scikit-complexity 0.2.0__py3-none-any.whl

skcomplex/models/biology/oncology/_immunotherapy.py

@@ -0,0 +1,1001 @@
+"""Oncology models: tumour-immune interactions under adoptive therapy, vaccines, cytokines, and checkpoints."""
+
+# Author: Georgios Douzas <gdouzas@icloud.com>
+# License: MIT
+
+from types import SimpleNamespace
+
+from sage.all__sagemath_symbolics import Expression, log
+
+from ....core.interactions import RateInteraction, ReactionInteraction
+from ....core.laws.utils import delayed, hill, where
+from ....core.system import System
+from ....engine.solvers import ScipyODESolver
+from ..._catalog import register_model
+from ..common.kinetics import MichaelisMentenInteraction
+from ..common.pharmacokinetics import DosingInteraction
+from ._checkpoint_tumour import CheckpointTumourElement
+from ._delayed_vaccinated_tumour import DelayedVaccinatedTumourElement
+from ._kirschner_panetta_tumour import KirschnerPanettaTumourElement
+from ._suppressed_tumour import SuppressedTumourElement
+from ._vaccinated_tumour import VaccinatedTumourElement
+
+BOOK_REFERENCE = 'Padmanabhan, Meskin, and Al Moustafa 2021'
+
+
+STIFF_SOLVER = ScipyODESolver(method='LSODA', rtol=1e-8, atol=1e-10)
+
+
+@register_model(
+    field='biology/oncology',
+    tags=('immunotherapy', 'ode', 'adoptive therapy', 'IL-2', 'oscillations'),
+    references=(BOOK_REFERENCE, 'Kirschner and Panetta 1998'),
+    defaults={'until': 1000.0, 'dt': 1.0, 'solver': STIFF_SOLVER},
+)
+def kirschner_panetta(
+    E: float = 1.0,
+    A: float = 1.0,
+    C: float = 1.0,
+    *,
+    alpha_a: float = 0.02,
+    r1: float = 0.18,
+    c1: float = 1.0,
+    a1: float = 500.0,
+    a2: float = 7e7,
+    u1: float = 0.0,
+    u2: float = 0.0,
+) -> System:
+    """Return the Kirschner-Panetta model of effector cells, tumour cells, and IL-2 under adoptive therapy and IL-2.
+
+    Untreated, a tumour of antigenicity in the oscillatory range, such as the default 0.02, and the effector cells
+    oscillate in long cycles in which the tumour nearly vanishes and regrows to about `4 10^5`. The adoptive therapy
+    adds `a1 u1` effector cells per day and the IL-2 injection `a2 u2` IL-2 per day. With `u1` and `u2` above 1, the
+    book's treatment factors `a1 = 500` and `a2 = 7 10^7` are exceeded and the tumour is cleared. The populations are
+    in volume units, the inputs in volume per day, and time in days, and the initial state is the book's.
+
+    Args:
+        E:
+            The initial effector cells.
+
+        A:
+            The initial tumour cells.
+
+        C:
+            The initial IL-2 concentration.
+
+        alpha_a:
+            The antigenicity of the tumour, in the book's range 0 to 0.05.
+
+        r1:
+            The growth rate of the tumour.
+
+        c1:
+            The kill rate of tumour cells by effector cells.
+
+        a1:
+            The effector cells per unit of adoptive therapy.
+
+        a2:
+            The IL-2 per unit of IL-2 injection.
+
+        u1:
+            The adoptive therapy input.
+
+        u2:
+            The IL-2 injection input.
+
+    Returns:
+        system:
+            The model, with the effector cells `site.E`, the tumour cells `site.A`, and the IL-2 `site.C`.
