cancers: A new paradigm in personalized medicine

Transcription

1 Immunotherapies for virus associated cancers: A new paradigm in personalized medicine

2 Acknowledgements QIMR Corey Smith Leone Beagley Andrea Schuessler Vijayendra Dasari Martina Sherritt Maher Gandhi Katherine Matthews Leanne Morrison Leanne Cooper Judy Tellam Tania Crough Leanne Morrison Linda Jones Suzanne Elliott Natasha Stevens Rebecca Elkington Susan walker Siok Tey Prince Charles Hospital Scott Bell Andrew Gailbraith Keith McNeil Dan Chambers Scott Campbell (PAH) Queen MaryHospital Hospital, Hong Kong John Nicholls Daniel Chua Janice Tsang Dora Kwong Briz Brain David Walker Amy Smalley Karolinska Institute Cecilia Söderberg Afsar Rahbar Royal Brisbane Hospital Geoff Hill James Morton Simon Durrant

3 Hallmarks of Cancer Douglas Hanahan & Robert A. Weinberg Cell (2000) 100: 57 70

4 Hallmarks of Cancer: The viral link HTLV1, HCV, EBV, HBV, HPV & KSHV HTLV1, HCV, EBV, HBV, HPV, CMV & KSHV HTLV1, HCV, EBV, HBV, HPV & KSHV HTLV1, HCV, EBV, HBV, HPV, CMV & KSHV HTLV1, HCV, EBV, HBV, HPV & KSHV HTLV1, HCV, EBV, HBV, HPV & KSHV Modified from Cell (2000) 100: 57 70

5 Hallmarks of Cancer: The Next Generation Douglas Hanahan & Robert A. Weinberg Cell 144, March 4, 2011

6 Hallmarks of Cancer: The viral link HTLV1, HCV, EBV, HBV, HPV, CMV & KSHV HTLV1, HCV, EBV, HBV, HPV, CMV & KSHV HTLV1, HCV, EBV, HBV, HPV, CMV & KSHV HTLV1, HCV, EBV, HBV, HPV, CMV & KSHV

7 Hallmarks of Cancer: The viral link

8 Virus associated cancers: Potential targets for immunotherapy VIRUS HBV HCV HPV EBV Hepatocellular carcinoma Hepatocellular carcinoma ASSOCIATED CANCER Cervical cancer; Vaginal cancer; vulvar cancer; Oropharyngeal cancer ; Anal cancer; Penile cancer; Squamous cell carcinoma of the skin Burkitt lymphoma; Non Hodgkin lymphoma; Hodgkin lymphoma; Nasopharyngeal carcinoma KSHV (HHV8) HTLV1 Kaposi sarcoma Adult T cell leukaemia/lymphoma CMV Glioblastoma

9 QIMR CIVD Immunotherapy Program T cell therapy for virus associated human malignancies Epstein Barr virus associated malignancies Post transplantlymphoproliferativedisease transplant lymphoproliferative (PTLD) Nasopharyngeal Carcinoma Hodgkin s Lymphoma Cytomegalovirus associated malignancies Glioblastoma multiforme

10 EBV-associated postebvpost-transplant lymphoproliferative disease (PTLD) Organ Transplant Intensive Immunosuppression T EBV-infected cells proliferate T T T Polyclonal lymphomas Loss of Virus-specific CD8+ T cells

11 Genesis of EBVEBV-associated lymphomas in Transplant Patients Solid Organ Tx Stem Cell Tx EBV transferred in the graft EBV Includes EBV+ B Cells EBV Tx recipient EBVspecific CTL immunity PTLD emerges g of donor origin EBV transferred from the g graft Solid g organ EBV+ cells in graft EBV donated with graft is released Infects recipient B cells EBV CTL immunity PTLD emerges g of recipient origin

12 Pre & Post autologous CTL i immunotherapy th for f PTLD in i SOT p recipient

13 Liver CT scan Pre & Post autologous CTL immunotherapy i th for f PTLD in i SOT p recipient

14 Summary of clinical outcome of T cell immunotherapy for f EBV PTLD n=9 9 n=2 20 n=5 54 n=1 107 %R Response e Complete Response i l Response Partial No Response Prophylaxis Therapeutic Prophylaxis Therapeutic SOT HSCT (data collated from studies carried out by multiple groups)

15 Alternative strategy for adoptive immunotherapy to treat PTLD EBV specific T cells from unrelated HLA matched healthy donors? Safe GvHD Therapeutic Prophylactic Yes No Yes Yes Haque and Crawford, 2003 Lancet Oncology Haque and Crawford, 2010 Transplantation Gandhi et. al Amer. J. Transplant Heslop et. al Blood

16 Allogeneic EBV specific T cells to treat EBV associated PTLD ders of respon Percentage /6 3/6 4/6 5/6 Number of HLA matches between patient and CTL donor % Respo onse Complete Response Partial Response No Response

17 Viral Gene Expression of EBVEBVassociated i t d type t II malignancies li i LMP1 LMP2 EBNA1 EBERs EBNA1 EBERs yi Latency y II Latency Burkitt s Lymphoma Hodgkin s lymphoma Nasopharyngeal carcinoma LMP1 LMP2 EBNA1-6 EBERs y III Latency Post-transplant lymphomas

