moffitt cancer center• weber, j.: immune checkpoint proteins: a new therapeutic paradigm for...
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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
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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)
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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)
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Immunotherapy for Solid Tumors: Basic Requirements for Successful
Clinical Response
Immune T cell infiltration into the tumor mass: More is better
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Adoptive T Cell Transfer
• Tumor Infiltrating Lymphocytes (TIL)
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Tumor-Infiltrating Lymphocytes (TIL) for Treatment of Metastatic Melanoma
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50-100 Billion TIL
Rapid Expansion
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Examples of Clinical Response to Adoptive Cell Therapy in Advanced Melanoma
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Response of a Brain Metastasis to TIL Therapy
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Response of Liver Metastases to TIL Therapy
.
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Rosenberg, S.A. et al CCR 2012
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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)
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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 -
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Ectopic Lymph Node Structures in a Solid Tumor with Adjacent Tumor
Destruction
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12-Chemokine GES Identifies Stage IV Melanoma Patients with Better Overall
Survival
Pe
rce
nt
su
rviv
al
p<0.0001
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Interrogation of an Immune Gene Expression Signature across 8,674 Solid Tumors of Differing Histology: TCGA Database
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Immunotherapy for Solid Tumors: Basic Requirements for Successful
Clinical Response
Gene mutation load: More is better (creation of foreign neoantigens)
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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
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Checkpoint proteins and their ligands
Int. Immunol. 19 (7): 813-824.
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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
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Epigenetic drug treatment of tumor cells can dramatically enhance the expression of a ~300 gene immune pathway response signature
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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)
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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
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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
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Jonathan W. Simons Cancer Immunol Res 2014;2:1034-1043
©2014 by American Association for Cancer Research
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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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