Diese Präsentation wurde erfolgreich gemeldet.
Wir verwenden Ihre LinkedIn Profilangaben und Informationen zu Ihren Aktivitäten, um Anzeigen zu personalisieren und Ihnen relevantere Inhalte anzuzeigen. Sie können Ihre Anzeigeneinstellungen jederzeit ändern.
DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is    current as of June 2...
DISCLAIMERParticipants have an implied responsibility to use the newly acquired information     to enhance patient outcome...
Disclosure of Conflicts of InterestThomas F. Gajewski, MD, PhD, reported a financial interest/relationship or affiliationi...
Welcome and Activity      Overview  Thomas F. Gajewski, MD, PhDThe University of Chicago Medicine
Learning Objectives             L       Upon completion of this activity, participants               should be better able...
Activity Agenda7:30 – 7:35 pm       Welcome and Activity Overview7:35 – 7:50 pm        Immuno-Oncology: Understanding the ...
Immuno-Oncology: Understanding BiologicalFoundations of the Immune    System in Cancer  Thomas F. Gajewski, MD, PhDThe Uni...
The Genetic Instability of Cancer Cells Creates           Antigens That Can Be Recognized by the                        Im...
Generation of Tumor Antigens   Point mutations in normal genes   Overexpressed normal genes   Molecular mishaps (revers...
Two Principal Means to Promote           Immune-Mediated Tumor Destruction:          Cytolytic T Lymphocytes and Antibodie...
CD8+ Cytotoxic T Lymphocyte Killing               an Antigen-Expressing Tumor Cell       How Do These CD8+ T Cells Initial...
T Cells Traffic Between the Tissues,              Lymphatics, and the Blood in Two Major                        Differenti...
Dendritic Cells (DCs) Pick Up Antigens From          Infected Tissues and Migrate to Lymph Nodes           Antigen uptake ...
The Main Costimulatory Receptor on                 T Cells is CD28, Which Binds to              B7-1/B7-2 on Activated Den...
Model for CD8+ T-Cell-Mediated Anti-Tumor            Immune Response In Vivo                           MHC I            MH...
Theoretical Reasons for Failure of Immune        System to Prevent Cancer Outgrowth             Failure to activate speci...
Model for CD8+ T-Cell-Mediated Anti-Tumor     Immune Response In Vivo: Interventions                                      ...
Model for CD8+ T-Cell-Mediated Anti-Tumor        Immune Response In Vivo: Interventions (cont.)                           ...
Toll-Like Receptors (TLRs)     First identified in Drosophila as receptor recognizing      pathogens for innate immunity...
TLR Pathway                         Plants              Drosophila                       Mammals                          ...
Imiquimod for Basal Cell Carcinoma (BCC)    Imiquimod is a TLR7 agonist that activates DCs    Randomized clinical trial ...
Key Takeaways            CD8+ T cells can recognize neoantigens expressed by             tumor cells            In order...
Melanoma: A Classic Tumor Model for Immunotherapy   Thomas F. Gajewski, MD, PhD The University of Chicago Medicine
Model for CD8+ T-Cell-Mediated Anti-Tumor        Immune Response In Vivo: Interventions (cont.)                           ...
Model for CD8+ T-Cell-Mediated Anti-Tumor        Immune Response In Vivo: Interventions (cont.)                           ...
Immunization Modalities   Antigen delivery strategy    – Targeting endogenous APCs       • Synthetic peptides or protein ...
Induction of Specific CTL Responses in Mice Using     Tumor Antigen Peptide-Loaded PBMC + IL-12                           ...
Resolution of Subcutaneous Metastases          Following Immunization With MelanA            Peptide-Pulsed PBMC + rhIL-12...
Vaccination of Patients With Multiple Melanoma     Antigen Peptides + IL-12 Can Induce High Levels        of Functional Sp...
Model for CD8+ T-Cell-Mediated Anti-Tumor        Immune Response In Vivo: Interventions (cont.)                           ...
CTLA-4 Blockade for                                     Immunopotentiation    CTLA-4 is receptor induced on activated T c...
CTLA-4 Is a Negative Regulator                      of T-Cell Activation                   Resting T Cell                 ...
Randomized Study of Vaccine Vs. Ipilimumab       Vs. Combination in Advanced MelanomaIpi = ipilimumab.Hodi et al, 2010.
Clinical Response in Melanoma With           Single Agent Anti-CTLA-4 mAb                           Screening          Wee...
T-Cell Infiltration in Skin and Gut    Following Anti-CTLA-4 mAb TreatmentSarnaik et al, 2009.
Model for CD8+ T-Cell-Mediated Anti-Tumor        Immune Response In Vivo: Interventions (cont.)                           ...
IL-2 in Melanoma: RR 16%Atkins et al, 1999.
Modified gp100 Peptide in Montanide                +/- Exogenous IL-2    Additional 19 patients treated with high-dose IL...
High-Dose IL-2 ± Peptide Vaccine Phase IIISchwartzentruber et al, 2011.
Model for CD8+ T-Cell Mediated Anti-          Tumor Immune Response In Vivo (cont.)                                MHC I  ...
Adoptive T-Cell Therapy   T cells are isolated, from    tumor site or generated in vitro   Adoptive                      ...
TIL Therapy for Melanoma:                            Rosenberg Approach             Tumor harvested, TILs collected and e...
Phase II Trial: Adoptive-Cell Therapy       •     Stage IV melanoma (N = 35)       •     Received autologous, tumor-      ...
Model for CD8+ T-Cell-Mediated Anti-Tumor        Immune Response In Vivo: Interventions (cont.)                           ...
Hypothesis         Clinical benefit when it does occur with potent cancer vaccines          (and other immunotherapies) h...
Expression of a Subset of Chemokine Genes Is         Associated With Presence of CD8 Transcripts                          ...
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Immuno-Oncology: An Evolving Approach to Cancer Care
Nächste SlideShare
Wird geladen in …5
×