+
+    Examples:
+        >>> from skcomplex.models.biology.oncology import kirschner_panetta
+        >>> kirschner_panetta(u1=1.0).elements[0].u1
+        1.0
+    """
+    site = KirschnerPanettaTumourElement(
+        'site',
+        E=E,
+        A=A,
+        C=C,
+        alpha_a=alpha_a,
+        r1=r1,
+        c1=c1,
+        a1=a1,
+        a2=a2,
+        u1=u1,
+        u2=u2,
+    )
+    interactions = [
+        RateInteraction('stimulation', target='site', state='E', rate=lambda s: s.target.alpha_a * s.target.A),
+        ReactionInteraction(
+            'effector_death',
+            target='site',
+            reactants={'E': 1},
+            propensity=lambda s: s.target.d1 * s.target.E,
+        ),
+        DosingInteraction('adoptive_therapy', target='site', state='E', dose=lambda s: s.target.a1 * s.target.u1),
+        MichaelisMentenInteraction(
+            'effector_proliferation',
+            target='site',
+            products={'E': 1},
+            substrate='C',
+            vmax=lambda s: s.target.rho1,
+            km=lambda s: s.target.alpha1,
+            modifiers={'E': 1},
+        ),
+        RateInteraction(
+            'tumour_growth',
+            target='site',
+            state='A',
+            rate=lambda s: s.target.r1 * s.target.A * (1 - s.target.b * s.target.A),
+        ),
+        MichaelisMentenInteraction(
+            'kill',
+            target='site',
+            reactants={'A': 1},
+            substrate='A',
+            vmax=lambda s: s.target.c1,
+            km=lambda s: s.target.alpha2,
+            modifiers={'E': 1},
+        ),
+        DosingInteraction('il2_injection', target='site', state='C', dose=lambda s: s.target.a2 * s.target.u2),
+        MichaelisMentenInteraction(
+            'il2_production',
+            target='site',
+            products={'C': 1},
+            substrate='A',
+            vmax=lambda s: s.target.rho2,
+            km=lambda s: s.target.alpha3,
+            modifiers={'E': 1},
+        ),
+        ReactionInteraction(
+            'il2_loss',
+            target='site',
+            reactants={'C': 1},
+            propensity=lambda s: s.target.du * s.target.C,
+        ),
+    ]
+    return System(elements=[site], interactions=interactions)
+
+
+@register_model(
+    field='biology/oncology',
+    tags=('immunotherapy', 'ode', 'vaccine', 'dendritic cells', 'dosing'),
+    references=(BOOK_REFERENCE, 'Castiglione and Piccoli 2006'),
+    defaults={'until': 2880.0, 'dt': 2.0, 'solver': STIFF_SOLVER},
+)
+def dendritic_cell_vaccine(
+    A: float = 0.1,
+    *,
+    rho2: float = 10.0,
+    r4: float = 1e-2,
+    dose: float = 0.5,
+    period: float = 168.0,
+    width: float = 1.0,
+    start: float = 0.0,
+    doses: int = 8,
+) -> System:
+    """Return helper and cytotoxic T cells, a tumour, dendritic cells, and IL-2 under a dendritic-cell vaccine.
+
+    Vaccinated dendritic cells drive the proliferation of helper cells, which secrete IL-2, and IL-2 with the antigen
+    drives the proliferation of cytotoxic cells, which kill the tumour. The book gives no initial state or schedule.
+    The T cells start at their resting level `s / d = 0.02`, the dendritic cells and IL-2 at 0, and the vaccine is a
+    one-hour injection of `dose` per hour every week, 8 times. Without vaccine the tumour settles at
+    `1 - c1 s2 / (d2 r3) = 0.9`. The populations are in cells per mm³ scaled by the carrying capacity, IL-2 in
+    pg/mm³, and time in hours.
+
+    Args:
+        A:
+            The initial tumour cells.
+
+        rho2:
+            The proliferation constant of cytotoxic T cells.
+
+        r4:
+            The IL-2 secretion rate.
+
+        dose:
+            The injection rate of dendritic cells during a dose, 0 for no vaccine.
+
+        period:
+            The time between the starts of doses.
+
+        width:
+            The duration of a dose.
+
+        start:
+            The time of the first dose.
+
+        doses:
+            The number of doses.
+
+    Returns:
+        system:
+            The model, with the helper cells `site.EH`, the cytotoxic cells `site.E`, the tumour `site.A`, the
+            dendritic cells `site.ED`, and the IL-2 `site.C`.
