Is Prostate Cancer Amenable to Immunotherapy Approaches?

New Frontiers in Urologic Oncology, September 12, 2015

J. J. Mulé Associate Center Director, Translational Research

U.S. Senator Connie Mack & Family Chair, Melanoma Research and Treatment

Moffitt Cancer Center

Disclosures • Celgene Corp. (Business Strategy Advisory

Board) • Etubics Corp. (SAB) • Kite Pharma, Inc. (Consultant) • Lion Biotechnologies (SAB) • Lycera Corporation (SAB) • OncoPep, Inc. (SAB) • Oxis Biotechnologies, Inc. (SAB) • Select Bioventures (Advisory Board) • Vault Nano, Inc. (SAB)

Immunotherapy for Solid Tumors: Basic Requirements for Successful

Clinical Response

1. Immune T cell infiltration into the tumor mass: More is better

2. Gene mutation load: More is better (creation of foreign neoantigens)

Immunotherapy for Solid Tumors: Basic Requirements for Successful

Clinical Response

Immune T cell infiltration into the tumor mass: More is better

Adoptive T Cell Transfer

• Tumor Infiltrating Lymphocytes (TIL)

Tumor-Infiltrating Lymphocytes (TIL) for Treatment of Metastatic Melanoma

50-100 Billion TIL

Rapid Expansion

Examples of Clinical Response to Adoptive Cell Therapy in Advanced Melanoma

Response of a Brain Metastasis to TIL Therapy

Response of Liver Metastases to TIL Therapy

.

Rosenberg, S.A. et al CCR 2012

Immune gene expression signature (GES) in solid tumors: “The haves and the have nots”

Green: negative for GES Red: positive for GES

Messina et al. Nature – Sci. Rep. (nature.com)

T cells

B cells

Capsule

T cells

B cells

Variation in lymphoid infiltrates observed in human cancer

None

Dispersed

Ectopic follicle

Ectopic follicle with capsule

Immune Gene Signature + Immune Gene Signature -

Ectopic Lymph Node Structures in a Solid Tumor with Adjacent Tumor

Destruction

12-Chemokine GES Identifies Stage IV Melanoma Patients with Better Overall

Survival

Pe

rce

nt

su

rviv

al

p<0.0001

Interrogation of an Immune Gene Expression Signature across 8,674 Solid Tumors of Differing Histology: TCGA Database

Immunotherapy for Solid Tumors: Basic Requirements for Successful

Clinical Response

Gene mutation load: More is better (creation of foreign neoantigens)

Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-8

Gene Mutation Load vs. Human Tumor Type

Checkpoint proteins and their ligands

Int. Immunol. 19 (7): 813-824.

Ipilimumab enhances TIL infiltration

• Ipilimumab prior to TIL harvest may increase the number of TIL that are infused.

• Provide disease control and decrease patient drop out rates prior to TIL transfer.

Immunohistochemistry (IHC) of TIL

Epigenetic drug treatment of tumor cells can dramatically enhance the expression of a ~300 gene immune pathway response signature

Epigenetic drug treatment upregulates, in tumor cells, (red circles) immunogenic signals, including the immune tolerance ligand PD-L1, antigens on the cell surface (tumor-associated antigens and MHC class 1, interferon driven signaling, etc. Yellow arrows show target step for anti-PD-1 antibody (Nivolumab)

A Snapshot of Immunotherapy Trials for Prostate Cancer

Type Agent Phase ClinicalTrials.gov

Therapeutic Vaccines Sipuleucel-T (Provenge) Approved

Prostvac II NCT01322490

Sipuleucel-T +/- pTVG-HP DNA (booster)

II NCT01706458

Sipuleucel-T pTVG-HP DNA alone II NCT01341652

Autologous dendritic cells/TARP II NCT02362451

Autologous dendritic cells/prostate cell lines

II NCT00970203

PSA vaccine after local therapy II NCT00583752

Oncolytic Virus ProstAtak + radiation (localized) III NCT01436968

Checkpoint Inhibitors Ipilimumab (anti-CTLA-4; Yervoy) + Provenge

II NCT01804465

Ipilimumab alone + hormone therapy II NCT02113657

Source: Cancer Research Institute

A Snapshot of Immunotherapy Trials for Prostate Cancer (continued)

Type Agent Phase ClinicalTrials.gov

Checkpoint Inhibitors Ipilimumab plus androgen suppression therapy

II NCT01498978

Ipilimumab plus degarelix II NCT02020070

Pembrolizumab (anti-PD-1; Keytruda – Merck) previously treated with enzalutamide

II NCT02312557

Atezolizumab (anti-PD-L1; MPDL 3280A – Genentech/Roche)

II NCT02458638

Sipuleucel-T, CT-011 (CureTech), Cy II NCT01420965

Adoptive Cells CAR-T: NYESO-1 II NCT01967823

CAR-T: NYESO-1 + dendritic cells/NYESO-1

II NCT01697527

Adjuvants Sipuleucel-T + inodoximad (IDO inhibitor)

II NCT01560923

Source: Cancer Research Institute

Jonathan W. Simons Cancer Immunol Res 2014;2:1034-1043

©2014 by American Association for Cancer Research

References

• Boussiotis, V.A.: Somatic mutations and immunotherapy outcome with CTLA-4 blockade in melanoma. N. Engl. J. Med. 371:2230-2232, 2014.

• Messina, J.L., Fenstermacher, D.A., Eschrich, S., Qu, X., Berglund, A.E., Lloyd, M.C., Schell, M.J., Sondak, V.K., Weber, J.S., and Mulé, J.J.: 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Nature - Scientific Reports (nature.com) 2:765-770, 2012.

• Weber, J.: Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical background: CTLA-4 and PD-1 blockade. Semin. Oncol. 37:430-439, 2010.

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