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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