Treatment strategies for combining immunostimulatory oncolytic virus therapeutics with dendritic cell injections

  • Received: 01 October 2014 Accepted: 29 June 2018 Published: 01 August 2015
  • MSC : Primary: 92C50, 92B05; Secondary: 37N25.

  • Oncolytic viruses (OVs) are used to treat cancer, as they selectively replicate inside of and lyse tumor cells. The efficacy of this process is limited and new OVs are being designed to mediate tumor cell release of cytokines and co-stimulatory molecules, which attract cytotoxic T cells to target tumor cells, thus increasing the tumor-killing effects of OVs. To further promote treatment efficacy, OVs can be combined with other treatments, such as was done by Huang et al., who showed that combining OV injections with dendritic cell (DC) injections was a more effective treatment than either treatment alone. To further investigate this combination, we built a mathematical model consisting of a system of ordinary differential equations and fit the model to the hierarchical data provided from Huang et al. We used the model to determine the effect of varying doses of OV and DC injections and to test alternative treatment strategies. We found that the DC dose given in Huang et al. was near a bifurcation point and that a slightly larger dose could cause complete eradication of the tumor. Further, the model results suggest that it is more effective to treat a tumor with immunostimulatory oncolytic viruses first and then follow-up with a sequence of DCs than to alternate OV and DC injections. This protocol, which was not considered in the experiments of Huang et al., allows the infection to initially thrive before the immune response is enhanced. Taken together, our work shows how the ordering, temporal spacing, and dosage of OV and DC can be chosen to maximize efficacy and to potentially eliminate tumors altogether.

    Citation: Joanna R. Wares, Joseph J. Crivelli, Chae-Ok Yun, Il-Kyu Choi, Jana L. Gevertz, Peter S. Kim. Treatment strategies for combining immunostimulatory oncolytic virus therapeutics with dendritic cell injections[J]. Mathematical Biosciences and Engineering, 2015, 12(6): 1237-1256. doi: 10.3934/mbe.2015.12.1237

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  • Oncolytic viruses (OVs) are used to treat cancer, as they selectively replicate inside of and lyse tumor cells. The efficacy of this process is limited and new OVs are being designed to mediate tumor cell release of cytokines and co-stimulatory molecules, which attract cytotoxic T cells to target tumor cells, thus increasing the tumor-killing effects of OVs. To further promote treatment efficacy, OVs can be combined with other treatments, such as was done by Huang et al., who showed that combining OV injections with dendritic cell (DC) injections was a more effective treatment than either treatment alone. To further investigate this combination, we built a mathematical model consisting of a system of ordinary differential equations and fit the model to the hierarchical data provided from Huang et al. We used the model to determine the effect of varying doses of OV and DC injections and to test alternative treatment strategies. We found that the DC dose given in Huang et al. was near a bifurcation point and that a slightly larger dose could cause complete eradication of the tumor. Further, the model results suggest that it is more effective to treat a tumor with immunostimulatory oncolytic viruses first and then follow-up with a sequence of DCs than to alternate OV and DC injections. This protocol, which was not considered in the experiments of Huang et al., allows the infection to initially thrive before the immune response is enhanced. Taken together, our work shows how the ordering, temporal spacing, and dosage of OV and DC can be chosen to maximize efficacy and to potentially eliminate tumors altogether.


    1. Introduction

    Consider the following Euler-Poisson system for the bipolar hydrodynamical model of semi-conductor devices:

    $ {n1t+j1x=0,j1t+(j21n1+p(n1))x=n1Ej1,n2t+j2x=0,j2t+(j22n2+q(n2))x=n2Ej2,Ex=n1n2D(x),
    $
    (1)

    in the region $ \Omega = {\bf (0, 1)}\times R_{+}$. In this paper, $ n_{1}(x, t)$, $ n_{2}(x, t)$, $ j_{1}(x, t)$, $ j_{2}(x, t)$ and $ E(x, t)$ represent the electron density, the hole density, the electron current density, the hole current density and the electric field, respectively. In this note, we assume that the $p$ and $q$ satisfy the $\gamma$-law:$p(n_1) = n_{1}^{2}$ and $q(n_2) = n_{2}^{2}$ ($\gamma = 2$), which denote the pressures of the electrons and the holes. The function $D(x)$, called the doping profile, stands for the density of impurities in semiconductor devices.