+
+    Examples:
+        >>> from skcomplex.models.biology.oncology import dendritic_cell_vaccine
+        >>> dendritic_cell_vaccine(dose=0.0).elements[0].dose
+        0.0
+    """
+    site = VaccinatedTumourElement(
+        'site',
+        A=A,
+        rho2=rho2,
+        r4=r4,
+        dose=dose,
+        period=period,
+        width=width,
+        start=start,
+        doses=doses,
+    )
+    interactions = [
+        DosingInteraction('helper_influx', target='site', state='EH', dose=lambda s: s.target.s1),
+        RateInteraction(
+            'helper_proliferation',
+            target='site',
+            state='EH',
+            rate=lambda s: s.target.rho1 * s.target.ED * s.target.r1 * s.target.EH * (1 - s.target.b1 * s.target.EH),
+        ),
+        ReactionInteraction(
+            'helper_death',
+            target='site',
+            reactants={'EH': 1},
+            propensity=lambda s: s.target.d1 * s.target.EH,
+        ),
+        DosingInteraction('cytotoxic_influx', target='site', state='E', dose=lambda s: s.target.s2),
+        RateInteraction(
+            'cytotoxic_proliferation',
+            target='site',
+            state='E',
+            rate=lambda s: s.target.rho2
+            * s.target.C
+            * (s.target.A + s.target.ED)
+            * s.target.r2
+            * s.target.E
+            * (1 - s.target.b2 * s.target.E),
+        ),
+        ReactionInteraction(
+            'cytotoxic_death',
+            target='site',
+            reactants={'E': 1},
+            propensity=lambda s: s.target.d2 * s.target.E,
+        ),
+        RateInteraction(
+            'tumour_growth',
+            target='site',
+            state='A',
+            rate=lambda s: s.target.r3 * s.target.A * (1 - s.target.b3 * s.target.A),
+        ),
+        ReactionInteraction(
+            'kill',
+            target='site',
+            reactants={'A': 1},
+            modifiers={'E': 1},
+            propensity=lambda s: s.target.c1 * s.target.A * s.target.E,
+        ),
+        DosingInteraction(
+            'vaccine',
+            target='site',
+            state='ED',
+            dose=lambda s: s.target.dose,
+            period=period,
+            width=width,
+            start=start,
+            count=doses,
+        ),
+        ReactionInteraction(
+            'dendritic_kill',
+            target='site',
+            reactants={'ED': 1},
+            modifiers={'E': 1},
+            propensity=lambda s: s.target.c2 * s.target.E * s.target.ED,
+        ),
+        RateInteraction(
+            'il2_production',
+            target='site',
+            state='C',
+            rate=lambda s: s.target.r4 * s.target.EH * s.target.ED,
+        ),
+        ReactionInteraction(
+            'il2_consumption',
+            target='site',
+            reactants={'C': 1},
+            modifiers={'E': 1},
+            propensity=lambda s: s.target.c3 * s.target.E * s.target.C,
+        ),
+        ReactionInteraction(
+            'il2_loss',
+            target='site',
+            reactants={'C': 1},
+            propensity=lambda s: s.target.d3 * s.target.C,
+        ),
+    ]
+    return System(elements=[site], interactions=interactions)
+
+
+@register_model(
+    field='biology/oncology',
+    tags=('immunotherapy', 'ode', 'checkpoint inhibitor', 'PD-1', 'dosing'),
+    references=(BOOK_REFERENCE, 'Nikolopoulou et al. 2018'),
+    defaults={'until': 150.0, 'dt': 0.5, 'solver': STIFF_SOLVER},
+)
+def anti_pd1_checkpoint(
+    E: float = 6e-3,
+    A: float = 0.3968,
+    *,
+    u_ap: float = 1e-10,
+    sigma: float = 5.0,
+    ENC: float = 1e-4,
+    r3: float = 0.18,
+    b: float = 1 / 0.8,
+    c_l: float = 1.0,
+) -> System:
+    """Return activated T cells, a tumour, and an anti-PD-1 drug that frees the T cells from checkpoint inhibition.
+
+    The PD-1-PD-L1 complex inhibits the activation and proliferation of T cells, and the drug lowers the free PD-1 on
+    T cells. The cytokines are at their steady states, as in the book. The book gives neither the naive T cells `ENC`
+    nor the association ratio `sigma`, which are set so that the T cells settle below the level that controls the
+    tumour. The ranged parameters take the low ends of the book's ranges, and the drug is the book's continuous
+    infusion of `10^-10` per day. A larger infusion frees more T cells and lowers the tumour. The book's free PD-1
+    `(rho_r - du1 UAP) E` turns negative once the drug exceeds `rho_r / du1`, and it is held at 0 there. With all PD-1
+    blocked nothing limits the T cells, which grow without bound and clear the tumour. Cells and the drug are in g/cm³
+    and time in days.
+
+    Args:
+        E:
+            The initial activated T cells.
+
+        A:
+            The initial tumour cells.
+
+        u_ap:
+            The infusion rate of the drug, 0 for no treatment.
+
+        sigma:
+            The ratio of association to dissociation of PD-1 and PD-L1.
+
+        ENC:
+            The naive T cells.
+
+        r3:
+            The growth rate of the tumour.
+
+        b:
+            The inverse carrying capacity of the tumour.
+
+        c_l:
+            The expression of PD-L1 on tumour cells relative to T cells.
+
+    Returns:
+        system:
+            The model, with the T cells `site.E`, the tumour `site.A`, and the drug `site.UAP`.
+
+    Examples:
+        >>> from skcomplex.models.biology.oncology import anti_pd1_checkpoint
+        >>> anti_pd1_checkpoint(u_ap=0.0).elements[0].u_ap
+        0.0
+    """
+    site = CheckpointTumourElement('site', E=E, A=A, u_ap=u_ap, sigma=sigma, ENC=ENC, r3=r3, b=b, c_l=c_l)
+
+    def free_receptor(s: SimpleNamespace) -> Expression:
+        """Return the free PD-1 on the T cells, which the drug lowers."""
