NY-ESO-1 specific responses in patients with advanced prostate cancer treated with ipilimumab

Jianda Yuan MD. Ph.D.

Immune Monitoring CoreLudwig Center for Cancer ImmunotherapyMemorial Sloan-Kettering Cancer Center

B7-CD28 signals and CTLA-4 blocking

MHC

TCR

T cell CTLA-4

APC

1. Co-stimulation via CD28 ligation transduces T cell activating signals

MHC

TCR

Anti-CTLA-4 Ab

T cell

CTLA-4

APC

T cell Activation

3. Blocking CTLA-4 ligation enhances T cell responses

MHC

TCR

T cell

APC

CD28

CTLA-4

T cell Inactivation

B7

2. CTLA-4 ligation on activated T cells down-regulates T cell responses

B7B7

T cell Activation

CD28 CD28

RT+ ipilimumab protocol MDX-010-21 : Time and events schema

3, 5 or 10 mg/kg

PI: Susan Slovin, MD, PhD

PSA changes after CTLA-4 blockade

Weeks

PSA (n

g/ml)

Pt. W/ BR(7/15)

Pt. W/O BR(8/15)

BR=biochemical response

The median time-to PSA-progression was 3.4 months (0.6 to 23.2+ months). Median follow-up 10.6 months.

• Expression in adult normal tissue is restricted to testis or/and placenta.

NY-ESO-1 expression on testis and cancer by IHC

Testis Placenta

Courtesy of Achim Junbluth Ludwig Institute of Cancer Research, New York Branch.

• Expression of NY-ESO-1 genes is associated with advanced disease and poor outcome.

• Spontaneous humoral or T cell immunity in cancer patients, with a high frequencyin patients with advanced NY-ESO-1-expressing tumors.

• Gene expression is detected in a fraction of tumors.

Lung Cancer

Response# patientsStatus at wk24 (%)

# NY-ESO-1 SERONEGATIVEStatus wk24 (%)

# NY-ESO-1SEROPOSITIVE Status wk24 (%)

CR 6 (5.1%) 4 2

PR 14 (12.0%) 9 5SD 25 (21.4%) 19 6

Clinical Benefit 45 (38.5%) 32 (33.7%) 13 (59.1%)

No Clinical Benefit 72 (61.5%) 63 (66.3%) 9 (40.9%)Total 117 (100%) 95 22

Correlation of NY-ESO-1 antibody with clinical coursefollowing anti-CTLA-4 treatment

In collaboration with Sacha Gnjatic, Jedd Wolchok, MSKCC/Ludwig Center and withRuth Halaban and Mario Sznol, Yale University - Melanoma sera

Patients with NY-ESO-1 antibodies at any time point during study

Fisher's exact test:P value 0.0498According to Immune-related response criteria:

CR: Complete ResponsePR: Partial ResponseSD: Stable DiseasePOD: Progression of Disease (includes MR: mixed response)DOD: Dead of Disease

Changes in NY-ESO-1 antibody titers following ipilimumab therapy.

PC-2 PC-13 PC-14 PC-9 PC-10

* *

*

*

NY-ESO-1 specific CD4+ and CD8+ T cell responsesIF

N-

Pre-therapy wk7 wk10/24

CD4

Pre-therapy wk7 wk10/24

PC-9

PC-10

CD8

0.04 4.4 0.4

0.11 0.17 0.39

0.06 1.3 0.8

0.05 0.07 0.14

NY-ESO-1 specific CD4+ and CD8+ T cell responses were induced after CTLA-4 blockade

Therapy Therapy

CD4+ T-cell

Therapy Therapy

CD8+ T-cell

Patients PC-1 and -2 are not included because they lacked baseline PBMCs for analysis.

NY-ESO-1 antibody and T cell responses

Four patterns of humoral and cellular immune responses to NY-ESO-1

Patients PC-1 and -2 are not included because they lacked baseline PBMCs for analysis.

Conclusions:

• CTLA-4 blockade enhanced NY-ESO-1 some pre-existing antibody responses and also induced de novo responses in some patients

•Seropositive patients also had CD4+ and CD8+ T cell responses augmented after ipilimumab treatment

•The prognostic importance of NY-ESO-1 immunity in response to CTLA-4 blockade will be prospectively assessed in an upcoming phase III trial

• NY-ESO-1 antibody responses can be detected in a subset of metastatic prostate cancer patients before immunotherapy

• What is the functional impact of anti-CTLA-4 therapy on NY-ESO-1 specific T cells?

Further Questions

• Which specific T cell populations are affected by CTLA-4 blockade?

• Why do some NY-ESO-1 seropositive patients (eg, PC-13) not respond to CTLA-4 blockade?

• Is NY-ESO-1 serostatus a general biomarker for responsiveness to immunotherapy or does the response to this specific antigen have a therapeutic impact?

Acknowledgement

LCCI: LICR: MedicineJames P. Allison Lloyd Old Susan SlovinJedd D. Wolchok Gerd Ritter Howard Scher

Sacha Gnjatic RSAErika Ritter

Immune Monitoring Core & Wolchok’s lab:Millie Gallardo Teresa Rasalan Yingyan Xu Sachi VyasBrian Ginsberg Zhen MuSapna Tandon Matthew AdamowArvin Yang Cailian LiuBrushra Zaidi Shigehisa KitanoFormer lab members:Geoffery Ku Hao LiFrancesca Orlandi Greg ManukianDavid Page Sebastian Schroeder

Israel Lowy, MD, Medarex

Patient demographics (n=15)

EBRT, external beam radiation therapy

Patient demographics (n=15)

CTLA-4 blockade induced polyfunctional CD8 T cell responses.%

of t

otal

CD

8+ T

cel

l res

pons

e

Pre-Therapy

Wk7

Non-PSA response PSA response4 3 2Functions

IFN-MIP-1TNF-CD107a

Pre-therapyWK7WK13/24

1

0.01

0.02

0.03

0.04

0.05

0.10.30.5

Wk13/24

A. B.