    For system $(1)$, the initial conditions are

    $ n_{i}(x, 0) = n_{i0}(x) \ge 0, \;\; j_{i}(x, 0) = j_{i0}(x), \;\; i = 1, 2, $ (2)

    and the boundary conditions at $x = 0$ and $x = 1$ are

    $ j_{i}(0, t) = j_{i}(1, t) = 0, \;\; i = 1, 2, \;\; E(0, t) = 0. $ (3)

    So, we can get the compatibility condition

    $ j_{i0}(0) = j_{i0}(1) = 0, \;\; i = 1, 2. $ (4)

    Moreover, in this paper, we assume the doping profile $D(x)$ satisfies

    $ D(x)\in C[0, 1]~ {\rm{and}}~ D^* = \mathop {{\rm{sup}}}\limits_x D(x)\ge \mathop {{\rm{inf}}}\limits_x D(x) = D_*. $ (5)

    Now, the definition of entropy solution to problem $(1)-(4)$ is given. We consider the locally bounded measurable functions $ n_{1}(x, t)$, $ j_{1}(x, t)$, $ n_{2}(x, t)$, $ j_{2}(x, t)$, $ E(x, t)$, where $ E(x, t)$ is continuous in $x$, a.e. in $t$.

    Definition 1.1. The vector function $ (n_{1}, n_{2}, j_{1}, j_{2}, E)$ is a weak solution of problem $(1)-(4)$, if it satisfies the equation $(1)$ in the distributional sense, verifies the restriction $(2)$ and $(3)$. Furthermore, a weak solution of system $(1)-(4)$ is called an entropy solution if it satisfies the entropy inequality

    $ \eta_{et}+ q_{ex}+\frac{j_{1}^2}{n_{1}}+\frac{j_{2}^2}{n_{2}}-j_{1}E+j_{2}E \leq0, $ (6)

    in the sense of distribution. And the $(\eta_{e}, q_{e})$ are mechanical entropy-entropy flux pair which satisfy

    $ \left\{ηe(n1,n2,j1,j2)=j212n1+n21+j222n2+n22,qe(n1,n2,j1,j2)=j312n21+2n1j1+j322n22+2n2j2.
    \right. $
    (7)

    For bipolar hydrodynamic model, the studies on the existence of solutions and the large time behavior as well as relaxation-time limit have been extensively carried out, for example, see [1][2][3][4][5][6] etc. Now, we make it into a semilinear ODE about the potential and the pressures with the exponent $\gamma = 2$. We can get the existence, uniqueness and some bounded estimates of the steady solution. Then, using a technical energy method and a entropy dissipation estimate, we present a framework for the large time behavior of bounded weak entropy solutions with vacuum. It is shown that the weak solutions converge to the stationary solutions in $L^2$ norm with exponential decay rate.

    The organization of this paper is as follows. In Section 2, the existence, uniqueness and some bounded estimates of stationary solutions are given. we present a framework for the large time behavior of bounded weak entropy solutions with vacuum in Section 3.


    2. Steady solutions

    In this part, we will prove the existence and uniqueness of steady solution to problem $(1)-(4)$. Moreover, we can obtain some important estimates on the steady solution $(N_1, N_2, \mathcal{E})$.

    The steady equation of $(1)-(4)$ is as following

    $ \left\{J1=J2=0,2N1N1x=N1E,2N2N2x=N2E,Ex=N1N2D(x),
    \right. $
    (8)

    and the boundary condition

    $ {\mathcal{E}}(0) = 0. $ (9)

    We only concern the classical solutions in the region where the density

    $ \mathop {{\rm{inf}}}\limits_x {N_1}>0~~~ {\rm {and}}~~~ \mathop {{\rm{inf}}}\limits_x {N_2}>0. $ (10)

    hold.

    Now, we introduce a new variation $\Phi(x)$, and make $\Phi'(x)$: = ${\mathcal{E}}(x)$. To eliminate the additive constants, we set $\int_0^1{\Phi(x)}dx = 0$. Then (2.1) turns into

    $ \left\{2N1x=Φx,2N2x=Φx,Φxx=N1N2D(x).
    \right. $
    (11)

    Obviously, $(11)_{1}$ and $(11)_{2}$ indicate

    $ \left\{N1(x)=12Φ(x)+C1,N2(x)=12Φ(x)+C2,Φxx(x)=12Φ(x)+C1+12Φ(x)C2D(x).
    \right. $
    (12)

    where $C_{1}$ and $C_{2}$ are two unknown positive constants. To calculate these two constants, we suppose*

    *Using the conservation of the total charge: integrating $(1)_1$ and $(1)_3$ from 0 to 1

    $ \big{(}\int_0^1 n_idx\big{)}_t = -\int_0^1 j_{ix}dx = 0, ~~{\rm{for}}~~ i = 1, 2, $

    we see this assumption is right.

