primary endpoint: Disease free survivalSecondary endpoint: Validation of gene signature predictive of response to therapy

Phase III, double blind randomized trial– DERMA Phase III, double blind randomized trial– DERMA (Kirkwood JM et al. J Clin. Oncol. ASCO Proceedings 2011, 29:Abstr. TPS 232)(Kirkwood JM et al. J Clin. Oncol. ASCO Proceedings 2011, 29:Abstr. TPS 232)

Resectable regionallyadvanced melanoma

Stratification• Stages (IIIB, IIIC)•TNM nodal category (N1-N3)• Primary category (Tx-0, T1-2, or T3 or T4)• Prior treatment (IFN, anti-CTLA4)

Randomization

Placebo

2 1

PRIMARY ENDPOINT• DFS

MAGE-A3+AS15

SECONDARY ENDPOINT• OS, safety, health-related quality of life, validation of gene signature associated with MAGE-A3+AS15 benefit

Schedule: q3w x 5 + q12w x 8

Recruiting

1300 patients

Surgery

2. rec. PAP/GM-CSF 2. rec. PAP/GM-CSF pulsedpulsed on mature DCs on mature DCs Sipuleucel-T (ProvengeSipuleucel-T (Provenge®®) (Dendreon) ) (Dendreon)

Leukapheresis Monocytes + PAP/GM-CSF DC40 hr

infuse

CTL attack tumor

cells

In vivoT cell

activation

CD4+

CD8+

Randomized Phase 3 IMPACT TrialRandomized Phase 3 IMPACT Trial ( (Kantoff P et al, N Engl J Med 2010 363:411)Kantoff P et al, N Engl J Med 2010 363:411)

Asymptomatic or Minimally Symptomatic Metastatic

Castrate Resistant

Prostate Cancer (N=512)

Placebo Q 2 weeks x 3

Sipuleucel-T Q 2 weeks x 3

2:1

SURVIVAL

Primary endpoint: Overall SurvivalSecondary endpoint: Time to Objective Disease Progression

IMPACT Overall SurvivalIMPACT Overall Survival

0 6 12 18 24 30 36 42 48 54 60 660

25

50

75

100

Per

cen

t S

urv

ival

Survival (months)

P = 0.032 (Cox model)HR = 0.775 [95% CI: 0.614, 0.979]

Median Survival Benefit = 4.1 Mos.

Sipuleucel-T (n = 341)Median Survival: 25.8 Mos.

Placebo (n = 171)Median Survival: 21.7 Mos.

23.1%

31.7%

Open label, randomized phase II study:Open label, randomized phase II study:sequencing of sipuleucel-T and ADT on immune responsessequencing of sipuleucel-T and ADT on immune responses

in patients with prostatic cancer in patients with prostatic cancer (Antonarakis S et al. ASCO 2011, 29:Abstr.TPS(Antonarakis S et al. ASCO 2011, 29:Abstr.TPS 189) 189)

Prostate Ca patients with rising PSApost-primary therapy, non-metastatic

STRATIFICATION• PSADT (≤ 3 mo vs >3 mo)• Type of primary therapy (RP or XRT vs RP+XRT)

Randomization

Sipuleucel q2w x 32wks ADT

ADT 3mo Sipuleucel

n=30 n=30

PRIMARY ENDPOINT• immune responses to PA2024 and PAP during Sipuleucel-T and after at wks 2, 6, 12 and months 6, 9, 12, 15, 18• PSA/Testosterone: every 3 months until month 18

SECONDARY ENDPOINT• Safety• Time of PSA recurrence• Change in PSADT

Accrual Dec. 2011

Randomized, open label phase III study: sipuleucel-T plus ADT vs ADTRandomized, open label phase III study: sipuleucel-T plus ADT vs ADT in patients with prostate cancer in patients with prostate cancer (Fizazi K et al. J Clin. Oncol. ASCO 2011, 29:Abstr.TPS 188)(Fizazi K et al. J Clin. Oncol. ASCO 2011, 29:Abstr.TPS 188)

Metastatic, androgen-dependent(hormone sensitive) prostate cancer

Randomization

Sipuleucel-T + ADTn=842

ADT only n=842

1 1

PRIMARY ENDPOINT• overall survival

SECONDARY ENDPOINTS• Safety• Time to castration resistance• Chemotherapy free survival

Accrual Dec. 2011

ADT until castration-level testosterone

The PSA-TRICOM vaccine: PSA LFA-3 ICAM-1 B7-1

COCOstimulatory MMolecules

TRITRIad

Pox viruses1. Replicate within the cytoplasm of infected cells. Do not insert their genetic sequences in the host genome2. Infect DCs and tumor cells3. Large genome (can accommodate large transgenes)4. Engineered recombinants are stable

