Immunotherapy for Prostate Cancer:Are we on the right target?

Susan F. Slovin, MD, PhDSidney Kimmel Center for Prostate and Urologic Cancers

Memorial Sloan-Kettering Cancer CenterNew York, New York

Rationale for Vaccines in Prostate Cancer

1. Well-characterized glycoprotein and carbohydrate antigens: PSA, PSMA, PSCA, Globo H, GM2, MUC-1,2, Tn, TF, Lewisy.

2. Biomarker (PSA) available to study disease progression.3. Can be used in all disease states: biochemical relapse thru

castration resistant disease.4. Can be potentiated via combinatorial approaches:

chemotherapy, biologic agents (GM-CSF) or checkpoint inhibitors (anti-CTLA-4, anti-PD-1).

Is there a “best” approach?

A (very) brief history of cancer vaccines

Whole cell orshed antigen

Purifiedprotein

Peptide

Where does immunotherapy end and vaccines begin?

Cell membrane

Intracellular

Extracellular

MoAb 7E11

J415, J591 - ADCC

PSMA Expression on LNCaP Cell

Modified from P. Smith-Jones 2004

MoAbs

ProstaScint Scan

NH2...

Vaccines: DNA, alhydrogel, DG, VRP -T cell

Antibody Drug Conjugate: auristatinmaytansinoid

Results of Clinical Trial Endpoints

• Tumor responds- target is hit

• Tumor responds- target is missed

• Tumor respond - target is hit

• Tumor respond - target is missed

All say something about the biology of the tumor and how the therapy should be directed

Immunotherapy / Vaccine Approaches in Development for Treatment of CRPC

• Tumor antigen vaccines– Vaccinate patient with antigens that activate tumor-specific T-cell

responses• Autologous dendritic cells (DCs)

– GM-CSF; lenalidomide• Cytokines and DC stimulation• CTLA-4 (cytotoxic T-lymphocyte-associated antigen)

blockade

Ipilimumab

• A fully human anti-CTLA-4 mAb (IgG1k) – Effectively blocks CTLA4–B7 interactions

• Currently in Phase III trials and in first and second line melanoma– Survival benefit in patients with treated melanoma – phase III

• Clinically significant and durable tumor regression in multiple tumors

(melanoma, prostate, renal, ovarian,…)– Immune Related Responses can occur with initial progression followed by

regression

• Immune-related adverse events (irAE)– Likely mechanism based; consistent with enhanced activity of T cells due

to the blockade of CTLA-4 function– Usually reversible and associated with clinical response in melanoma, renal

cell, and prostate cancer

Peptide/MHC

CTLA-4CD28TCR

B7-1,2

APC

Tumor

APC

IL-2

Attenuated orTerminatedProliferation

CTLA-4 BlockadeEnhances Tumor-Specific Immune Responses

UnrestrainedProliferation

Necrotic DeathVaccinesChemotherapyIrradiationHormone therapyAnti-angiogenesis Leach & Allison

Science 1996

M.O.A. of CTLA-4

Door to CTLA-4activation isclosed

TCR + Agon DC = Engagement

“Go or No Go?”–Awaiting T cell activationor shutdown

Full go !!T cell proliferation… or…

Abort!

12

3 4 5

Skin reactions at the GVAX injection

sites

GVAX IT aloneGVAX IT + MDX-010

(0.3 mg/kg)GVAX IT + MDX-010

(3 mg/kg)After 1 week

Injection site reactions were the most common adverse event (100%)No DLTs nor auto-immunity observed

PSA curves – Dose Level 3 (3 mg/kg)

0102030405060708090

100

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101520253035404550

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a :

b:

c:

13Mar06: SAE -Hypophysitis (7 mo)03Feb06: Hypophysitis (5 mo)09Feb06: SAE – Hypophysitis (5 mo)

ab

c

Pt 7 Pt 8

Pt 9

Gerritsen, ASCO 2006

15Sept05

Patient 8

29Mar06

Bone Scan Improvement in Patient 8 (3 mg/kg)

Gerritsen ASCO2006

14Feb06 16May06

Objective Tumor ResponsePatient 12 (5 mg/kg)

Gerritsen, ASCO 2006

Immune Breakthrough Events (IBE)• No IBE in DL 1 and 2• 5 of 6 patients in 3 mg/kg and 5 mg/kg with IBE

– All associated with PSA response– All delayed– All endocrine-related & treatable with

standard hormone replacement therapy

Patient Primary Event

Onset Secondary Events

007 Hypophysitis 7 mo Adrenal Insuff

008 Hypophysitis 5 mo Adrenal Insuff

009 Hypophysitis 5 mo Adrenal InsuffLeukopeniaHypothyroidism

010 Hypophysitis 4.5 mo Adrenal InsuffHypothyroidism

012 Alveolitis (IBE?) 2 mo Low TSH

Histopathologic analyses of selected patients experiencing autoimmune events.