    $ \int_0^1\bigg{(}n_i(x, 0)-N_i(x)\bigg{)}dx = 0 ~~{\rm{for}}~~ i = 1, 2, $ (13)

    then

    $ \bar{n}_1: = \int_0^1n_1(x, 0)dx = \int_{0}^{1}N_1(x)dx = \int_{0}^{1}\big{(}\frac{\Phi(x)}{2}+C_1\big{)}dx = C_1, \\ \bar{n}_2: = \int_0^1n_2(x, 0)dx = \int_{0}^{1}N_2(x)dx = \int_{0}^{1}\big{(}-\frac{\Phi(x)}{2}+C_2\big{)}dx = C_2. $ (14)

    Substituting $(14)$ into $(12)_3$, we have

    $ \Phi_{xx} = \Phi(x)+\bar{n}_1-\bar{n}_2-D(x). $ (15)

    Clearly, we can prove the existence and uniqueness of solutions to $(15)$ with the Neumann boundary condition

    $ \Phi_x(0) = \Phi_x(1) = 0. $ (16)

    Integrate$(15)$ from $x = 0$ to $x = 1$, we get

    $ \bar{n}_1-\bar{n}_2 = \int_{0}^{1}D(x)dx. $ (17)

    Suppose $\Phi(x)$ attains its maximum in $x_0\in [0, 1]$, then we get $\Phi_{xx}(x_0) \le 0$ and

    If $x_0\in (0, 1)$, then $\Phi_x(x_0) = 0, $ $\Phi_{xx}(x_0) \le 0$ clearly. If $x_0 = 0$ or $x_0 = 1$, the Taylor expansion

    $ \Phi(x) = \Phi(x_0)+\Phi'(x_0)(x-x_0)+{{\Phi''}(x_0)\over 2}(x-x_0)^2+o(x-x_0)^2, $

    the boundary condition ($16$) indicates ${\Phi''}(x_0) \le 0$.

    $ \Phi(x_0)+\bar{n}_1-\bar{n}_2-D(x_0)\leq0 . $

    So we get

    $ \Phi(x_0)\leq D^{*}+\bar{n}_2-\bar{n}_1 . $ (18)

    Similarly, if $\Phi $ attains its minimum in $x_1\in [0, 1]$, we obtain

    $ \Phi(x_1) \ge D_{*}+\bar{n}_2-\bar{n}_1 . $ (19)

    Moreover, from $(12), (14), (15), (18)$, and $(19)$, we have

    $ \frac{D_*+\bar{n}_2+\bar{n}_1}{2}\leq N_1(x)\leq \frac{D^*+\bar{n}_2+\bar{n}_1}{2}, \\\\ \frac{-D^*+\bar{n}_2+\bar{n}_1}{2}\leq N_2(x)\leq \frac{-D_*+\bar{n}_2+\bar{n}_1}{2}, $ (20)
    $ D_* \le (N_1-N_2)(x) \le D^* ~~{\rm {for~any }}~~ x\in [0, 1]. $ (21)

    Above that, the theorem of existence and uniqueness of steady equation is given.

    Theorem 2.1. Assume that $(5)$ holds, then problem $(8)$, $(9)$ has an unique solution $(N_1, N_2, {\mathcal{E}})$, such that for any $x\in [0, 1]$

    $ n_* \le N_1(x) \le n^*, ~~ n_* \le N_2(x) \le n^*, $ (22)

    and

    $ D_* \le (N_1-N_2)(x) \le D^*, $ (23)

    satisfy, where

    $ n^*: = \max\bigg{\{}{\frac{D^*+\bar{n}_2+\bar{n}_1}{2}, \frac{-D_*+\bar{n}_2+\bar{n}_1}{2}}\bigg{\}}, \\\\ n_*: = \min\bigg{\{}{\frac{D_*+\bar{n}_2+\bar{n}_1}{2}, \frac{-D^*+\bar{n}_2+\bar{n}_1}{2}}\bigg{\}}, $ (24)

    $ \bar{n}_{1} $, $ \bar{n}_{2} $ are defined in $(14)$.