Immuno-Oncology: An Evolving Approach to Cancer Care

22.541 Aufrufe

Veröffentlicht am

Immuno-Oncology: An Evolving Approach to Cancer Care

Review a downloadable slide deck by Thomas F. Gajewski, MD, PhD, covering the most clinically relevant new data reported from Immuno-Oncology: An Evolving Approach to Cancer Care.


Target Audience

This activity is designed to meet the educational needs of oncologists and other healthcare professionals involved in cancer care.

Format: Microsoft PowerPoint (.ppt) | File size: 26.2 MB | Date posted: 6/20/2012


Slide Deck Disclaimer

This slide deck in its original and unaltered format is for educational purposes and is current as of June 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CE provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.



Usage Rights

This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.

Veröffentlicht in: Bildung, Gesundheit & Medizin, Business
  • You can start destroying your Type 2 Diabetes right now . We had found a way to Destroy Type 2 Diabetes. I couldn’t believe the results… Soon, over 38,000 people had used it. Learn more https://youtu.be/5kmJd4AA5H0
       Antworten 
    Sind Sie sicher, dass Sie …  Ja  Nein
    Ihre Nachricht erscheint hier
  • Very interesting analysis of CET 2016, must read for CET Aspirants http://catking.in/2016/09/30/exam-analysis-mh-cet-2016/ #TargetJBIMS #JBIMSorNothing #CET2017
       Antworten 
    Sind Sie sicher, dass Sie …  Ja  Nein
    Ihre Nachricht erscheint hier
  • Njce! Thanks for sharing.
       Antworten 
    Sind Sie sicher, dass Sie …  Ja  Nein
    Ihre Nachricht erscheint hier
  • Great presentation! Thanks! For better options in treatment, please, visit cancercuremedicine.com, read: http://www.amazon.com/s/ref=nb_sb_noss_1/183-5035389-4416932?url=search-alias%3Daps&field-keywords=travis+christofferson
       Antworten 
    Sind Sie sicher, dass Sie …  Ja  Nein
    Ihre Nachricht erscheint hier