3. Recombinant proteins 3. Recombinant proteins encodedencoded by poxviruses by poxviruses

PROSTVAC: PSA-TRICOM (Therion Biologics Corporation)PROSTVAC: PSA-TRICOM (Therion Biologics Corporation)

Poxviral-based PSA targeted immunotherapy in metastatic castration resistant prostate cancerPhase II randomized, controlled, double blind study(NCI study) ((NCI study) (Kantoff P et al, J Clin Oncol 2010, 28:1094)Kantoff P et al, J Clin Oncol 2010, 28:1094)

Vaccinia-PSA-Tricom

Fowlpox-PSA-Tricom

0 1/2 2 3 4 51

GM-CSF

months

prime

boosts

Placebo: empty vector

Heterologous prime-boost regimen

On PSA-TRICOM 25.1 8.5On placebo 16.6

median OS (mo) median OS benefit (mo)

p=0.006

0

5

10

15

20

25

30

35

40

All patients Patients withHalabi <18 mo

Patients withHalabi >18 mo

OS

(m

onth

s) Median survival predictedby Halabi

Actual medianOS

Halabi nomogram: LDH, PSA, alkaline phosphatase, hemoglobin, Gleacon sum , ECOG performance status, visceral disease

17.4

26.6

12.3

14.620.9

37.3

p=0.035

(Gulley JL et al, CII 2010, 59:663)(Gulley JL et al, CII 2010, 59:663)

Immunologic and prognostic factors associated with overallImmunologic and prognostic factors associated with overall survival employing survival employing a poxviral-based PSA vaccine in metastatica poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancercastrate-resistant prostate cancer

Randomized phase II study: flutamide with or without Randomized phase II study: flutamide with or without PSA-TRICOM in patients with prostate cancer PSA-TRICOM in patients with prostate cancer

(NCI) (Bilusic M et al. ASCO 2011)(NCI) (Bilusic M et al. ASCO 2011)

non-metastatic, castrate resistant prostatecancer patients with rising PSA

STRATIFICATION• PSADT

Randomization

Flutamide+

PSA-TRICOM

Flutamide

PRIMARY ENDPOINT• TTP (biochemical recurrence, metastatic disease)

n=32 n=32

PSA-TRICOM combined with Docetaxel and Prednisone in treating patients with PSA-TRICOM combined with Docetaxel and Prednisone in treating patients with metastatic castrate resistant prostate cancer (Phase II/ NCI)metastatic castrate resistant prostate cancer (Phase II/ NCI)

Schedule: Course-1 Course-2

Days: 1 15 29 43 59

VacciniaPSA-TRICOM

FowlpoxPSA-TRICOM

Docetaxel q21dPrednisone q1dx2

x 12 cycles

85 - 106

(1) - (21)

Arm I: PSA-TRICOM + chemo

Objectives:Primary: OSSecondary: - Time to radiographic progression - PSA response rates - Immune responses

Arm II: chemo

Recruiting

Randomization

PSA-TRICOM (Bavarian Nordic) Randomized PSA-TRICOM (Bavarian Nordic) Randomized double-blind Phase III Studydouble-blind Phase III Study

Primary endpoint: Overall SurvivalSecondary endpoint: Progression Free Survival

Asymptomatic or Minimally

Symptomatic Metastatic Castrate Resistant


Asymptomatic or Minimally

Symptomatic Metastatic Castrate Resistant


Empty vector +placebo

Empty vector +placebo

PROSTVAC-VFTricom + GM

PROSTVAC-VFTricom + GM P

R O

G R E S

S I O N

P R O

G R E S

S I O N

SURVIVAL

SURVIVAL

Treated at physician discretion

Treated at physician discretion

PROSTVAC-VFTricom + placebo

PROSTVAC-VFTricom + placebo

Not recruiting yet

Optimizing the vaccine formulation for developingOptimizing the vaccine formulation for developingeffective therapeutic vaccineseffective therapeutic vaccines

tumorantigen

adjuvant vehicle

Polyvalentantigens

PoxvirusDCsTLR-L ?

PGE2PGE2

AdenosineAdenosine

ROSROS

TGF-TGF-ββ IL-10IL-10IDOIDO ArginaseArginase

iNOSiNOS

COX2COX2ectonucleotidasesectonucleotidasesPD-L1PD-L1

MICA/BMICA/B

TMVTMV

gangliosidesgangliosides

tumorantigen

adjuvant vehicle

Polyvalentantigens

PoxvirusDCsTLR-L ?

tumorantigen

adjuvant vehicle

Polyvalentantigens

PoxvirusDCsTLR-L ?

tumorantigen

adjuvant vehicle

Polyvalentantigens

PoxvirusDCsTLR-L ?