    3. Large time behavior

    Now, our aim is to prove the weak-entropy solution of $(1)-(4)$ convergences to corresponding stationary solution in $L^2$ norm with exponential decay rate. For this purpose, we introduce the relative entropy-entropy flux pair:

    $ η(x,t)=2i=1(j2i2ni+n2iN2i2Ni(niNi))(x,t)=(ηe2i=1Qi)(x,t)0,
    $
    (25)
    $ q(x,t)=2i=1(j3i2n2i+2niji2Niji)(x,t)=(qe2i=1Pi)(x,t),
    $
    (26)

    where

    $Q_i = {N_i^2+2N_i(n_i - N_i)}, \;\; P_i = 2N_ij_i, $

    $\eta_e$ and $q_e$ are the entropy-entropy flux pair defined in $(1.7)$.

    The following theorem is our main result in section 3.

    Theorem 3.1(Large time behavior) Suppose $(n_1, n_2, j_1, j_2, E)(x, t)$ be any weak entropy solution of problem $(1.1)-(1.4)$ satisfying

    $ 2(2D^*-\bar{n}_1-\bar{n}_2)<(n_1-n_2)(x, t)< 2(2D_*+\bar{n}_1+\bar{n}_2), $ (27)

    for a.e. $x\in [0, 1]$ and $t>0$. $(N_1, N_2, {\mathcal{E}})(x)$ is its stationary solution obtained in Theorem 2.1. If

    $ \int_0^1 \eta^*(x, 0)dx<\infty, ~~ \int_0^1\bigg{(}n_i(s, 0)-N_i(s)\bigg{)}ds = 0, $ (28)

    then for any $t>0$, we have

    $ \int_0^1[j_1^2+j_2^2+(E-{\mathcal{E}})^2+(n_1-N_1)^2+(n_2-N_2)^2](x, t)dx\\\\ \;\;\;\; \le C_0e^{-\tilde{C}_0t}\int_0^1 \eta^*(x, 0)dx. $ (29)

    holds for some positive constant $C_0$ and $\tilde{C}_0$ .

    Proof. We set

    $ y_i(x, t) = -\int_0^{x}\bigg{(}n_i(s, t)-N_i(s)\bigg{)}ds, ~~~~ i = 1, 2, ~ x\in[0, 1], ~ t>0. $ (30)

    Clearly, $y_i(i = 1, 2)$ is absolutely continuous in $x$ for a.e. $t>0$. And

    $ y_{ix} = -(n_i-N_i), \;\;\;\; y_{it} = j_i, \\\\ y_2-y_1 = E-{\mathcal{E}}, \;\;\;\; y_i(0, t) = y_i(1, t) = 0, $ (31)

    following (1.1), (2.1), and ($2.1$). From $(1.1)_2$ and $(2.1)_2$, we get $y_1$ satisfies the equation

    $ y_{1tt}+(\frac{y_{1t}^2}{n_1})_x-y_{1xx}+y_{1t} = {n_1}E-N_{1}\mathcal{E}. $ (32)

    Multiplying $y_1$ with $(32)$ and integrating over $(0, 1)$, we have

    For weak solutions, ($1$) satisfies in the sense of distribution. We choose test function $\varphi_n(x, t)\in C_0^\infty \bigg{(}(0, 1)\times [0, T)\bigg{)}$ and let $\varphi_n(x, t)\to y_i(x, t)$ as $n\to +\infty $ for $i = 1, 2$.

    $ ddt10(y1y1t+12y21) dx10(y21tn1)y1x dx10(n21N21)y1xdx10y21t dx=10(N1(y2y1)y1+Ex2y21)dx.
    $
    (33)

    In above calculation, we have used the integration by part. Similarly, from $(1.1)_4$ and $(2.1)_3$, we get

    $ ddt10(y2y2t+12y22) dx10(y22tn2)y2x dx10(n22N22)y2x dx10y22t dx=10(N2(y2y1)y2+Ex2y22) dx.
    $
    (34)

    Add ($33$) and ($34$), we have

    $ ddt10(y1y1t+12y21+y2y2t+12y22) dx10(n21N21)y1xdx10(n22N22)y2x dx=10((y21tn1)y1x +(y22tn2)y2x) dx+10(y21t+y22t) dx+10(N1(y2y1)y1+Ex2y21N2(y2y1)y2Ex2y22) dx.
    $
    (35)