Immuno-Oncology: An Evolving Approach to Cancer Care

  1. 1. DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of June 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice,diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
  2. 2. DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline forpatient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USE This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. PIM and IMER do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of PIM and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
  3. 3. Disclosure of Conflicts of InterestThomas F. Gajewski, MD, PhD, reported a financial interest/relationship or affiliationin the form of: Consultant, Amgen, Bristol-Myers Squibb Company, GlaxoSmithKlineplc, Merck & Co., Inc., Roche Pharmaceuticals, Inc.; Contracted Research, Bristol-Myers Squibb Company, CureTech Ltd., GlaxoSmithKline plc, Morphotek, Inc.,Roche-Genentech.Charles G. Drake, MD, PhD, reported a financial interest/relationship or affiliation inthe form of: Royalty, Amplimmune, Inc., Bristol-Myers Squibb Company; Receipt ofIntellectual Property Rights/Patent Holder, Amplimmune, Inc., Bristol-Myers SquibbCompany; Consultant, Amplimmune, Inc., Bristol-Myers Squibb Company, DendreonCorporation, ImmuneXcite, Inc.; Ownership Interest, Amplimmune, Inc.John Powderly II, MD, CPI, reported a financial interest/relationship or affiliation inthe form of: Receipt of Intellectual Property Rights/Patent Holder, BioCytics, Inc.;Consulting Fees, Amplimmune, Inc., Bristol-Myers Squibb Company, GenentechBioOncology; Speakers Bureau, Bristol-Myers Squibb Company; ContractedResearch, Amplimmune, Inc., Bristol-Myers Squibb Company, GenentechBioOncology; Company Ownership Interest, BioCytics, Inc.Michael B. Atkins, MD, reported a financial interest/relationship or affiliation in theform of: Consultant, AstraZeneca Pharmaceuticals LP, AVEO Pharmaceuticals, Inc.,Bristol-Myers Squibb Company, Genentech BioOncology, Prometheus.
  4. 4. Welcome and Activity Overview Thomas F. Gajewski, MD, PhDThe University of Chicago Medicine
  5. 5. Learning Objectives L Upon completion of this activity, participants should be better able to: Enhance knowledge on the biological foundations of immuno- oncology approaches to the treatment of cancer Describe the roles, targets, and mechanisms of action of novel and emerging immuno-oncologic agents Evaluate new safety and efficacy data on recently approved and emerging immuno-oncologic agents across tumor types Identify unique patterns of clinical response in patients treated with immuno-oncologic agents Monitor and manage immune-related adverse effects associated with immuno-oncologic agents Describe how new immuno-oncologic agents are being integrated into existing treatment evidence-based guidelines
  6. 6. Activity Agenda7:30 – 7:35 pm Welcome and Activity Overview7:35 – 7:50 pm Immuno-Oncology: Understanding the Biological Foundations of the Immune System in Cancer7:50 – 8:10 pm Melanoma: A Classic Tumor Model for Immunotherapy8:10 – 8:25 pm The Evolving Role of Immunotherapy for Prostate Cancer8:25 – 8:40 pm The Emerging Role of Immunotherapy for Lung Cancer8:40 – 8:55 pm Emerging Immunotherapies for Renal Cell Carcinoma8:55 – 9:15 pm Interactive Case Studies: Applying Current Immunotherapies Into Practice9:15 – 9:25 pm Expert Panel Perspectives: Placing Current and Emerging Immunotherapies in Clinical Context9:25 – 9:30 pm Questions & Answers and Activity Conclusion
  7. 7. Immuno-Oncology: Understanding BiologicalFoundations of the Immune System in Cancer Thomas F. Gajewski, MD, PhDThe University of Chicago Medicine
