Pattern formation during effector and memory immune responses to cancer

Transcription

1 Pattern formation during effector and memory immune responses to cancer Raluca Eftimie Division of Mathematics University of Dundee, UK June, 2016

2 Why effector& memory immune responses? Changes in CD8+ T cell numbers and phenotype folloing Vaccina&on or infec&on (Nolz, Harty, 2011) Genera&ng a large popula&on of memory T cells is an appealing goal for vaccine design against a variety of human diseases (Nolz, Harty, 2011) The overall number of memory T cells present at the &me of infec&on correlates ith the ability to confer host protec&on against a range of different pathogens

3 Prime-Boost strategies: best approach to generate high nbrs. of immune cells Prime boost vaccination: relies on the re-stimulation of antigen specific immune cells folloing primary memory formation (Nolz, Harty, 2011): Homologous boost: similar primary and secondary viral vectors Heterologous boost: dis6nct primary and secondary viral vectors Ø E.g.: HIV, malaria, tuberculosis vaccines

4 Prime-Boost strategies: best approach to generate high nbrs. of immune cells Prime boost vaccination: relies on the re-stimulation of antigen specific immune cells folloing primary memory formation (Nolz, Harty, 2011): Homologous boost: similar primary and secondary viral vectors Heterologous boost: dis6nct primary and secondary viral vectors Ø E.g.: HIV, malaria, tuberculosis vaccines Can this approach be used to obtain high levels of effector cells that can eliminate cancer cells, and memory cells that can prevent cancer relapse?

5 Tumour vaccination Vaccine viruses: aim to evoke tumour-specific immunity that eradicate tumours & maintain immunological memory Oncolytic viruses (OVs): viruses genetically modified to selectively infect, replicate in and kill tumour cells (Pol et al., 2012) OVs have limited or no impact on normal tissues For a long time: therapeutic efficacy depends on direct viral-tumour interaction (immune system impaires virus delivery & spread) Oncolytic viruses virocentric vie More recently: OVs induce anti-tumour immunity, hich is a key factor in treatment outcome virus in action.jpg immunocentric vie

6 Bartle' et al, Oncoly/c viruses as therapeu/c cancer vaccines, Molecular cancer, 2013, 12:103 Figure 1 ICD of cancer cells induced by OVs leads to antitumor immunity. An OV, delivered either intratumorally or systemically, reaches to tumor tissue and selectively replicates in tumor or/and stromal cells. This leads to induction of death of these cells, presenting eat me signals on the cell surface and later release of danger signals from necrotic cells. Apoptotic bodies are engulfed by APC, and TAAs are processed and presented along ith MHC complex and costimulatory molecules. The released DAMPs (and PAMPs) activate and mature DCs, and TAAs are cross-presented to naive T cells. This process can be further enhanced at different steps by other immunomodulatory agents (in a combination strategy). The resulting cytotoxic immune response against tumor and associated stromal cells, involving CD4 + and CD8 + T cells, may help in complete eradication of tumor mass. Additional immunotherapies targeting DCs, T cells, and the immunosuppressive TME can further enhance this antitumor immune response. Issue ith using viral vectors used to trigger anti-tumour immune responses: the immune response against viral antigen can overhelm the immune response against TAA Potential solution: heterologous prime-boost strategies

7 Experimental protocol (McMaster University, Canada): day 0 day 5 day 19 time ~5days 14 days tumor introduced Melanoma cells (skin cancer) immunization ith a virus expressing a tumor associated antigen Adenovirus (Ad) oncolytic virus + same tumor associated antigen Vesicular Stomatitis Virus (VSV)

8 Experimental protocol (McMaster University, Canada): day 0 day 5 day 19 time ~5days 14 days tumor introduced Melanoma cells (skin cancer) immunization ith a virus expressing a tumor associated antigen Adenovirus (Ad) oncolytic virus + same tumor associated antigen Vesicular Stomatitis Virus (VSV) Expectations: a higher immune response folloing 2nd virus; an even higher immune response folloing the delay of 2nd virus (Bridle et al, 2010) Magnitude of therapeutic effect d 1 d 2 not tested experimentally (length of time beteen primary & secondary antigen administration) a * 7 days c 4 days 100 days

9 Modelling dual-immunisation protocol: complex model Modelling heterologous prime-boost strategies (Eftimie et al., 2010, JTB) McMaster University: dual immunization protocol against tumours: Protocol: (mice) Dynamics of cells: (model) time day 0 ω v d v T day 5 day 14 tumour immunization ith oncolytic virus introduced a virus expressing a + the same (Melanoma cells) tumor associated antigen tumor associated antigen (Adenovirus) (Vesicular Stomatitis Virus) Peripheral Tissue Lymphoid Tissue m r E d pl p i d ef l i d c d m u M r E l d t i mc dy p m pv role role p v rolc p lp rolc δ ω ω v ω VSV (oncolytic) Adenovirus (vaccine) T=tumour cells E=immune effector cells (kill tumor) M=immune memory cells (proliferate)

