Peter Selby FACP(UK) Richard Alan Steve - PowerPoint PPT Presentation

“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

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

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?

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

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

Timeline: The history of cancer immunotherapy Allogeneic BMT (1991, 1994) Human Immune Discovery tumour- infiltrates of MHC1- in tumours restricted associated First study Chemotherapies Regulatory Cancer HPV CD8 T cell antigens with IL-2 and adoptive T cell “immunosurveillance” T cell vaccination transfer 1863 1898 1957 1973 1974 1976 1983 1985 1991 1992 1995 1996 2002 2008 2009 2010 Dendritic Toll – like Sipuleucel-T Treatment with Crosspresentation Adoptive cell TNF in Imiquimod cell in prostate bacterial products transfer in cancer melanoma receptors cancer and and sarcoma ipilimumab in BCG in bladder melanoma IFN α cancer

Cancer Immunotherapy (1971 – 2017) 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)

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

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) Epitope sequence (HLA restriction) gp100 (154 – 162) KTWGQYWQV (A2) gp100 (280 – 288) YLEPGPVTA (A2) MAGE-1 (161 – 169) EADPTGHSY (A1) MAGE-3 (161 – 169) EVDPIGHLY (A1) MAGE-3 (271 – 279) FLWGPRALV (A2) Melan-A/MART-1 (27 – 35) AAGIGILTV (A2) Tyrosinase (1 – 9) MLLAVLYCL (A2) Tyrosinase (368 – 376) YMDGTMSQV (A2) Smith et al, Clinical Cancer Research (2001)

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)

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)

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

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

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

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

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)

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

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

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

Oncolytic Virotherapy and Tumour Immunotherapy

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

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

PROSTATE VACCINE MELANOMA VACCINE (3 injections) (3 injections) PROSTATE TC2/ASEL B16/ASMEL Survival (%) Survival (%) MELANOMA PROSTATE B16/ASEL MELANOMA TC2/ASMEL Time (d) Time (d) Nature Medicine (2011) 17: (7) 854 - 859 Nature Biotechnology (2012) 30: (4) 337 - 43

Checkpoint inhibition improves VSV B16 cDNA library vaccine (ASMEL) therapy

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

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