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Not Only Chemotherapy Anti-Tumor Vaccines for Tumor Eradication Irit Avivi Department of Hematology and BMT Rambam Medical Health Care Campus Rambam Medical.

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Presentation on theme: "Not Only Chemotherapy Anti-Tumor Vaccines for Tumor Eradication Irit Avivi Department of Hematology and BMT Rambam Medical Health Care Campus Rambam Medical."— Presentation transcript:

1 Not Only Chemotherapy Anti-Tumor Vaccines for Tumor Eradication Irit Avivi Department of Hematology and BMT Rambam Medical Health Care Campus Rambam Medical Health Care Campus Haifa Haifa

2 Talk Plan The immune system in the healthy person The immune system in the healthy person Why does the immune system fail to eradicate cancer ? Why does the immune system fail to eradicate cancer ? Strategies to overcome this immunological impairment Strategies to overcome this immunological impairment Vaccine studies in Myeloma Vaccine studies in Myeloma Future directions Future directions

3 Current Approach to Cancer Current Approach to Cancer Targeting tumor cells chemotherapy – attacking divided cells The tumor is a foreign entity Is their any evidence for anti-tumor response?

4 Evidence for the Role of the Immune System on Cancer Growth Allogeneic stem cell transplantation recipient donor

5 Evidence for the Role of the Immune System on Cancer Growth Allogeneic stem cell transplantation recipient donor Graft-vs-host disease is associated with graft vs tumor effect

6 More Evidence for the Role of the Immune System on Cancer Growth T cells & Antibodies directed against tumor cells T cells & Antibodies directed against tumor cells exist in the circulation exist in the circulation However However Immune responses are ineffective in preventing disease establishment and progression

7 Why ?

8 The Immune Response B DC T FORIEGN B T T T T T

9 Dendritic Cells- The most important Antigen Presenting Cells T T T T DC maturation iDC Monocytes mDC

10 Berzofsky et al JCI 2004

11 CD40L MHC- peptide Antigen Presentation mDC T T cell activation

12 How does the Tumor Escape the Immune System? How does the Tumor Escape the Immune System? DC T T T T Tumor Activation Anergy VEGF IL6

13 Antigen Presentation

14 How does the Tumor Escape the Immune System? How does the Tumor Escape the Immune System? DC T T T T Tumor Activation Anergy VEGF IL6 CTLA-4 Trg PDL1 PD1 PDL1 PD1 T T

15 How Does the Tumor Escape the Immune System? How Does the Tumor Escape the Immune System? The tumor expresses Host Ags The tumor expresses Host Ags It impairs DC maturation and function It impairs DC maturation and function Interferes with Antigen presentation Interferes with Antigen presentation The tumor interacts with T cells Anergy The tumor interacts with T cells Anergy The tumor express inhibitory molecules The tumor express inhibitory molecules The tumor induces accumulation of regulatory T cells The tumor induces accumulation of regulatory T cells

16 Strategies to Overcome Tumor-Induced Immunological Defects Tumor escape Overcoming Tumor escape Overcoming Host Ags Tumor specific Ags Host Ags Tumor specific Ags Immunogenic stimulators Immunogenic stimulators Impaired DCs Maturation Ex vivo DCs maturation Impaired DCs Maturation Ex vivo DCs maturation T cell Anergy Interfere with T cell Anergy Interfere with mechanisms involved mechanisms involved in anergy in anergy

17 Ex vivo DC Maturation Results in Potent Mature DCs DC T T T Ex vivo In Vivo= with Tumor T DC maturation

18 Strategies to Load Tumor Antigens onto DC Tumor cell fusion Loading of Tumor lysate Loading of Tumor peptides Individual Ag Whole Cell

19 Vaccination with Individual Antigens Advantages Advantages Tumor specificity Tumor specificity Feasibility Feasibility Monitoring response against defined Ag Monitoring response against defined Ag Lower risk for autoimmunity Lower risk for autoimmunity Disadvantages Disadvantages Limited number of antigens Limited number of antigens HLA restriction HLA restriction Tumor evasion through down regulation of antigen expression Tumor evasion through down regulation of antigen expression

20 Vaccination with Whole Cell Derived Antigens Advantages Advantages Broad response limits risk of tumor evasion Broad response limits risk of tumor evasion Presentation of unidentified & patient’s -tumor specific Ags Presentation of unidentified & patient’s -tumor specific Ags Presence of helper (DC4) and CTL (CD8) response crucial for maintenance of long term immune response Presence of helper (DC4) and CTL (CD8) response crucial for maintenance of long term immune response Disadvantages Disadvantages Technical challenge of manipulating whole cells for multi-center setting Technical challenge of manipulating whole cells for multi-center setting Risk of auto-immunity Risk of auto-immunity