10 Modelling dual-immunisation protocol: complex model Modelling heterologous prime-boost strategies (Eftimie et al., 2010, JTB) McMaster University: dual immunization protocol against tumours: Protocol: (mice) Dynamics of cells: (model) time day 0 ω v T d v day 5 day 14 tumour immunization ith oncolytic virus introduced a virus expressing a + the same (Melanoma cells) tumor associated antigen tumor associated antigen (Adenovirus) (Vesicular Stomatitis Virus) Peripheral Tissue Lymphoid Tissue m r E d pl p i d ef l i d m c d u M r E l d t ii mc mc dy p v p rolc m pv role role p lp rolc δ ω ω v ω VSV (oncolytic) Adenovirus (vaccine) T=tumour cells E=immune effector cells (kill tumor) M=immune memory cells cells (proliferate)

11 Modelling dual-immunisation protocol: complex model Modelling heterologous prime-boost strategies (Eftimie et al., 2010, JTB) McMaster University: dual immunization protocol against tumours: time day 0 day 5 day 14 Protocol: tumour immunization ith oncolytic virus (mice) introduced a virus expressing a + the same (Melanoma cells) tumor associated antigen tumor associated antigen (Adenovirus) (Vesicular Stomatitis Virus) Peripheral Tissue Lymphoid Tissue m Dynamics r d p i d i m E pl ef l d T c d M of cells: u r E l d ii (model) mc mc d t v dy y m p v pv p rolc role role p lp rolc δ ω v ω ω v ω VSV (oncolytic) Adenovirus (vaccine) T=tumour cells E=immune effector cells (kill tumor) M=immune memory cells cells (proliferate)

12 Modelling dual-immunisation protocol: complex model Modelling heterologous prime-boost strategies (Eftimie et al., 2010, JTB) McMaster University: dual immunization protocol against tumours: time day 0 day 5 day 14 Protocol: tumour immunization ith oncolytic virus (mice) introduced a virus virus expressing a + the same (Melanoma cells) tumor associated antigen tumor associated antigen (Adenovirus) (Vesicular Stomatitis Virus) Peripheral Tissue Lymphoid Tissue m Dynamics r E d pl p i d i of cells: T ef l d d m c u M r E l d ii (model) mc mc d t v dy d m y p v pv rolc role p role p lp rolc δ ω v ω ω v ω VSV (oncolytic) Adenovirus (vaccine) T=tumour cells E=immune effector cells M=immune memory cells cells (kill tumor) (proliferate)

13 Modelling dual-immunisation protocol: complex model Modelling heterologous prime-boost strategies (Eftimie et al., 2010, JTB) McMaster University: dual immunization protocol against tumours: time day 0 day 5 day 14 day 19 Protocol: tumour immunization ith oncolytic oncolytic virus virus + same (mice) introduced a virus virus expressing a + tumor associated the same antigen (Melanoma cells) tumor associated antigen tumor associated (Vesicular Stomatitis antigen Virus) (Adenovirus) (Vesicular Stomatitis Virus) Peripheral Tissue Lymphoid Tissue m Dynamics r d pl i d i of cells: ef l d T E p d m c u M r E l d ii (model) mc mc d t v dy d m pv v p role p v y p rolc role p lp rolc δ ω v ω ω v ω Vesicular Stomatitis VSV (oncolytic) Virus (oncolytic) Adenovirus (vaccine) T=tumour cells E=immune effector cells M=immune memory cells cells (kill tumor) (proliferate)

14 Modelling dual-immunisation protocol: complex model Mathematical model (Eftimie et al., 2010, JTB): ODE since only temporal data available Uninfected tumor: x = rx ( 1 k(x + y) ) x d v η + x v dux z p η 0 + z p Infected tumor: y x z p = d v v δy duy η + x η 0 + z p VSV: v = c v (t) + δby ω v v Ad: = ω Memory: z c = i mc z c + p C () + pv C (v) + m pl (t)z p r l (v)z c d c z c ly(t) Effector Lymph. z l = i l + p E (v)z l + p E ()z l + r l (v)z c d l z l m lp z l ly(t) Effector Periph. z p = m lp z l d pz p d t xz p m pl (t)z p ly(t). Initial Conditions (day 0=day hen Ad injected): Uninfected tumor: x(0) = No infected tumor: y(0) = 0 Ad just injected:(0) = 10 8 No VSV: v(0) = 0 lo immune response: z c (0) = 1, z l (0) = 1.5, z p(0) = 1.5