  8. 8. The Genetic Instability of Cancer Cells Creates Antigens That Can Be Recognized by the Immune System Normal cell presents self peptides bound to MHC molecules New peptides created by mutation or increased expression Normal cell A point mutation in a self protein allows A point mutation in a self peptide creates binding of a new peptide to MHC molecules a new epitope for recognition by T cells Tumor cell Tumor cellMHC = major histocompatibility complex.www.immunoweb.com/tu10.htm
  9. 9. Generation of Tumor Antigens Point mutations in normal genes Overexpressed normal genes Molecular mishaps (reverse strand, intron sequences, alternative splicing) Embryonic genes Tissue-restricted differentiation antigens Translocation fusion proteins Viral genes Alternative glycosylation
  10. 10. Two Principal Means to Promote Immune-Mediated Tumor Destruction: Cytolytic T Lymphocytes and AntibodiesNK = natural killer.
  11. 11. CD8+ Cytotoxic T Lymphocyte Killing an Antigen-Expressing Tumor Cell How Do These CD8+ T Cells Initially Become Activated to Fight Tumors?TCR = T-cell receptor.Boissonnas et al, 2007.
  12. 12. T Cells Traffic Between the Tissues, Lymphatics, and the Blood in Two Major Differentiation States Lymphocytes and Naïve lymphocytes lymph return to blood enter lymph nodes via thoracic duct from blood heart Lymph node Antigens from sites of Infected infection reach lymph Tumor peripheral nodes via lymphatics tissueJaneway et al, 2001.
  13. 13. Dendritic Cells (DCs) Pick Up Antigens From Infected Tissues and Migrate to Lymph Nodes Antigen uptake by Langerhans’ cells leave the skin Langerhans’ cells in the skin and enter the lymphatic system Langerhans’ cells enter the B7-positive dendritic cells lymph node to become dendritic stimulate naïve T cells cells expressing B7 Discovery of dendritic cells by Ralph Steinman earned Nobel Prize in 2011Banchereau et al, 1998.
  14. 14. The Main Costimulatory Receptor on T Cells is CD28, Which Binds to B7-1/B7-2 on Activated Dendritic Cells T cell TCR/CD3 CD28 complex CD4 B7.1 or B7.2 APC MHC class IIAPC = antigen presenting cell.Janeway et al, 1996; Topalian et al, 2011.
  15. 15. Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo MHC I MHC II Immature DC Migration From Tumor Tumor granzymes TCR eCD8 B7 APC Mature DC Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  16. 16. Theoretical Reasons for Failure of Immune System to Prevent Cancer Outgrowth  Failure to activate specific T cells – Inadequate antigen processing/presentation – Insufficient T-cell repertoire – Available T cells below activation threshold setpoint  Ineffective T-cell differentiation into effector cells  Inadequate expansion of T cells to needed frequency  Lack of homing of primed T cells to tumor sites  Immunosuppression in tumor microenvironment – CTLA-4 on T cells (inhibitory receptor) – PD-1 on T cells (binds PD-L1 on tumor cells) – T-cell anergy (deficient B7 costimulation) – CD4+CD25+FoxP3+ Tregs (extrinsic suppression) – Indoleamine-2,3-dioxygenase (IDO tryptophan catabolism)Gajewski et al, 2007; Zou, 2005.
  17. 17. Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions TLR ligands Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  18. 18. Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) TLR ligands Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  19. 19. Toll-Like Receptors (TLRs) First identified in Drosophila as receptor recognizing pathogens for innate immunity At least 11 mammalian homologues identified Expressed on DCs and other APCs Mediate activation and maturation of APCs to render them optimal for T-cell activation Ligands should be excellent vaccine adjuvants Discovery of Innate Immune Sensing Systems by Bruce Beutler and Jules Hoffmann Earned Nobel Prize in 2011Takeda et al, 2004.