21 Fusion Vaccines

22 Why did we Choose Myeloma? 7 year survival Relapse rate Khaled Y et al, BMT 44:325, 2009

23 Myeloma- Immunomodulated Disease

24 “Vaccination” with DC/MM Fusions

25 Vaccination with DC/MM Fusions: Trial Design Phase I dose escalation trial Phase I dose escalation trial Eligibility Eligibility Patients with advanced stage myeloma Patients with advanced stage myeloma Presence of measurable disease Presence of measurable disease > 20% plasma cells in bone marrow for vaccine generation > 20% plasma cells in bone marrow for vaccine generation Vaccination Schedule: Vaccination Schedule: 3 subcutaneous vaccinations in conjunction with GM-CSF administered every 3 weeks 3 subcutaneous vaccinations in conjunction with GM-CSF administered every 3 weeks

26 Adherent PBMCs cultured for 5-7 days with GM-CSF & IL-4; TNF-  added for hours Myeloma cells isolated DCs assessed for DC & tumor specific markers Myeloma cells assessed for tumor & DC specific markers DC & myeloma fused with 50% PEG at DC: tumor, 3:1 to 10:1 Fusion cells quantified by measuring dual expression of unique DC & tumor markers Doses prepared & frozen microbiology testing sent Leukapharesis Bone marrow aspiration CD38 MUC1 DR CD86 CD38 CD40 CD83 CD80 CD138 GM-CSF 100ug at vaccine site for 4 days Monocytes n=18

27 Myeloma Cells CD-38 Dendritic Cells CD86 Vaccine Characterization Fusion cell

28 Adverse Events Treatment associated events, transient grade I-II: Treatment associated events, transient grade I-II: Injection site reactions 37 Injection site reactions 37 Edema 6 Edema 6 Muscle Aches 5 Muscle Aches 5 Fatigue 2 Fatigue 2 Fever 1 Fever 1 Chills/sweats 2 Chills/sweats 2 Diarrhea 1 Diarrhea 1 Pruritis 1 Pruritis 1 Rash 2 Rash 2 Anorexia 1 Anorexia 1 No Autoimmune disorders No Autoimmune disorders Episode of DVT/PE with antecedent history of DVT Episode of DVT/PE with antecedent history of DVT

29 Vaccine site reaction: Skin Biopsy

30 Immunological Response: Vaccine Site Reaction Recruitment of “ attacking” CD8 T cells Recruitment of antigen- presenting DCs (CD1a)

31 Stimulation Index (SI) ( n=16) Fusion Cells Stimulate Allo – CD8 +T cell

32 Tumor Lysate Induced IFNγ Expression by CD8+ T cells

33 Pre- vaccination# month post vaccination Pre- mobilization Post- transplantation IFN  CD8 FITC Vaccination Induced Immune Response

34 Persistent Response against Tumor Specific Antigen % MUC1 CD8 Pre vaccine 1 month post 3 months post Immunologic response associated with disease stabilization

35 Vaccination with DC/Myeloma Fusions: Conclusions Vaccination is feasible and well tolerated Vaccination is feasible and well tolerated Majority of patients show immunologic response Majority of patients show immunologic response Disease stabilization in a majority of patients Disease stabilization in a majority of patients

36 How to Improve the Efficacy of Fusion Vaccines? Administer to patients with Administer to patients with minimal residual disease minimal residual disease Administer after eliminating Regulatory T cells Administer after eliminating Regulatory T cells

37 High Dose Therapy (HDT) Provides minimal residual disease Provides minimal residual disease Induces a significant reduction in Induces a significant reduction in suppressive regulatory T cells suppressive regulatory T cells “ A vaccine supportive environment ”

38 Induction Therapy Cohort 2 Cohort 1 and 2 Inclusion: ASCT ; Exclusion: Autoimmunity

39 Study Update 41 patients enrolled to date All underwent successful vaccine generation 21 - completed vaccinations, Med FU 22 - ongoing study Vaccine details: Mean percent of fusion: 40%; Fusion viability: 78% Mean percent of fusion: 40%; Fusion viability: 78% Mean dose: 3.9 x 10 6 fusion cells Mean dose: 3.9 x 10 6 fusion cells Safety: unchanged. 2 ANA without symptoms Safety: unchanged. 2 ANA without symptoms

40 Percentage of CD4+ T cells expressing IFN  Percentage of CD8+ T cells expressing IFN  Mean Percentage of Tumor Reactive T Cells Pre TxPost TxPeak Post Vaccine Peak Post Vaccine Post Tx Pre Tx CD4 CD8 Immunological Response to Vaccine

41 Clinical Response Transplant Vaccination Post-tx 1 month Post-tx 4 months Post-tx 9 months CR/nCR 67%

42 Response Rate Percentage of Patients Achieving CR Over Time 68% -complete response or very good partial response >>>> 40% with HDT only

43 Vaccination with DC/MM Fusions Following SCT Conclusions Feasible & well tolerated Feasible & well tolerated Induces a significant anti-myeloma Induces a significant anti-myeloma immune response immune response Results in a high response rate Results in a high response rate Strong correlation between immunological and clinical responses Strong correlation between immunological and clinical responses