+        expression = s.target.rho_r - s.target.du1 * s.target.UAP
+        receptor: Expression = where(expression > 0, expression, 0) * s.target.E
+        return receptor
+
+    interactions = [
+        RateInteraction(
+            'activation',
+            target='site',
+            state='E',
+            rate=lambda s: (
+                s.target.r1 * s.target.ENC * hill(s.target.C1_ss, s.target.C1_50)
+                + s.target.r2 * s.target.E * hill(s.target.C2_ss, s.target.C2_50)
+            )
+            / (
+                1
+                + s.target.sigma
+                * free_receptor(s)
+                * s.target.sigma_l
+                * (s.target.E + s.target.c_l * s.target.A)
+                / s.target.psi_pp
+            ),
+        ),
+        ReactionInteraction(
+            'effector_death',
+            target='site',
+            reactants={'E': 1},
+            propensity=lambda s: s.target.d1 * s.target.E,
+        ),
+        RateInteraction(
+            'tumour_growth',
+            target='site',
+            state='A',
+            rate=lambda s: s.target.r3 * s.target.A * (1 - s.target.b * s.target.A),
+        ),
+        ReactionInteraction(
+            'kill',
+            target='site',
+            reactants={'A': 1},
+            modifiers={'E': 1},
+            propensity=lambda s: s.target.a_rho * s.target.A * s.target.E,
+        ),
+        DosingInteraction('infusion', target='site', state='UAP', dose=lambda s: s.target.u_ap),
+        ReactionInteraction(
+            'binding',
+            target='site',
+            reactants={'UAP': 1},
+            modifiers={'E': 1},
+            propensity=lambda s: s.target.a_rl * free_receptor(s) * s.target.UAP,
+        ),
+        ReactionInteraction(
+            'clearance',
+            target='site',
+            reactants={'UAP': 1},
+            propensity=lambda s: s.target.du2 * s.target.UAP,
+        ),
+    ]
+    return System(elements=[site], interactions=interactions)
+
+
+@register_model(
+    field='biology/oncology',
+    tags=('immunotherapy', 'delay', 'vaccine', 'dendritic cells', 'regulatory T cells'),
+    references=(BOOK_REFERENCE, 'Qomlaqi et al. 2017'),
+    defaults={'until': 30.0, 'dt': 0.1, 'solver': STIFF_SOLVER},
+)
+def delayed_dc_vaccine(
+    *,
+    dose: float = 1e6,
+    period: float = 7.0,
+    width: float = 1.0,
+    start: float = 0.0,
+    doses: int = 4,
+    tau1: float = 1.26,
+    tau2: float = 0.45,
+    tau3: float = 0.47,
+) -> System:
+    """Return a tumour and eight innate and adaptive immune populations, with division delays, under a vaccine.
+
+    Natural killer cells divide in `tau1`, CD8+ cells mature after seven divisions `7 tau2`, and naive helper cells
+    become type 1 helper cells after two divisions `2 tau3`. Regulatory T cells, driven by the tumour and IL-2, inhibit
+    natural killer, CD8+, and helper cells. The book's growth term `m1 ED E` of mature CD8+ cells has no saturation and
+    makes them diverge within a day, so it saturates in the dendritic cells as `m1 ED E / (g3 + ED)`, like every other
+    term the dendritic cells drive. The book gives no schedule, and the vaccine is a one-day injection of `dose`
+    dendritic cells per day every week, 4 times. The parameters and initial state are the book's, and with them the
+    regulatory T cells hold the adaptive response down, so the tumour grows toward its capacity `b`. Cells are counts,
+    IL-2 is in IU/L, and time in days.
+
+    Args:
+        dose:
+            The injection rate of dendritic cells during a dose, 0 for no vaccine.
+
+        period:
+            The time between the starts of doses.
+
+        width:
+            The duration of a dose.
+
+        start:
+            The time of the first dose.
+
+        doses:
+            The number of doses.
+
+        tau1:
+            The division time of natural killer cells.
+
+        tau2:
+            The division time of CD8+ cells.
+
+        tau3:
+            The division time of helper cells.
+
+    Returns:
+        system:
+            The model, with the tumour `site.A`, the natural killer cells `site.ENK`, the naive and mature CD8+ cells
+            `site.ENC` and `site.E`, the dendritic cells `site.ED`, the IL-2 `site.C`, the regulatory cells `site.ER`,
+            and the naive and type 1 helper cells `site.ENH` and `site.E1H`.
+
+    Examples:
+        >>> from skcomplex.models.biology.oncology import delayed_dc_vaccine
+        >>> delayed_dc_vaccine(tau2=0.5).elements[0].tau2
+        0.5
+    """
+    site = DelayedVaccinatedTumourElement(
+        'site',
+        dose=dose,
+        period=period,
+        width=width,
+        start=start,
+        doses=doses,
+        tau1=tau1,
+        tau2=tau2,
+        tau3=tau3,
+    )
+    interactions = [
+        RateInteraction(
+            'tumour_growth',
+            target='site',
+            state='A',
+            rate=lambda s: s.target.r1 * s.target.A * log(s.target.b / s.target.A),
+        ),
+        ReactionInteraction(
+            'cytotoxic_kill',
+            target='site',
+            reactants={'A': 1},
+            modifiers={'E': 1},
+            propensity=lambda s: s.target.a1
+            * (log(s.target.E) / log(s.target.A)) ** 5
+            / ((log(s.target.E) / log(s.target.A)) ** 5 + s.target.g1)
+            * s.target.A,
+        ),
+        ReactionInteraction(
+            'nk_kill',
+            target='site',
+            reactants={'A': 1},
+            modifiers={'ENK': 1},
+            propensity=lambda s: s.target.a2 * s.target.ENK * s.target.A,
+        ),
+        DosingInteraction('nk_influx', target='site', state='ENK', dose=lambda s: s.target.s1),
+        ReactionInteraction(
+            'nk_death',
+            target='site',
+            reactants={'ENK': 1},
+            propensity=lambda s: s.target.d1 * s.target.ENK,
+        ),
+        RateInteraction(
+            'nk_proliferation',
+            target='site',
+            state='ENK',
+            rate=lambda s: s.target.rho1
+            * delayed(s.target.ENK, s.target.tau1)
+            * delayed(s.target.C, s.target.tau1)
+            / (s.target.g2 + delayed(s.target.C, s.target.tau1)),
+        ),
+        ReactionInteraction(
+            'nk_suppression',
+            target='site',
+            reactants={'ENK': 1},
+            modifiers={'ER': 1},
+            propensity=lambda s: s.target.psi1 * s.target.ENK * s.target.ER,
+        ),
+        DosingInteraction('naive_cytotoxic_influx', target='site', state='ENC', dose=lambda s: s.target.s2),
+        ReactionInteraction(
+            'naive_cytotoxic_death',
+            target='site',
+            reactants={'ENC': 1},
+            propensity=lambda s: s.target.d2 * s.target.ENC,
+        ),
+        MichaelisMentenInteraction(
+            'cytotoxic_priming',
+            target='site',
+            reactants={'ENC': 1},
+            modifiers={'ENC': 1},
+            substrate='ED',
+            vmax=lambda s: s.target.rho2,
+            km=lambda s: s.target.g3,
+        ),
+        ReactionInteraction(
+            'cytotoxic_death',
+            target='site',
+            reactants={'E': 1},
+            propensity=lambda s: s.target.d3 * s.target.E,
+        ),
+        RateInteraction(
+            'primed_expansion',
+            target='site',
+            state='E',
+            rate=lambda s: s.target.rho3
+            * delayed(s.target.ENC, 7 * s.target.tau2, 7 * tau2)
+            * delayed(s.target.ED, 7 * s.target.tau2, 7 * tau2)
+            / (s.target.g3 + delayed(s.target.ED, 7 * s.target.tau2, 7 * tau2)),
+        ),
+        RateInteraction(
+            'dendritic_expansion',
+            target='site',
+            state='E',
+            rate=lambda s: s.target.m1
+            * delayed(s.target.ED, s.target.tau2)
+            * delayed(s.target.E, s.target.tau2)
+            / (s.target.g3 + delayed(s.target.ED, s.target.tau2)),
+        ),
+        RateInteraction(
+            'il2_expansion',
+            target='site',
+            state='E',
+            rate=lambda s: s.target.rho4
+            * delayed(s.target.E, s.target.tau2)
+            * delayed(s.target.C, s.target.tau2) ** 2
+            / (s.target.g4 + delayed(s.target.C, s.target.tau2) ** 2),
+        ),
+        ReactionInteraction(
+            'cytotoxic_suppression',
+            target='site',
+            reactants={'E': 1},
+            modifiers={'ER': 1},
+            propensity=lambda s: s.target.psi2 * s.target.E * s.target.ER,
+        ),
+        ReactionInteraction(
+            'dendritic_death',
+            target='site',
+            reactants={'ED': 1},
+            propensity=lambda s: s.target.d4 * s.target.ED,
+        ),
+        MichaelisMentenInteraction(
+            'antigen_presentation',
+            target='site',
+            products={'ED': 1},
+            substrate='A',