15 Modelling dual-immunisation protocol: complex model Results: delay in tumour groth folloing Ad+VSV (Eftimie et al., 2010, JTB) tumor size (a) (c) 1.8e e e e+08 1e+08 8e+07 6e+07 4e+07 2e e e e e+08 1e+08 8e+07 6e+07 4e+07 2e+07 Only Ad days after Ad Ad+VSV days after Ad (b) effector cells effector cells (d) Central memory cells Effector cells (lymph.) Effector cells (periph.) Only Ad days after Ad Ad+VSV Central memory cells Effector cells (lymph.) Effector cells (periph.) days after Ad central memory cells central memory cells

16 Modelling dual-immunisation protocol: complex model Anti-tumour immune response vs. anti-tumour viral response (Eftimie et al, 2010, JTB) tumor size tumor size (a) tumor size 2e e+08 1e+08 5e+07 Ad + TAA VSV e+08 Ad, VSV (no TAA) e+08 1e+08 5e days after Ad Ad (b) effector cells (y ep ) effector cells (y ep ) VSV y ep days after Ad 1.2e+09 1e+09 8e+08 6e+08 4e+08 2e+08 oncolytic virus (VSV) oncolytic virus (VSV) remove anti-tumour immune response, but keep anti-viral immune response <=> inject oncolytic virus ithout tumour antigens virus eventually kills the tumour consistent ith results in (Bridle et al, 2010): lack of tumour antigens leads to very poor survival both anti-tumour viral & immune responses are necessary!

17 Modelling dual-immunisation protocol: complex model For the anti-tumour immune response: Can e understand the role of effector vs memory cells in the anti-tumour immune response? are effector cells more important than memory cells?

18 Modelling dual-immunisation protocol: complex model For the anti-tumour immune response: Can e understand the role of effector vs memory cells in the anti-tumour immune response? are effector cells more important than memory cells? use a simplified mathematical model

19 Modelling dual-immunisation protocol: simplified model The simplified model (a) Timeline for dual immunization protocol day 0 day 5 day 19 time Tumor introduced (melanoma B16 cells) 1st innoculated virus (vaccine) 2nd innoculated virus (oncolytic) day 0 time Mathematical modeling timeline (b) VSV virus (v) p m p m d v Memory ym p e Effector y e d e d x d t Tumor cells r x u x i dv δb ω

20 Modelling dual-immunisation protocol: simplified model The simplified model (Macnamara, Eftimie, JTB, 2015) Uninfected tumor: dxu dt Infected tumor: dx i dt VSV: dv dt Memory: dxm dt Effector: dxe dt ( x u + x i ) x u x e = rx u 1 dv v d ux u k h u + x u h e + x e x e x u = d v v δx i d ux i h u + x u h e + x e = δbx i ω vv = p m v h v + v xm (1 xm M = p e v + x u h v + v + x u x m d ex e d tx ux e. )

21 Modelling dual-immunisation protocol: simplified model Long-term dynamics: steady states (Macnamara, Eftimie, JTB, 2015) (a) (b) p e =0.2 p e =0.4 p e =0.8 d e =0.2 d e =0.1 d e =0.05 p e = rate at hich memory cells > effector cells d e = effector cells half-life

22 Modelling dual-immunisation protocol: simplified model Virus-absent case: role of initial memory size (Macnamara, Eftimie, JTB, 2015) A small change in the initial memory population can lead to tumour escape or tumour control Tumour cell population controlled by the effector cell population

23 Modelling dual-immunisation protocol: simplified model Virus-present case: role of initial memory size (Macnamara, Eftimie, JTB, 2015) Tumour controlled by the virus & the effector cell population Paradox: more initial memory cells => higher tumour size at steady state

24 Modelling dual-immunisation protocol: simplified model Summing-up Focus on temporal patterns due to available data Both anti-tumour viral and immune responses are necessary for tumour control (supported by ne experiments: Bridle et al., 2013, OncoImmunology) phase I: virus mediates direct oncolysis of tumour; phase II: anti-tumour immune response The size of the memory population has an important effect on the final outcome of the therapy Bi-stability phenomena for medium levels of memory cells; lo memory ->high tumour; high memory-> lo tumour (under tumour detection limit) Rich long-term dynamics of the model;

25 Modelling dual-immunisation protocol: simplified model Acknoledgements Cicely Macnamara (University of St. Andres) David J.D. Earn (McMaster University) Jonathan L. Bramson (McMaster University) & Bramson s lab Byram W. Bridle (University of Guelph) Jonathan Dushoff (McMaster University)