18 World-wide World wide incidence of EBV EBVassociated nasopharyngeal carcinoma

19 NPC immunotherapy: multiepitope Technology: E1E1-LMPpolyTM EBNA1 GA LMP polyepitope pad5f35 (AdE1 LMPpoly) (AdE1 LMPpoly) E1 LMPpoly Epitope Sequence Antigen HLA Restriction PYLFWLAA LMP2A A23 A24, A23, A24 A30 SSCSSCPLSKI LMP2A A11 TYGPVFMCL LMP2A A24 RRRWRRLTV LMP2A B27 LLSAWILTA LMP2A A2.03 LTAGFLIFL LMP2A A2.06 CLGGLLTMV LMP2A A2.01 VMSNTLLSAW LMP2A A25 IEDPPFNSL LMP2A B40 YLLEMLWRL LMP1 A2.01, A68, A69 YLQQNWWTL LMP1 A2.01 ALLVLYSFA LMP1 A2 IALYLQQNW LMP1 B57, B58 FLYALALLL LMP2A A2.01 WTLVLLI LMP2A B63 CPLSKILL LMP2A B8

20 NPC immunotherapy Production Process

21 NPC Therapy Production Process Cellular Therapy Production Suite (Q-Gen)

22 T cell expansions from stage IV NPC patients using E1E1-LMPpolyTM 11ChLe E1 LMPpoly mediated T cell expansion Control 0.37% IFN--γ 0.26% LMP-1/2 0.27% 27.9% EBNA % Day % Day 14 CD8

23 100 LMP1&2 % CD D8+ IFN-γ po ositive cellls % CD8+ IFN-γ po ositive cellls E1-LMPpolyTM is highly efficient in expanding E1LMP1/2 and EBNA1 EBNA1--specific T cells from stage IV NPC patients Preexpansion p Postexpansion p 100 EBNA Preexpansion p Postexpansion p fold expansion p of LMP1/2 and EBNA-1-specific p T cells

24 E1--LMPpoly T cell therapy is safe E1 with minimal side effects G0 G1 G2 G3 G4 Flu like Sx 14/15 1/15 Malaise 12/15 3/15 Dryy Cough g 13/15 / 2/15 / LBP 14/15 1/15 One SAE occurred for subject 17TaHo

25 Impact of EBVEBV-specific T cell therapy on OS and TTP of stage IV NPC patients Perc cent surrvival 100 Treated (n = 14) 80 Median survival: days Range of TTP: m Mean TTP: 10.2m Median TTP: 9.2m Time (Days)

26 EBV--specific T cell numbers and time to EBV diagnosis of progressive disease Number N of LMP/EEBNA1 speccific T ce ells 107 Spearman r = p = ns Time (months)

27 Future Direction: Combining EBV T cell i immunotherapy th with ith chemo/radiotherapy h / di th 1 wk Before Immunotherapy 4 wk after immunotherapy 12 wks after immunotherapy and 1 cycle of chemotherapy Phase I/II open-label clinical trial of autologous Epstein-Barr virus- specific T cell therapy as consolidative treatment following chemotherapy for metastatic EBV-associated nasopharyngeal carcinoma

28 CMV and Glioblastoma i k to Glioblastoma? Gli bl? A Vi Virall Link Circumstantial evidence hints that cytomegalovirus, y g, a common herpesvirus, p, may play a role in the aggressive brain cancer, but big questions remain

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30 CMV--specific T cell responses in CMV Gli bl t Glioblastoma patients ti t VTE (pp50) HLA A*0101 QIK (IE (IE 1) 1) HLA B*0801 APC lab belled HLA pep M Multimer TPR ((pp65) 65) HLA B* % % 104 TRA (pp65) ( 65) HLA Cw* % % CD8 Quantitative Analysis p= p= % pos sitive %CD8+ HLA A-peptide Multimerr+ cells 100 p=ns Qualitative Analysis Healthy Donors GBM Patients (Healthy) (GBM) (Healthy) (GBM)

31 In vitro stimulation with CMV antigen and C cytokines restores T cell function Pre stimulation APC labelled HLA pep Mulltimer Post stimulation % % % Pre stimulation (Day 0) CD8 Pre stimulation 8% 23% 31% 17% 73% 49% 2% 3% Post stimulation Post stimulation 43% 8% 10% 47% GBM01 59% 12% No cytokines 71% 0% 13% 6% 6% 21% 18% 4% 14% 15% 24% Post stimulation (Day 14) 4% 3% 4% 0% C p = B 63.7% % CD8+ IFN γ + T cells A 2 cytokines 0% 6% 12% 8% 3 cytokines 4 cytokines 17% 22% 62% 65% 18% GBM02 1 cytokine GBM03 GBM04

32 CMV T cell therapy for recurrent GBM patients Total number of patients recruited: 15 Number of patients who have completed: 9 T cell therapy Number of patients undergoing T cell therapy: 1 Number of patients who were unable to complete 2 T cell therapy: Number of patients who were excluded due 3 to progressive disease: