Ponente
Descripción
Chimeric Antigen Receptor T-cell therapy, known as CAR-T cell therapy,
constitutes one of the most recent and innovative strategies in cancer
immunotherapy. This therapy consists of genetically modifying a patient's own
T lymphocytes so that they express chimeric receptors capable of recognizing
specific antigens present on tumor cells. However, its long-term efficacy
remains limited by tumor relapse and the emergence of resistance mechanisms.
Among these, the loss or downregulation of the target antigen represents an
important pathway of tumor escape, since it reduces the ability of CAR-T cells
to recognize and eliminate cancer cells. In addition, the tumor microenvironment
may induce immune suppression, impairing CAR-T cell expansion, persistence,
and cytotoxic activity.
In this talk, we present and analyze a unified nonlinear mathematical model
describing the interaction between effector CAR-T cells and heterogeneous tumor
populations, composed of antigen-positive and antigen-negative cells. The
model incorporates antigen-mediated phenotypic transitions, induced by the
therapeutic pressure exerted by CAR-T cells, together with the possible
recovery of antigen expression. In addition, it includes tumor-induced immune
suppression, allowing us to investigate how the tumor microenvironment may
reduce therapeutic effectiveness.
Using tools from the qualitative theory of ordinary differential equations,
we provide rigorous analytical insight into the mechanisms associated with
therapeutic success and tumor relapse. We prove the existence of a compact
positively invariant region, characterize the flow near infinity, and derive
conditions for the existence and stability of a coexistence equilibrium.
Furthermore, we identify a transcritical bifurcation between the tumor-free
and therapy-failure equilibria, which delineates the boundary between
therapeutic success and relapse.
Moreover, we analytically prove the occurrence of a Hopf bifurcation around
the coexistence equilibrium, giving rise to sustained oscillations of CAR-T
and tumor cells. In addition, we identify a generalized Hopf bifurcation, or
Bautin bifurcation, which allows us to establish the existence of a parameter
region where two limit cycles coexist. This scenario reveals a more complex
dynamics, in which the system may transition between controlled tumor responses
and larger-amplitude oscillations associated with recurrent episodes of tumor
expansion and CAR-T immune response. Our results show that the dynamical regime
of the system is mainly determined by the interplay between the proliferative
capacity of CAR-T cells and tumor-induced suppression of cytotoxicity.