44 How to improve?

45 How does the Tumor Escape the Immune System? How does the Tumor Escape the Immune System? DC T T T T Tumor Activation Anergy VEGF IL6 CTLA-4 Trg PDL1 PD1 PDL1 PD1 T T

46 PD-L1/PD-1 Pathway PD-L1 -an inhibitory ligand expressed by APCs Signals via the costimulatory complex promotes Induces apoptosis of memory effector cells & disrupts CTL mediated lysis Inhibits T cell activation

47 PDL-1 Expressed by Tumor is Associated with Tolerance Shin & Rehermann Nature Medicine 2006

48 IgG PDL1 DC MM PDL-1 is Expressed by DCs and Myeloma Cells

49 17.3%4.8% ControlMyeloma Patients IgG PD-1 CD 4 PD-1 Expression on T cells

50 p=0.004 Mean PD-1 Expression on CD4 T cells : Increase with Advanced Disease % Expression (CD 4 T Cells)

51 CD4 T cell expressing PD-1 Increase Following Fusion Stimulation % Expression of PD-1 (CD 4 T cells)

52 PDL-1 Expression on DC/Myeloma Fusions CD 86 CD 38 PDL-1

53 PD-1 Blockade CT-011: clinical humanized PD1 antibody CT-011: clinical humanized PD1 antibody Binds effector memory Tcs, resulting in their activation and inhibition of apoptosis Binds effector memory Tcs, resulting in their activation and inhibition of apoptosis In animal models, administration induced anti-tumor immune responses & tumor regression In animal models, administration induced anti-tumor immune responses & tumor regression Clinical Trials: Clinical Trials: Phase I trial : tolerated with evidence of clinical benefit Phase I trial : tolerated with evidence of clinical benefit Administration post ASCT results in increased CD4+ effector memory T cells (Rotem-Yehudar et al., A1216; Ash 2009) Administration post ASCT results in increased CD4+ effector memory T cells (Rotem-Yehudar et al., A1216; Ash 2009)

54 % Expression of PD-1 (CD 4 T cells ) PD-1 Blockade Results in Downregulation of PD-1 Expression on CD 4 T Cells following Fusion Stimulation

55 p=0.048 % Expression of IFNγ (CD4 T cells) PD-1 Blockade Results in Increased Interferon-gamma Following Fusion Stimulation

56 CD8/IFNgCD8/IgGCD8/IFNg In Vivo Vaccine Primed Tumor Reactive T cells are Increased in the Presence of Ex-vivo PD-1 Blockade ) Pre-Vaccine #1 1 month post vaccines FL1-H FL1-H FL1-H CD8 CD8 INFG CD8INFG + AntiPD1

57 PD-1 Blockade Results in Increased Lysis of Autologous Tumor by Fusion Stimulated T Cells Granzyme Tumor + Anti-PD-1 Control 23% 32%

58 PD1-PDL1 pathway in Myeloma Strong in vitro data supporting the potential role of PD1-PDL1 pathway in myeloma Strong in vitro data supporting the potential role of PD1-PDL1 pathway in myeloma - High expression of PDL1 on DCs & MM cells - High expression of PDL1 on DCs & MM cells - High expression of PDL on T cells - High expression of PDL on T cells PD1-PDL1 blockade improved anti-tumor response in vitro PD1-PDL1 blockade improved anti-tumor response in vitro The in vitro data provide strong platform for combining anti PD1-PDL1 hrapy with The in vitro data provide strong platform for combining anti PD1-PDL1 hrapy with

59 Directions Choose the right tumor: Choose the right tumor: Immunogenic vs “Non Immunogenic? Immunogenic vs “Non Immunogenic? Improve the immunogenic target: Improve the immunogenic target: specific peptides vs whole tumor ? specific peptides vs whole tumor ? Control the inhibitory environment Control the inhibitory environment

60 Potential Approaches Potential Approaches DC T T T T Tumor Activation Anergy VEGF IL6 CTLA-4 Trg PDL1 PD1 PDL1 PD1 T T

61 The Rambam- Harvard Vaccine Program DC/MM – anti PD1L Myeloma vaccine study DC/MM – anti PD1L Myeloma vaccine study DC/MM- immuno-mudulatory drug study DC/MM- immuno-mudulatory drug study DC/AML- anti PD1L Myeloma vaccine study DC/AML- anti PD1L Myeloma vaccine study DC/RCC – Sunitinib Study DC/RCC – Sunitinib Study Sunitinib -kinase inhibitor of Flt3, Kit, VEGF Sunitinib -kinase inhibitor of Flt3, Kit, VEGF and PDGF receptors and PDGF receptors Pre-clinical study for vaccination for CLL Pre-clinical study for vaccination for CLL

62 Acknowledgments Hematology Department, RMC Hematology Department, RMC Tami Katz, Tami Katz, Lina Bisharat, Lina Bisharat, Jacob M Rowe Jacob M Rowe Hematology Department, BIDMC Hematology Department, BIDMC Jacalyn Rosenblat Jacalyn Rosenblat David Avigan David Avigan

63 Thanks


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