(C) Colon biopsy from Patient 9 illustrating severe colitis with infiltration of the lamina propria with neutrophils, lymphocytes, monocytes, plasmacytes and eosinophils. Neutrophils and lymphocytes also infiltrate the crypts; numerous mitotic figures can be seen in the epithelial cells lining the crypts (20X).

Immunohistochemistry evaluating expression of CD3+ (D), CD4+ (E), and CD8+ markers (F) (20X).

Source: Abstract #3424, ASCO 2003

Pathology of Autoimmune Breakthrough Events: Colitis

C D

FE

CD3

CD8CD4

Rationale: Radiotherapy as an Immune-Supportive Intervention for CTLA-4 Blockade

CTLA-4

CTLA-4

Anti-CTLA4 mAb

Anti-CTLA4 mAb

Modified after: Demaria, et al, Int. J. Radiation Oncology Biol. Phys., Vol. 63, No. 3, pp. 655–666, 2005

Subject 3020, 10 mg/kg monotherapy

0

50

100

150

200

-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

Weeks

%B

asel

ine

PS

A

#302010 mg/kg mono< 1 cycle (2.5)

PSA0= 655

(-) Prior ChemoPSA - CR

RECIST - uCRS-irAEs:hepatitis, colitis,

irAE - abnormal TFTs

ColitisHepatitis

abnl TSH CRPRPRPR

Beer, et al, ASCO 2008

Subject 3020:Resolution of Prostate Mass

Screening 14 months

Best PSA Changes: Each Subject

-100.00

-50.00

0.00

50.00

100.00

Be

st

PS

A C

ha

ng

e f

rom

Ba

se

line

(%

)

Mono XRT in NoCHEMO XRT in CHEMO

Slovin, et al, ASCO 2009)

Time-to-Response and Durability of Confirmed PSA Response

Time-to-Response (>50% decrease) Response Durability

0 10 20 30 40 50 60

Mono +

**Mono +

Mono

Mono

Mono +

XRT CHEMO

XRT NoCHEMO

XRT NoCHEMO

*XRT NoCHEMO +

*XRT NoCHEMO +

Weeks

*: PSA CR **: Objective CR +: Durability ongoingSlovin, et al, ASCO 2009

Conclusions• Safety of Ipilimumab 10 mg/kg +/- additional XRT in patients with mCRPC

– No new emergent toxicity due to XRT in 32 subjects– Tolerated in both chemo naïve and chemo experienced population– 15/50 patients (30%) with Grade 3 or 4 irAE– Severity, rate and duration similar to Ipilimumab oncology program– Resolution using established management algorithms

• Ten subjects had confirmed 50% reductions in PSA responses (20%)– 2 of these declines were correlated with a serious irAE– Duration of declines: median 30.5 weeks; range: 6.0 to 60+ weeks– Occurrence of declines seen with or without XRT– Occurrence of declines in both chemo naïve and chemo experienced patients– Differences not significant in these small cohorts

• Objective response by RECIST) was observed.– All with 50% PSA declines had SD according to RECIST criteria except one patient who

had CR for both PSA and RECIST.

• Ipilimumab has anti-tumor activity in mCRPC, with and without XRT, and in both the chemo experienced and chemo naïve settings and should be explored in larger studies

Sipuleucel-T Immunotherapy for Advanced Prostate Cancer: A Randomized, Double-Blind, Placebo-

Controlled Phase 3 Trial

IMPACT STUDY

AUA, 2009

Vaccination With Antigen (GM-CSF/PAP) Loaded APCs

Leukapheresis

Isolation of APC

Antigen-loadedAPCs

PAP-GM-CSF“Antigen”

Patient

Sheikh et al, 2008.

