The next steps for effective cancer immunotherapy and viral vaccines. Peter Selby FACP(UK)

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1 The next steps for effective cancer immunotherapy and viral vaccines Peter Selby FACP(UK) Richard Alan Steve Sasha Matt Nav Vile Melcher Griffin Zougman Bentham Vasudev Adel Nick Gemma Liz Samson Hornigold Migneco Ilett

2 The next steps for effective cancer immunotherapy and viral vaccines Thank you for the FACP(UK) A view of effective cancer vaccines and immunotherapy from a career long perspective at the state-of-the-art in the near future

3 The next steps for effective cancer immunotherapy and viral vaccines Basic ideas remain rather constant: 1) we need to understand what determinants on cancer cells may stimulate an immune response 2) we need to understand what aspects of the biological context might influence whether such a response occurs (danger signals) 3) what presentation of which antigenic determinants can we make to enhance a response? 4) what non-specific stimulation or removal of inhibition might we be able to apply?

4 The next steps for effective cancer immunotherapy and viral vaccines 1) we need to understand what determinants on cancer cells may stimulate an immune response Known tumour associated antigens; polyepitopes of antigens; person specific neoantigen mutation repertoires; cdna antigenic libraries 2) we need to understand what aspects of the biological context might influence whether such a response occurs Non-specific adjuvants (mycobacteria and oncolytic viruses); cytokines (IL-2, 12, 21, etc); Checkpoint inhibitors

5 PRIMING ANTI-TUMOUR IMMUNITY DENDRITIC CELL Innate NK CELL Adjuvant Adaptive Suppression tumour cell

6 Timeline: The history of cancer immunotherapy Immune infiltrates in tumours Allogeneic BMT Cancer immunosurveillance Discovery of MHC1- restricted CD8 T cell First study with IL-2 (1991, 1994) Human tumourassociated antigens Regulatory T cell Chemotherapies and adoptive T cell transfer HPV vaccination Treatment with bacterial products Dendritic cell Crosspresentation BCG in bladder cancer Adoptive cell transfer in cancer IFNα TNF in melanoma and sarcoma Toll like receptors Imiquimod Sipuleucel-T in prostate cancer and ipilimumab in melanoma

7 Cancer Immunotherapy ( ) 1.Non-specific enhancers cytokines (1993, 1999) and checkpoint inhibitors ( 2017) 2.TAAs polyepitopes (2001) and cdna libraries ( 2017) 3.Costimulation and adjuvants mycobacteria (2008) and oncolytic viruses ( 2017)

8 Cancer Immunotherapy (1990s) 1) Non-specific enhancers: System cytokines appeared to improve survival in RCC Interleukin-2 in renal cancer (Cancer Biotherapy, 1993) Interferon-alpha and survival in metastatic renal carcinoma (Lancet, 1999)

9 2) Human dendritic cells genetically engineered to express a melanoma polyepitope DNA vaccine Polyepitope DNA vaccines encoding T-cell epitopes generate multiple cytotoxic T-cell responses in mice We demonstrated human melanoma polyepitope stimulating lymphocytes to generate multiple responses Tumor antigens and related epitopes included in the poly-mel polyepitope Tumor antigen (epitope position) gp100 ( ) gp100 ( ) MAGE-1 ( ) MAGE-3 ( ) MAGE-3 ( ) Melan-A/MART-1 (27 35) Tyrosinase (1 9) Tyrosinase ( ) Epitope sequence (HLA restriction) KTWGQYWQV (A2) YLEPGPVTA (A2) EADPTGHSY (A1) EVDPIGHLY (A1) FLWGPRALV (A2) AAGIGILTV (A2) MLLAVLYCL (A2) YMDGTMSQV (A2) Smith et al, Clinical Cancer Research (2001)

10 Human dendritic cells genetically engineered to express a melanoma polyepitope DNA vaccine induce multiple cytotoxic T-cell responses Smith et al, Clinical Cancer Research (2001)

11 3) An evaluation of a preparation of Mycobacterium vaccae (SRL172) as an immunotherapeutic agent in renal cancer Costimulants and adjuvants Patel et al, EJC (2008)

12 Checkpoint inhibitors as successful non-specific enhancers of immune responses We were still thinking polyepitopes and IL-2 when.. IPILIMUMAB IN METASTATIC MELANOMA But only a small proportion of patients benefit

13 Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma Postow et al, NEJM (2015)

14 Checkpoint inhibitors associations with neoepitopes Who benefits and why? Snyder et al, NEJM (2014)

15 Checkpoint inhibitors associations with neoepitopes Snyder et al, NEJM (2014)

16 Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer Tackling the coverage of the antigenic repertoire Individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach Identification of individual mutations, prediction of neo-epitopes, and manufacture a vaccine for each patient Sahin et al, Nature (2017)

17 Challenges to the development of effective cancer vaccines 1) Poor or complex/expensive coverage of the tumour antigenic repertoire 2) Lack of effective strategies to present the antigenic repertoire in an immunologically appropriate environment 3) Absence of appropriate, safe, clinical vectors to target tumours 4) Resistance is acquired rapidly

18 The next steps for effective cancer immunotherapy and viral vaccines. so what can we do now? COMBINING ONCOLYTIC VIROTHERAPY with TUMOUR IMMUNOTHERAPY

19 Meeting the Challenges for Successful Tumour Immunotherapy Virus mediated cdna library vaccines Identify RELEVANT tumour associated antigens (TAA) cdna library RELEASE relevant TAA for presentation to antigen presenting cells viral-mediated infection in LN RECRUIT/ACTIVATE APC to site of release of relevant TAA for highly immunostimulatory presentation of relevant TAA to potentially tumour antigen specific T cells immunogenicity of VSV The danger signals INCREASE the frequency of fully activated T cells with specificity for relevant TAA viral-associated presentation of TAA

20 Oncolytic Virotherapy and Tumour Immunotherapy

21 Organ Specific Oncolytic Virus (VSV) Incorporated Antigen Library T7 leader N P M G N P M G N P M G GFP cdna L L L RBZ T7 term VSV-XN2 VSV-GFP VSV-cDNA mrna from Target Cell Type: Normal Mouse Prostate Normal Human Prostate Mouse Prostate Tumour Human Prostate Tumour Embryonic Cells Vesicular stomatitis virus

22 Survival (%) PROSTATE CANCER VACCINE IN MICE ASEL-CD8 ASEL-NK ASEL NINE INJECTIONS REMOVE NK CELLS REMOVE T LYMPHOCYTES ASEL-CD4 Time (d)

23 Survival (%) Survival (%) PROSTATE VACCINE (3 injections) MELANOMA VACCINE (3 injections) PROSTATE TC2/ASEL B16/ASMEL MELANOMA TC2/ASMEL PROSTATE B16/ASEL MELANOMA Time (d) Time (d) Nature Medicine (2011) 17: (7) Nature Biotechnology (2012) 30: (4)

24 Checkpoint inhibition improves VSV B16 cdna library vaccine (ASMEL) therapy

25 Conclusions and next steps: Oncovirvax 1) cdna library vaccines can work in mouse in two viruses and three tumour types 2) Biomarker experiments are giving early data much to do 3) Challenging translation to clinical studies

26 Thank you! Richard Alan Steve Sasha Matt Nav Vile Melcher Griffin Zougman Bentham Vasudev Adel Nick Gemma Liz Samson Hornigold Migneco Ilett