Therapeutic efficacy of MUC1- specific CTL and CD137 co ...
Transcript of Therapeutic efficacy of MUC1- specific CTL and CD137 co ...
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Therapeutic efficacy of MUC1-specific CTL and CD137 co-stimulation in a spontaneous
mammary cancer model
Pinku Mukherjee
&
Sandra Gendler
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Goal of Immunotherapy
• Boosting the low level anti-tumor immune response
• Generate long lasting strong anti-tumor CTL and helper response
• Avoid tumor-induced immune suppression
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MUC1 is a target for Immunotherapy
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Schematic representation of a mouse model of spontaneous metastatic breast cancer and
approximate time-line of tumor progression from hyperplasia to adenocarcinomas and metastasis.
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Increased MUC1 expression as tumors progress
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Immunotherapy (Preclinical Trials)Immunotherapy (Preclinical Trials)
Single tumor antigen-based vaccine
Dendritic cells pulsed with liposomal-MUC1 peptide (JI 2000, JIT 2003, and Glycoconjugate J. 2003)
Tumor – based vaccine
Dendritic cells fused with primary resectable tumor cells (JI 2003, Immunol 2004, and JS 2002)
Dendritic cells fed with whole tumor cell lysate + co-stimulatory factors (41BB, OX40, CD40 antibody)
Cytotoxic T cell adoptive therapy
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MUC1-specific Cytotoxic T lymphocytes isolated from a
pancreatic cancer model
• MET mice naturally develop MUC1-specific CTLs as the pancreas tumor progresses
• Several clones of MUC1-specific CTLs were isolated from these MET mice and characterized
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Epitopes recognized by MUC1-specific
CTL line and clone.
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CTL clone expresses high levels of perforin and granzyme B
Perforin and Granzyme A and B are components of the cytolytic granule of cytotoxic T cells and NK cells that mediates lymphocyte-dependent killing
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Adoptive transfer of MUC1-specific CTLseradicates injected tumors that express MUC1 and generates a strong memory
response
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Adoptively transferred MUC1-specific CTL clone inhibits tumor progression in MMT mice.
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Immunosuppressive factor (TGF-β) is expressed and
secreted in the tumor microenvironment
A.Growth inhibition of MvlLu cells that are sensitive to TGF-β inhibition B. Inhibition of CTL cytolytic function
• Bioactive form of TGF-β is secreted by MET tumor cells in culture.
• Supernatant derived from MET tumor cells inhibits cytolyticactivity of the CTL clone.
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Immunosuppressive Factor (IL-10) is secreted in the tumor microenvironment
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COX-2 and PGE2 is present in the mammary tumor microenvironment
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Adoptively transferred CTLs home and divide within the tumor
microenvironment
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CD137
• Member of the tumor necrosis factor receptor superfamilyexpressed on primed but not on naïve CD4+ and CD8+ T cells
• Binds to a high affinity ligand expressed on APCs and delivers a mitogenic signal for T cell activation and proliferation
• CD137 monoclonal antibodies can amplify T cell-mediated immune responses and can eradicate established tumors
• Postulated to reverse T cell tolerance induced by tumor cells
• Tested efficacy of CD137 antibody therapy in reversing tolerancein the in vivo breast cancer model
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Flow cytometric profile of TCR Vβ5+/CD8+ T
cells sorted from TILs by flow cytometry
TILs were isolated from tumors of MMT mice that received adoptively transferred MUC1-specific CTL clone
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Adoptively transferred CTL become tolerant to MUC1 antigen within the tumor
microenvironment
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Adoptively transferred CTL are cytolytically
inactive within the tumor microenvironment.
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Adoptively transferred CTL are negative for granzyme expression within the tumor
microenvironment.
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Anti 4-1BB in combination with MUC1-specific CTL therapy is more efficient in reducing tumor burden than CTL therapy alone
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
CTL injection
Anti-CD137
sacrificed
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Conclusions
• Inefficiency of MUC1 CTLs to affect tumor burden and survival in spontaneous tumor models is due to the immunosuppressive tumor microenvironment that renders the infiltrating CTLs inactive
• Adoptively transferred CTL become tolerant to MUC1 and are cytolytically inactive after encounter with tumor cells.
• Anti-CD137 antibody can reverse tolerance in MMT mice and has synergistic anti-tumor affect when combined with MUC1-specific CTL therapy.
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Acknowledgements
Teresa Tinder Dr. Sandra GendlerLatha Pathangey Dr. Leiping ChenDr. Gargi Basu
Carol WilliamsMarvin Ruona (Visual Communication)Histology Core in ScottsdaleJim Tarara (Flow Cytometry)Animal Facility in Scottsdale