  20. 20. TLR Pathway Plants Drosophila Mammals PAM P Protease PAM Spätzle P IL-1 Toll TLR4 IL-1R Extracellular Pathogen Cytoplasm or PAMP MyD88 TIRAP MyD88 MyD88 RPP5, N, L6 Immune response Immune response Immune response Triggers activation of dendritic cells and other APCsMedzhitov et al, 2001.
  21. 21. Imiquimod for Basal Cell Carcinoma (BCC) Imiquimod is a TLR7 agonist that activates DCs Randomized clinical trial done in patients with BCC 100% RR with BID dosing compared to 19% with vehicle alone! Also active on warts and cutaneous metastases of melanoma Other TLR ligands are in clinical trials, including CpG 7909 (TLR9 agonist) TLR agonists being combined with tumor antigens in cancer vaccines (eg, GSK-Bio MAGE3 vaccine)RR = response rate.Sapijaszko, 2005; Goldman et al, 2009.
  22. 22. Key Takeaways  CD8+ T cells can recognize neoantigens expressed by tumor cells  In order for antigen-specific T cells to become activated to differentiate into cytolytic effector cells, they need to be stimulated by activated DCs in lymph nodes  DCs must be activated via innate immune sensing pathways (TLRs)  Activated CTL recirculate and traffic tumor tumors where they have a chance to destroy cancer cells  In cancer, failure can occur at various stages of this process, which generates multiple opportunities for therapeutic interventionCTL = cytotoxic T lymphocyte.
  23. 23. Melanoma: A Classic Tumor Model for Immunotherapy Thomas F. Gajewski, MD, PhD The University of Chicago Medicine
  24. 24. Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  25. 25. Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  26. 26. Immunization Modalities Antigen delivery strategy – Targeting endogenous APCs • Synthetic peptides or protein in adjuvant • Recombinant viruses, bacteria • Irradiated tumor transfectants • Antigen/antibody complexes • Antigen/TLR ligand fusions • Plasmids (CpG oligonucleotides) – Ex vivo loaded APCs • Peptide, protein, tumor lysates, etc. Additional modulators – Cytokines, adjuvants, modulatory antibodies
  27. 27. Induction of Specific CTL Responses in Mice Using Tumor Antigen Peptide-Loaded PBMC + IL-12 PBMC-P1A PBMC-P1A + IL-12 PBMC + IL-12 PBS Percent Specific Lysis E:T RatioPBMC = peripheral blood mononuclear cells; IL-12 = interleukin-12.Fallarino et al, 1999.
  28. 28. Resolution of Subcutaneous Metastases Following Immunization With MelanA Peptide-Pulsed PBMC + rhIL-12 After 3 Vaccines After 9 Vaccines ORR ~ 10%, With Another 20% SDrhIL-12 = recombinant human IL-12; ORR = overall response rate; SD = stable disease.Peterson et al, 2003.
  29. 29. Vaccination of Patients With Multiple Melanoma Antigen Peptides + IL-12 Can Induce High Levels of Functional Specific T Cells in the Blood However, only a minority of patients (10%) have clinical responses. (Why? – We will return to this question later [predictive biomarkers])Peterson et al, 2003.
  30. 30. Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  31. 31. CTLA-4 Blockade for Immunopotentiation CTLA-4 is receptor induced on activated T cells Ligation inhibits T cell activation CTLA-4 deficient mice develop autoimmunity  dominant role is negative Two defined ligands expressed largely on APC populations: B7-1 and B7-2 Neutralizing mAbs against CTLA-4 augment T-cell activation and promote tumor rejection in several mouse models Two anti-CTLA-4 mAbs explored in clinical trials Ipilimumab approved by FDA in 2011CTLA-4 = cytotoxic T lymphocyte antigen-4; mAbs = monoclonal antibodies.Pardoll, 2012; YervoyTM prescribing information, 2012.
  32. 32. CTLA-4 Is a Negative Regulator of T-Cell Activation Resting T Cell Activated T Cell B7 B7 CD28 CD28 T Cell TCR APC T Cell TCR APC CTLA4 B7Pardoll, 2012; Korman et al, 2006.
  33. 33. Randomized Study of Vaccine Vs. Ipilimumab Vs. Combination in Advanced MelanomaIpi = ipilimumab.Hodi et al, 2010.