+            vmax=lambda s: s.target.kappa1,
+            km=lambda s: s.target.g5,
+        ),
+        DosingInteraction(
+            'vaccine',
+            target='site',
+            state='ED',
+            dose=lambda s: s.target.dose,
+            period=period,
+            width=width,
+            start=start,
+            count=doses,
+        ),
+        DosingInteraction('il2_influx', target='site', state='C', dose=lambda s: s.target.s3),
+        ReactionInteraction(
+            'il2_loss',
+            target='site',
+            reactants={'C': 1},
+            propensity=lambda s: s.target.d5 * s.target.C,
+        ),
+        RateInteraction(
+            'cytotoxic_secretion',
+            target='site',
+            state='C',
+            rate=lambda s: s.target.rho5 * s.target.E**2 * s.target.C / (s.target.g6 + s.target.E**2),
+        ),
+        MichaelisMentenInteraction(
+            'helper_secretion',
+            target='site',
+            products={'C': 1},
+            modifiers={'C': 1},
+            substrate='E1H',
+            vmax=lambda s: s.target.rho6,
+            km=lambda s: s.target.g7,
+        ),
+        DosingInteraction('regulatory_influx', target='site', state='ER', dose=lambda s: s.target.s4),
+        ReactionInteraction(
+            'regulatory_death',
+            target='site',
+            reactants={'ER': 1},
+            propensity=lambda s: s.target.d6 * s.target.ER,
+        ),
+        RateInteraction(
+            'antigen_expansion',
+            target='site',
+            state='ER',
+            rate=lambda s: s.target.rho7
+            * delayed(s.target.ER, s.target.tau3)
+            * delayed(s.target.A, s.target.tau3) ** 2
+            / (s.target.g8 + delayed(s.target.A, s.target.tau3) ** 2),
+        ),
+        RateInteraction(
+            'il2_regulatory_expansion',
+            target='site',
+            state='ER',
+            rate=lambda s: s.target.rho8
+            * delayed(s.target.ER, s.target.tau3)
+            * delayed(s.target.C, s.target.tau3)
+            / (s.target.g9 + delayed(s.target.C, s.target.tau3)),
+        ),
+        DosingInteraction('naive_helper_influx', target='site', state='ENH', dose=lambda s: s.target.s5),
+        ReactionInteraction(
+            'naive_helper_death',
+            target='site',
+            reactants={'ENH': 1},
+            propensity=lambda s: s.target.d7 * s.target.ENH,
+        ),
+        MichaelisMentenInteraction(
+            'helper_priming',
+            target='site',
+            reactants={'ENH': 1},
+            modifiers={'ENH': 1},
+            substrate='ED',
+            vmax=lambda s: s.target.rho9,
+            km=lambda s: s.target.g3,
+        ),
+        ReactionInteraction(
+            'helper_death',
+            target='site',
+            reactants={'E1H': 1},
+            propensity=lambda s: s.target.d8 * s.target.E1H,
+        ),
+        RateInteraction(
+            'primed_helper_expansion',
+            target='site',
+            state='E1H',
+            rate=lambda s: s.target.m2
+            * delayed(s.target.ED, 2 * s.target.tau3, 2 * tau3)
+            * delayed(s.target.ENH, 2 * s.target.tau3, 2 * tau3)
+            / (s.target.g3 + delayed(s.target.ED, 2 * s.target.tau3, 2 * tau3)),
+        ),
+        ReactionInteraction(
+            'helper_suppression',
+            target='site',
+            reactants={'E1H': 1},
+            modifiers={'ER': 1},
+            propensity=lambda s: s.target.psi3 * s.target.ER * s.target.E1H,
+        ),
+        RateInteraction(
+            'helper_expansion',
+            target='site',
+            state='E1H',
+            rate=lambda s: s.target.rho10
+            * delayed(s.target.ED, s.target.tau3)
+            * delayed(s.target.E, s.target.tau3)
+            / (s.target.g3 + delayed(s.target.ED, s.target.tau3)),
+        ),
+    ]
+    return System(elements=[site], interactions=interactions)
+
+
+@register_model(
+    field='biology/oncology',
+    tags=('immunotherapy', 'ode', 'immunosuppression', 'cytokines', 'antigenicity'),
+    references=(BOOK_REFERENCE, 'Robertson-Tessi, El-Kareh, and Goriely 2012'),
+    defaults={'until': 200.0, 'dt': 0.5, 'solver': STIFF_SOLVER},
+)
+def tumour_immune_suppression(
+    *,
+    alpha_a: float = 1e-3,
+    r1: float = 0.333,
+    r2: float = 333.0,
+    EMC: float = 1e4,
+    EMH: float = 1e4,
+    EMR: float = 1e4,
+) -> System:
+    """Return a tumour against dendritic, cytotoxic, helper, and regulatory T cells with IL-2, IL-10, and TGF-beta.