    Since

    $ 10(N1(y2y1)y1+Ex2y21N2(y2y1)y2Ex2y22) dx=10n1N1n2+N2D(x)2y21dx+10n2N2n1+N1+D(x)2y22dx10N1+N22(y1y2)2dx,
    $
    (36)

    then, from $(31)_1$ and $(36)$ we get

    $ ddt10(y1y1t+12y21+y2y2t+12y22) dx+10(N1+n1)y21x+10(N2+n2)y22xdx+10N1+N22(y1y2)2dx=10((y21tn1)y1x+(y22tn2)y2x) dx+10(y21t+y22t) dx+10(n1N1n2+N2D(x)2y21+n2N2n1+N1+D(x)2y22)dx.
    $
    (37)

    Moreover, since

    $ |y_i(x)| = |\int_0^xy_{is}(s)ds| \le x^{1\over 2}(\int_0^x y_{is}^2ds)^{1\over 2} \le x^{1\over 2}(\int_0^1 y_{is}^2ds)^{1\over 2}, \;\; x\in [0, 1], $ (38)

    we can obtain

    $ \|y_i\|^2_{L^2} = \int_0^1|y_i|^2dx \le {1\over 2}\|y_{ix}\|_{L^2}^2, $ (39)

    verifies for $i = 1, 2$. If the weak solutions $n_1(x, t)$ and $n_2(x, t)$ satisfy $(27)$ then

    $ \label{3.16}\mathop {{\rm{inf}}}\limits_x \{{N_1+n_1\}}>\mathop {{\rm{sup}}}\limits_x \bigg{\{}{\frac{n_1-N_1-n_2+N_2-D(x)}{4}}\bigg{\}}, $ (40)

    and

    $ \mathop {{\rm{inf}}}\limits_x \{{N_2+n_2\}}>\mathop {{\rm{sup}}}\limits_x \bigg{\{}{\frac{n_2-N_2-n_1+N_1+D(x)}{4}}\bigg{\}}, $ (41)

    hold, where we have used the assumption $(5)$ and the estimate $(23)$.

    Following ($39$), ($40$) and ($41$), we have

    $ \int_0^1\frac{n_1-N_1-n_2+N_2-D(x)}{2}y_1^2dx<\int_0^1(N_1+n_1)y_{1x}^2dx, $ (42)

    and

    $ \int_0^1\frac{n_2-N_2-n_1+N_1+D(x)}{2}y_2^2dx<\int_0^1(N_2+n_2)y_{2x}^2dx. $ (43)

    Thus (36), (42), and (43) indicate there is a positive constant $\beta>0$, such that

    $ ddt10(y1y1t+12y21+y2y2t+12y22) dx+β10(y21x+y22x)dx+10N1+N22(y1y2)2dx10((y21tn1)y1x+(y22tn2)y2x) dx+10(y21t+y22t) dx=10(N1y21tn1+N2y22tn2) dx.
    $
    (44)

    In view of the entropy inequality ($6$), and the definition of $\eta^*$ and $q^*$ in ($25$) and ($26$), the following inequality holds in the sense of distribution.

    $ ηet+qex+j21n1+j22n2j1E+j2E=ηt+2i=1Qit+qx+2i=1Pix+j21n1+j22n2j1E+j2E=ηt+qx+j21n1+j22n2j1E+j2E+j1Ej2E0.
    $
    (45)

    Since

    $ -j_1E+j_2E+j_1{\mathcal{E}}-j_2{\mathcal{E}} = (E-{\mathcal{E}})(j_2-j_1) = (y_2-y_1)(y_{2t}-y_{1t}), $ (46)

    then ($44$) turns into

    $ \eta^*_t+q^*_x+\frac{y_{1t}^2}{n_{1}}+\frac{y_{2t}^2}{n_{2}}+(y_2-y_1)(y_{2t}-y_{1t}) \le 0. $ (47)

    We use the theory of divergence-measure fields, then

    $ {d\over{dt}}\int_0^1 (\eta^*+{1\over 2}(y_2-y_1)^2)dx+\int_0^1 ( \frac{y_{1t}^2}{n_1} +\frac{y_{2t}^2}{n_2}) ~dx~ \leq 0, $ (48)

    where we use the fact

    $ \int_0^1 q^*_x~dx~ = 0. $ (49)