Small, et al, JCO, 2006

Randomized Phase 3 IMPACT Trial(IMmunotherapy Prostate AdenoCarcinoma Treatment)

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

Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512)

Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512)

Placebo Q 2 weeks x 3Placebo Q 2 weeks x 3

Sipuleucel-T Q 2 weeks x 3

Sipuleucel-T Q 2 weeks x 3

P R O G R E S S I O N

P R O G R E S S I O N

2:1

SURVIVAL

SURVIVAL

Treated at Physician discretion and/or Salvage Protocol

Treated at Physician discretion and/or Salvage Protocol

Treated at Physician discretion

Treated at Physician discretion

Patient Demographics and Baseline Characteristics

Sipuleucel-T(N = 341)

Placebo(N = 171)

Age, median yrs (range) 72 (49 – 91) 70 (40 – 89)

Race, white (%) 89.4 91.2

ECOG status, 0 (%) 82.1 81.3

Gleason Score ≤ 7 (%) 75.4 75.4

Disease localization

Bone only (%) 50.7 43.3

Soft tissue only (%) 7.0 8.2

Bone & soft tissue (%) 41.9 48.5

>10 bone mets (%) 42.8 42.7

Bisphosphonate use 48.1 48.0

Prior docetaxel (%) 15.5 12.3

IMPACT Overall Survival: Primary EndpointIntent-to-Treat Population

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

25

50

75

100

Per

cent

Sur

viva

l

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.

Overall Survival SummarySurvival Percentiles (months)

N 75% 50% 25%

Sipuleucel-T 341 15.1 25.8 41.3

Placebo 171 11.0 21.7 35.6

% Survival (K-M estimates)

24 Mos. 36 Mos. 48 Mos.

Sipuleucel-T 52.1 31.7 20.5

Placebo 41.2 23.0 16.0

Survival Consistency Between Population Subsets

0.0 0.5 1.0 1.5

Below MedianHemoglobin: Above Median

Below MedianAlkaline Phos: Above Median

Below MedianLDH: Above Median

Below MedianPSA: Above Median

Below MedianAge: Above Median

0ECOG Performance Status: 1

Bone + Soft TissueDisease Localization: Single

10No. Bone Metastases: > 10

3 4Primary Gleason Grade:

NoBisphosphonate Use: Yes

Favors sipuleucel-T

Hazard Ratio (95% Confidence Interval)

Serious Adverse Events*Safety Population

SAE Preferred Term

Sipuleucel-TN=338

%

PlaceboN=168

%

Any SAE 24.0 23.8

Pyrexia 1.8 0.6

Cerebrovascular accident 1.8 1.8

Pulmonary embolism 1.2 0.0

Spinal cord compression 1.2 1.2

Nausea 0.9 1.2

Atrial fibrillation 0.9 0.6

Dehydration 0.9 0.6

Cardiac failure congestive 0.6 1.2

Pneumonia 0.6 1.2

Hematuria 0.6 1.2

Deep vein thrombosis 0.3 1.8

Renal failure acute 0.3 2.4*Occurring in ≥ 4 patients.

Consistency Across Phase 3 StudiesD9901*

(N = 127)

D9902A*

(N = 98)

IMPACT **

(N = 512)

Hazard Ratio

p-value

0.586

p = 0.010

0.786

p = 0.331

0.775

p = 0.032

Median Survival Benefit (months)

4.5 3.3 4.1

36-Month survival (%)

sipuleucel-T

placebo

34%

11%

32%

21%

32%

23%

*Unadjusted Cox model & log rank**Cox model adjusted for PSA and LDH

Integrated**

(N=737)

0.735

p < 0.001

3.9

33%

20%

Sipuleucel-T

(n = 341)

Placebo

(n = 171)

Any Intervention 81.8% 73.1%

Any Chemotherapy 65.4% 53.8%

Docetaxel 57.2% 50.3%

Hormone Therapy 12.3% 8.8%

Radiation Therapy 21.1% 26.3%

Surgical Intervention 1.5% 2.3%

Kantoff P, et al. 2010 Genitourinary Cancers Symposium. Abstract 8.

Phase III Study of Sipuleucel-T (D9902B, IMPACT)

Sipuleucel-T

(n = 341)

Placebo

(n = 171)

Chills 54.1% 12.5%

Pyrexia 29.3% 13.7%

Headache 16.0% 4.8%

Myalgia 9.8% 4.8%

Adverse Events

Post-Study Interventions

36

Conclusions

• Greater awareness of need to standardize immune monitoring for all trials

• Improving trial design to address both clinical and research questions – meet expectations of FDA

• How to reconcile trials where there is an overall survival benefit in the absence of anti-tumor effect?

• Provenge, Prostvac – no impact on PSA or disease? Thoughts?.......

• Immunologic tolerance can be broken via multiple vaccine strategies.

• Anti-tumor effects documented with possible survival benefits

• Concerns: do vaccines need immune modulators to exert more relevant responses?

• Is autoimmunity good in the short

but bad in the long run?

Conclusions