+
+    A tumour of one cell grows exponentially, then as a power of its size, and only its accessible fraction is killed.
+    Its antigen matures dendritic cells, which recruit T cells from the memory pools, and the regulatory cells with
+    IL-10 and TGF-beta suppress the response. A weakly antigenic tumour escapes, a moderately antigenic one oscillates,
+    and a strongly antigenic one is held to a few cells. The book's growth rows are garbled, and the exponential rate
+    is read as 0.333 per day and the power coefficient as 333 cells^(1/2) per day, within the book's range 100 to
+    1000, so the growth turns from exponential to power at `10^6` cells. The book gives no memory pools, which are
+    taken as constant at `10^4` cells each. The other parameters are the book's, the initial immune cells are
+    `10^-5`, cells are counts, cytokines in ng/ml, and time in days.
+
+    Args:
+        alpha_a:
+            The antigenicity of the tumour, in the book's range `10^-5` to `10^5`.
+
+        r1:
+            The exponential growth rate of the tumour.
+
+        r2:
+            The power growth coefficient of the tumour.
+
+        EMC:
+            The memory cytotoxic T cells.
+
+        EMH:
+            The memory helper T cells.
+
+        EMR:
+            The memory regulatory T cells.
+
+    Returns:
+        system:
+            The model, with the tumour `site.A`, the dendritic cells `site.EUD` and `site.ED`, the T cells `site.EPC`,
+            `site.E`, `site.EPH`, `site.EH`, `site.EPR`, and `site.ER`, and the cytokines `site.C1`, `site.C2`, and
+            `site.C3`.
+
+    Examples:
+        >>> from skcomplex.models.biology.oncology import tumour_immune_suppression
+        >>> tumour_immune_suppression(alpha_a=1.0).elements[0].alpha_a
+        1.0
+    """
+    site = SuppressedTumourElement('site', alpha_a=alpha_a, r1=r1, r2=r2, EMC=EMC, EMH=EMH, EMR=EMR)
+
+    def accessible(s: SimpleNamespace) -> Expression:
+        """Return the fraction of the tumour accessible to the cytotoxic T cells."""
+        fraction: Expression = s.target.A / (1 + (s.target.A ** (1 - s.target.q) / s.target.g3) ** s.target.p) ** (
+            1 / s.target.p
+        )
+        return fraction
+
+    def maturation(s: SimpleNamespace) -> Expression:
+        """Return the maturation by IL-2 of proliferating T cells, which TGF-beta suppresses."""
+        factor: Expression = hill(s.target.C1, s.target.EC1_50) / (1 + s.target.C3 / s.target.EC3_50)
+        return factor
+
+    interactions = [
+        RateInteraction(
+            'tumour_growth',
+            target='site',
+            state='A',
+            rate=lambda s: s.target.A
+            / ((1 / s.target.r1) ** s.target.p + (s.target.A ** (1 - s.target.n) / s.target.r2) ** s.target.p)
+            ** (1 / s.target.p),
+        ),
+        ReactionInteraction(
+            'kill',
+            target='site',
+            reactants={'A': 1},
+            modifiers={'E': 1},
+            propensity=lambda s: s.target.a1
+            * accessible(s)
+            * s.target.E
+            / (s.target.E + accessible(s) / s.target.g1 + s.target.ER / s.target.g2)
+            / (1 + s.target.C3 / s.target.C3_50),
+        ),
+        RateInteraction(
+            'antigen_uptake',
+            target='site',
+            state='EUD',
+            rate=lambda s: s.target.alpha_a
+            * accessible(s)
+            / ((1 + s.target.C2 / s.target.C2_50) * (1 + s.target.ER / s.target.ER_50)),
+        ),
+        ReactionInteraction(
+            'licensing',
+            target='site',
+            reactants={'EUD': 1},
+            products={'ED': 1},
+            propensity=lambda s: s.target.lambda_a * s.target.EUD / (1 + s.target.EUD / s.target.EMH),
+        ),
+        ReactionInteraction(
+            'immature_death',
+            target='site',
+            reactants={'EUD': 1},
+            propensity=lambda s: s.target.d1 * s.target.EUD,
+        ),
+        ReactionInteraction(
+            'licensed_death',
+            target='site',
+            reactants={'ED': 1},
+            propensity=lambda s: s.target.d2 * s.target.ED,
+        ),
+        RateInteraction(
+            'cytotoxic_priming',
+            target='site',
+            state='EPC',
+            rate=lambda s: s.target.a2
+            * s.target.EMC
+            * s.target.ED
+            / (s.target.ED + s.target.g4 * (s.target.EMC + s.target.EMH + s.target.EMR)),