  34. 34. Clinical Response in Melanoma With Single Agent Anti-CTLA-4 mAb Screening Week 12: Progression Week 20: Regression Week 36: Still RegressingWolchok et al, 2008.
  35. 35. T-Cell Infiltration in Skin and Gut Following Anti-CTLA-4 mAb TreatmentSarnaik et al, 2009.
  36. 36. Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  37. 37. IL-2 in Melanoma: RR 16%Atkins et al, 1999.
  38. 38. Modified gp100 Peptide in Montanide +/- Exogenous IL-2 Additional 19 patients treated with high-dose IL-2 after gp100 209M vaccination In this study, 8 patients (42%) showed objective tumor regression Suggests IL-2 may help expand relevant T cells or support their trafficking Caveat: Effect of IL-2 alone?Rosenberg et al, 1998.
  39. 39. High-Dose IL-2 ± Peptide Vaccine Phase IIISchwartzentruber et al, 2011.
  40. 40. Model for CD8+ T-Cell Mediated Anti- Tumor Immune Response In Vivo (cont.) MHC I MHC II Immature DC Migration From Tumor Tumor granzymes TCR eCD8 B7 APC Mature DC Adoptive T-cell therapy eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  41. 41. Adoptive T-Cell Therapy T cells are isolated, from tumor site or generated in vitro Adoptive transfer Ex vivo enrichment and into expansion of antigen-specific patient In vitro effector T cells expansion and activation T cells are reintroduced back to the patient T cells Usually the patient is isolated “conditioned” first with lympho from depleting chemotherapy or patient other agentsYee, 2009.
  42. 42. TIL Therapy for Melanoma: Rosenberg Approach  Tumor harvested, TILs collected and expanded for infusion  In interim, patients receive lymphoablative chemotherapy to “make space”  T cells are transferred and patients are given IL-2  Results: 6 of 13 patients respondedTILs = tumor-infiltrating lymphocytes.Dudley et al, 2003.
  43. 43. Phase II Trial: Adoptive-Cell Therapy • Stage IV melanoma (N = 35) • Received autologous, tumor- reactive, expanded tumor- infiltrating lymphocytes + IL-2 after lymphodepleting conditioning with cyclophosphamide and fludarabine • Results – 3 CR; 15 PR (RR: 51%; DOR: 11.5 mos) – Adoptively transferred CTLs persisted in several patients > 1 year • > 50% RR has held up with further studiesCR = complete response; PR = partial response; RR = response rate; DOR = duration of response.Dudley et al, 2005.
  44. 44. Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response In Vivo: Interventions (cont.) Blockade of suppression MHC I MHC II Immature DC Migration From Tumor Vaccines Tumor granzymes TCR eCD8 B7 Costimulation APC Mature DC Cytokines Chemokines Lymph Node eCD8 nCD8 Migration From Migration to Lymph Node Lymph Node CD28 IL-2Harlin et al, 2009; Gajewski et al, 2006.
  45. 45. Hypothesis  Clinical benefit when it does occur with potent cancer vaccines (and other immunotherapies) has generally not correlated with T cell responses as measured in the blood  Features of the tumor microenvironment could dominate at the effector phase of the anti-tumor T-cell response – T-cell trafficking into tumor – Immune suppressive mechanisms at tumor site – Tumor cell biology and susceptibility to immune-mediated killing – Complexities of the tumor stroma (vasculature, fibrosis)  Reasoned these features could be interrogated through pre- treatment gene expression profiling of tumor site in each individual patient  Such an analysis could identify a predictive biomarker profile associated with clinical response, and also highlight new biologic barriers that need to be overcome to optimize therapeutic efficacy of vaccinesGajewski et al, 2009.
  46. 46. Expression of a Subset of Chemokine Genes Is Associated With Presence of CD8 Transcripts CD8b CCL2 CCL4 CCL5 CXCL9 CXCL10 CCL19 CCL21Harlin et al, 2009.

×