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 IMMUNITY DENDRITIC CELL NK CELL

Adaptive Innate

tumour cell

Suppression

Adjuvant

1863 1898 1957 1973 1974 1976 1983 1985 1991 1992 1995 1996 2002 2008 2009 2010

Timeline: The history of cancer immunotherapy

Immune infiltrates in tumours Treatment with bacterial products Allogeneic BMT Cancer “immunosurveillance” Discovery

• f MHC1-

restricted CD8 T cell First study with IL-2 (1991, 1994) Human tumour- associated antigens Regulatory T cell Chemotherapies and adoptive T cell transfer HPV vaccination Dendritic cell Crosspresentation BCG in bladder cancer IFNα Adoptive cell transfer in cancer TNF in melanoma and sarcoma Toll –like receptors Imiquimod Sipuleucel-T in prostate cancer and ipilimumab in melanoma

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

• ncolytic viruses ( 2017)

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)

2) Human dendritic cells genetically engineered to express a melanoma polyepitope DNA vaccine

Smith et al, Clinical Cancer Research (2001)

• 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 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)

Tumor antigens and related epitopes included in the poly-MEL polyepitope

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

Patel et al, EJC (2008)

Costimulants and adjuvants

IPILIMUMAB IN METASTATIC MELANOMA

Checkpoint inhibitors as successful non-specific enhancers of immune responses

We were still thinking polyepitopes and IL-2 when ……….. 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

Snyder et al, NEJM (2014)

Who benefits and why?

Checkpoint inhibitors – associations with neoepitopes

Snyder et al, NEJM (2014)

Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer

Sahin et al, Nature (2017)

• 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

Tackling the coverage of the antigenic repertoire

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

COMBINING ONCOLYTIC VIROTHERAPY with TUMOUR IMMUNOTHERAPY ……. so what can we do now?

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

N P M L

leader RBZ T7 T7 term

G

VSV-XN2

GFP cDNA

VSV-cDNA VSV-GFP

N P M G N P M G L L

mRNA from Target Cell Type: Normal Mouse Prostate Normal Human Prostate Mouse Prostate Tumour Human Prostate Tumour Embryonic Cells

Organ Specific Oncolytic Virus (VSV) Incorporated Antigen Library

Vesicular stomatitis virus

ASEL ASEL-CD8 ASEL-NK ASEL-CD4

Time (d) Survival (%)

PROSTATE CANCER VACCINE IN MICE

NINE INJECTIONS REMOVE NK CELLS

REMOVE T LYMPHOCYTES

PROSTATE VACCINE (3 injections) MELANOMA VACCINE (3 injections)

TC2/ASMEL TC2/ASEL

Survival (%) Time (d)

MELANOMA PROSTATE B16/ASEL B16/ASMEL

Survival (%) Time (d)

PROSTATE MELANOMA

Nature Medicine (2011) 17: (7) 854 - 859 Nature Biotechnology (2012) 30: (4) 337 - 43

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

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

Conclusions and next steps: Oncovirvax

Thank you!

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