+        ),
+        ReactionInteraction(
+            'cytotoxic_precursor_death',
+            target='site',
+            reactants={'EPC': 1},
+            propensity=lambda s: s.target.d3 * s.target.EPC,
+        ),
+        RateInteraction(
+            'cytotoxic_maturation',
+            target='site',
+            state='E',
+            rate=lambda s: s.target.a3 * s.target.EPC * maturation(s),
+        ),
+        ReactionInteraction(
+            'cytotoxic_death',
+            target='site',
+            reactants={'E': 1},
+            propensity=lambda s: s.target.d4 * s.target.E,
+        ),
+        RateInteraction(
+            'helper_priming',
+            target='site',
+            state='EPH',
+            rate=lambda s: s.target.a4
+            * s.target.EMH
+            * (s.target.ED + s.target.EUD)
+            / (s.target.ED + s.target.EUD + s.target.g4 * (s.target.EMC + s.target.EMH + s.target.EMR)),
+        ),
+        ReactionInteraction(
+            'helper_precursor_death',
+            target='site',
+            reactants={'EPH': 1},
+            propensity=lambda s: s.target.d5 * s.target.EPH,
+        ),
+        RateInteraction(
+            'helper_maturation',
+            target='site',
+            state='EH',
+            rate=lambda s: s.target.a5 * s.target.EPH * maturation(s),
+        ),
+        ReactionInteraction(
+            'conversion',
+            target='site',
+            reactants={'EH': 1},
+            products={'ER': 1},
+            modifiers={'C3': 1},
+            propensity=lambda s: s.target.a6 * s.target.EH * s.target.C3 / (s.target.g5 + s.target.C3),
+        ),
+        ReactionInteraction(
+            'helper_death',
+            target='site',
+            reactants={'EH': 1},
+            propensity=lambda s: s.target.d6 * s.target.EH,
+        ),
+        RateInteraction(
+            'regulatory_priming',
+            target='site',
+            state='EPR',
+            rate=lambda s: s.target.a7
+            * s.target.EMR
+            * s.target.ED
+            / (s.target.ED + s.target.g4 * (s.target.EMC + s.target.EMH + s.target.EMR)),
+        ),
+        ReactionInteraction(
+            'regulatory_precursor_death',
+            target='site',
+            reactants={'EPR': 1},
+            propensity=lambda s: s.target.d7 * s.target.EPR,
+        ),
+        RateInteraction(
+            'regulatory_maturation',
+            target='site',
+            state='ER',
+            rate=lambda s: s.target.a8 * s.target.EPR * hill(s.target.C1, s.target.EC1_50),
+        ),
+        ReactionInteraction(
+            'regulatory_death',
+            target='site',
+            reactants={'ER': 1},
+            propensity=lambda s: s.target.d8 * s.target.ER,
+        ),
+        RateInteraction(
+            'il2_secretion',
+            target='site',
+            state='C1',
+            rate=lambda s: s.target.a9
+            * s.target.EPH
+            / ((1 + s.target.C3 / s.target.CC3_50) * (1 + s.target.C2 / s.target.CC2_50)),
+        ),
+        ReactionInteraction(
+            'il2_loss',
+            target='site',
+            reactants={'C1': 1},
+            propensity=lambda s: s.target.C1 / s.target.tau1,
+        ),
+        RateInteraction(
+            'regulatory_il10',
+            target='site',
+            state='C2',
+            rate=lambda s: s.target.r3 * s.target.ER,
+        ),
+        RateInteraction(
+            'tumour_il10',
+            target='site',
+            state='C2',
+            rate=lambda s: s.target.r4 * s.target.A,
+        ),
+        ReactionInteraction(
+            'il10_loss',
+            target='site',
+            reactants={'C2': 1},
+            propensity=lambda s: s.target.C2 / s.target.tau2,
+        ),
+        RateInteraction(
+            'regulatory_tgf_beta',
+            target='site',
+            state='C3',
+            rate=lambda s: s.target.r5 * s.target.ER,
+        ),
+        RateInteraction(
+            'tumour_tgf_beta',
+            target='site',
+            state='C3',
+            rate=lambda s: s.target.r6 * s.target.A,
+        ),
+        ReactionInteraction(
+            'tgf_beta_loss',
+            target='site',
+            reactants={'C3': 1},
+            propensity=lambda s: s.target.C3 / s.target.tau3,
+        ),
+    ]
+    return System(elements=[site], interactions=interactions)