    Let $\lambda>2+2n^*>0$. Then, we multiply $(48)$ by $\lambda$ and add the result to $(44)$ to get

    $ {d\over{dt}}\int_0^1 (\lambda \eta^*+{\lambda\over 2}(y_2-y_1)^2 + y_1y_{1t}+\frac12y_1^2+y_2y_{2t}+\frac12y_2^2)dx+\beta\int_0^1(y_{1x}^2+y_{2x}^2)dx\\\\ \;\;\;\; +\int_0^1{{N_1+N_2}\over{2}}(y_1-y_2)^2dx+\int_0^1\bigg{(}(\lambda-N_1) \frac{y_{1t}^2}{n_1} +(\lambda-N_2)\frac{y_{2t}^2}{n_2}\bigg{)} dx\leq 0. $ (50)

    Using the estimate ($22$) in Theorem 2.1. and the Poinc${\rm{\acute{a}}}$re inequality ($39$), we have

    $ {d\over{dt}}\int_0^1 (\lambda \eta^*+{\lambda\over 2}(y_2-y_1)^2 + y_1y_{1t}+\frac12y_1^2+y_2y_{2t}+\frac12y_2^2) dx+{\beta\over 2}\int_0^1(y_{1x}^2+y_{2x}^2)dx\\\\ \;\;\;\; +{\beta\over 2}\int_0^1(y_{1}^2+y_{2}^2)dx+n_*\int_0^1(y_1-y_2)^2dx+\int_0^1\bigg{(} \frac{y_{1t}^2}{n_1} +\frac{y_{2t}^2}{n_2}\bigg{)} dx\leq 0. $ (51)

    Now, we consider $ \eta^* $ in ($25$). Clearly

    $ n_i^2-N_i^2-2N_i(n_i-N_i), $ (52)

    is the quadratic remainder of the Taylor expansion of the function $n_i^{2}$ around $N_i>n_*>0$ for $i = 1, 2$. And then, there exist two positive constants $C_1$ and $C_2$ such that

    $ C_1y_{ix}^2 \le n_i^2-N_i^2-2N_i(n_i-N_i) \le C_2y_{ix}^2. $ (53)

    Making $C_3 = \min\{C_1, {{1\over 2}}\}$ and $C_4 = \max\{C_2, {{1\over 2}\}}$, then we get

    $ C_3({{y_{1t}^2}\over {n_1}}+{y_{2t}^2\over {n_2}}+y_{1x}^2+y_{2x}^2) \leq \eta^* \leq C_4({{y_{1t}^2}\over {n_1}}+{y_{2t}^2\over {n_2}}+y_{1x}^2+y_{2x}^2). $ (54)

    Let

    $ F(x, t) = \lambda \eta^*+{\lambda\over 2}(y_2-y_1)^2 + y_1y_{1t}+\frac12y_1^2+y_2y_{2t}+\frac12y_2^2, $

    then there exist positive constants $C_5$, $C_6$, and $C_7$, depending on $\lambda, n_*, \beta$, such that

    $ \int_0^1F(x, t)dx = \int_0^1[\lambda \eta^*+{\lambda\over 2}(y_2-y_1)^2 + y_1y_{1t}+\frac12y_1^2+y_2y_{2t}+\frac12y_2^2]dx \\\\ \leq C_5\int_0^1[({y_{1t}^2\over {n_1}} +{y_{2t}^2\over {n_2}})+ n_*(y_2-y_1)^2+ {\beta\over 2}(y_{1x}^2 +y_{2x}^2)~ + {\beta\over 2}(y_{1}^2 +y_{2}^2)]dx\\\\ \le C_6 \int_0^1\eta^*dx, $ (55)

    and

    $ 0<C_7\int_0^1[({y_{1t}^2\over {n_1}} +{y_{2t}^2\over {n_2}})+ n_*(y_2-y_1)^2+ {\beta\over 2}(y_{1x}^2 +y_{2x}^2)~ + {\beta\over 2}(y_{1}^2 +y_{2}^2)]dx\\\\ \leq \int_0^1[\lambda \eta^*+{\lambda\over 2}(y_2-y_1)^2 + y_1y_{1t}+\frac12y_1^2+y_2y_{2t}+\frac12y_2^2]dx = \int_0^1F(x, t)dx. $ (56)