Combinatorial treatmentsCombinatorial treatments

Vaccine + something

chemotherapy

- PSA-TRICOM + Docetaxel/Prednisone- MAGRIT (MAGE-A3 + Platinum)- IMPRINT (IMA901 + cyclo)

- Temozolomide (TMZ) + telomerase helper peptide (phase I/II / stage IV melanoma) (Norwegian Cancer Society)(Kyte JA et al. Clin. Cancer Res. 2011, 17:4568)

-TG-4010/MVA-MUC1-IL2 (Transgene/Novartis) + chemo in NSCLC (stage IV) (Phase III)- CDX-110/EGFRvIII-KLH (Celldex Therapeutics)+ TMZ in glioblastoma (phase III)

- Autologous Id-KLH+GM-CSF (BiovaxID /Biovest International)+chemotherapy in Follicular lymphoma (Phase III) (Schuster SJ et al. JCO 2011, 29:2748)

- Stimuvax BLP25 (MUC1+TLR-4L in liposome) (Oncothyreon/Merck) + cyclo in NSCLC after chemoradiotherapy (Phase III)

Combinatorial treatmentsCombinatorial treatments

Vaccine + something Biological therapy

tyrosine kinase inhibitors

• Sunitinib + IMA901 in RCC (IMPRINT/Phase III) (Immatics)

• DCs+AuTu mRNA+CD40L (AGS-003) + sunitinib in RCC (Phase III) (Argos Therapeutics)

Combinatorial treatmentsCombinatorial treatmentsVaccine + something

hormonaltherapy

clinicallylocalizeddisease

biochemicalrecurrence

castration-resistantdisease (non-metastatic)

metastatic disease(hormone sensitive)

Androgen ablation

• Primary therapy (radiotherapy and/or surgery)• androgen ablation

• monitoring• androgen ablation

Secondaryandrogen ablation

increasingPSA level

sipuleucel T

sipuleucel T

PSA-TRICOM

Cancer vaccines must induce cellular immune responses beforeCancer vaccines must induce cellular immune responses beforethey can affect tumor burden or patient survivalthey can affect tumor burden or patient survival

Immunotherapy

Proper activation of the immune system

Robust immunologic antitumor response

Clinical efficacy

Patients to be vaccinated should be sufficiently healthy for a sufficiently long time to benefit

Vaccinate at earlier disease stage or in the adjuvant setting/metastatic indolent disease

• Phase II PSA-TRICOM study

• Ongoing Phase III PSA-TRICOM study

• Phase II MAGE-A3 study in NSCLC

• Phase III MAGE-A3 MAGRIT

• Phase III MAGE-A3 DERMA

• Phase III BiovaxID study with follicular lymphoma patients

• Phase III Oncophage study (autologous HSP gp96 preparations) patients with stage I and stage II RCC → trend for increased RFS

• Phase III OncoVAX study (autologous irradiated tumor cells+BCG) patients with stage II but not stage III colorectal cancer → significant increase of RFS

• Phase II E75 study (HER-2 (369-377)) breast cancer patients with less aggressive tumors (HER-1+, 2+, low grade) had significant increased RFS

Vaccinate at earlier disease stage or in the adjuvantVaccinate at earlier disease stage or in the adjuvant setting/metastatic indolent diseasesetting/metastatic indolent disease

ConclusionsConclusions

• Improvements in vaccine formulations

• Combinatorial treatments

• Vaccinating patients with low tumor burden (i.e. early disease, adjuvant setting) will improve clinical efficacy

• Prognostic and predictive biomarkers are needed

• Intermediate biomarkers by early disease

AcknowledgementsAcknowledgements

CIICDr. SA PerezDr. M PapamichailDr. IF VoutsasDr. AD GritzapisDr. P TzonisE. PappouE. Anastasopoulou

Urology ClinicDr. A ThanosDr. S Bisias

Antigen Express Inc.Dr. R HumphreysDr. E von Hofe

University of TurinProf. G ForniProf. F Cavallo

MD Anderson Medical Center TX, USA Dr. EA Mittendorf Dr. GE Peoples

University of TuebingenDr. C Gouttefangeas

Thank you – Questions?Thank you – Questions?

THERAPEUTIC CANCER VACCINES Cancer Immunology and Immunotherapy Center St. Savas Cancer Hospital.

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Transcript of THERAPEUTIC CANCER VACCINES Cancer Immunology and Immunotherapy Center St. Savas Cancer Hospital.