    Then

    $ {d\over{dt}}\int_0^1 F(x, t) ~dx + {1\over {C_5}}\int_0^1 F(x, t)dx \leq 0, $ (57)

    and

    $ \int_0^1[({y_{1t}^2\over {n_1}} +{y_{2t}^2\over {n_2}})+ n_*(y_2-y_1)^2+ {\beta\over 2}(y_{1x}^2 +y_{2x}^2)~ + {\beta\over 2}(y_{1}^2 +y_{2}^2)]dx\\ \le{1\over {C_7}}\int_0^1F(x, t)dx \le {1\over {C_7}}e^{-{{t}\over {C_5}}}\int_0^1F(x, 0)dx\\ \le C_8e^{-{t\over {C_5}}}\int_0^1\eta^*(x, 0)dx. $ (58)

    are given, following the Growall inequality and the estimates ($55$) and ($56$). Up to now, we finish the proof of Theorem 3.1.


    Acknowledgments

    In the process of the selected topic and write a paper, I get the guidance from my tutor: Huimin Yu. In the teaching process, my tutor helps me develop thinking carefully. The spirit of meticulous and the rigorous attitude of my tutor gives me a lot of help. Gratitude to my tutor is unable to express in words. And this paper supported in part by Shandong Provincial Natural Science Foundation (Grant No. ZR2015AM001).


    Conflict of interest

    The author declare no conflicts of interest in this paper.


    [1] Surgery, 156 (2014), 263-269.
    [2] J. Theor. Biol., 225 (2003), 257-274.
    [3] PLoS Comput. Biol., 7 (2011), e1001085.
    [4] J. Theor. Biol., 252 (2008), 109-122.
    [5] Bull. Math. Biol., 72 (2010), 469-489.
    [6] Immunity, 21 (2004), 341-347.
    [7] Cancer Res., 61 (2001), 5453-5460.
    [8] J. Virol., 75 (2001), 10663-10669.
    [9] Front Oncol, 3 (2013), p56.
    [10] Cancer Res., 67 (2007), p8420.
    [11] Clin. Cancer Res., 13 (2007), 4677-4685.
    [12] Cancer Gene Ther., 16 (2009), 873-882.
    [13] Cancer Gene Ther., 18 (2011), 305-317.
    [14] Bull. Math. Biol., 73 (2011), 2-32.
    [15] Expert Rev Vaccines, 12 (2013), 1155-1172.
    [16] Cancer Res., 66 (2006), 2314-2319.
    [17] J. Virol., 74 (2000), 2895-2899.
    [18] Mol. Ther., 18 (2010), 264-274.
    [19] J. Virol., 80 (2006), 3549-3558.
    [20] Biomaterials, 31 (2010), 1865-1874.
    [21] Biomaterials, 32 (2011), 2314-2326.
    [22] (submitted).
    [23] Nat. Med., 7 (2001), 781-787.
    [24] J. Theor. Biol., 263 (2010), 530-543.
    [25] PLoS ONE, 5 (2010), e15482.
    [26] Nat Commun, 4 (2013), p1974.
    [27] Mol. Ther., 18 (2010), 888-895.
    [28] Gene Ther., 15 (2008), 247-256.
    [29] J. Theor. Biol., 239 (2006), 334-350.
    [30] Mol. Ther., 19 (2011), 1008-1016.
    [31] Nat. Rev. Microbiol., 12 (2014), 23-34.
    [32] Clin. Cancer Res., 15 (2009), 2352-2360.
    [33] Bioinformatics, 30 (2014), 1884-1891.
    [34] J. Theor. Biol., 294 (2012), 56-73.
    [35] Gene Ther., 19 (2012), 543-549.
    [36] Nat. Biotechnol., 30 (2012), 658-670.
    [37] Clin. Cancer Res., 18 (2012), 6679-6689.
    [38] Nat Immunol., 2 (2001), 423-429.
    [39] Nat Immunol., 1 (2000), 47-53.
    [40] Mol. Cancer Ther., 5 (2006), 362-366.
    [41] Cancer Res., 61 (2001), 3501-3507.
    [42] Math Biosci Eng, 10 (2013), 939-957.
    [43] PLoS ONE, 4 (2009), e4271.
    [44] Hum. Gene Ther., 8 (1997), 37-44.
    [45] Bull. Math. Biol., 66 (2004), 605-625.
    [46] Pathol. Oncol. Res., 18 (2012), 771-781.
    [47] Neoplasia, 15 (2013), 591-599.
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