Dynamics of melanoma tumor therapy with vesicular stomatitis virus: explaining the variability in outcomes using mathematical modeling.

Tumor selective, replication competent viruses are being tested for cancer gene therapy. This approach introduces a new therapeutic paradigm due to potential replication of the therapeutic agent and induction of a tumor-specific immune response. However, the experimental outcomes are quite variable, even when studies utilize highly inbred strains of mice and the same cell line and virus. Recognizing that virotherapy is an exercise in population dynamics, we utilize mathematical modeling to understand the variable outcomes observed when B16ova malignant melanoma tumors are treated with vesicular stomatitis virus in syngeneic, fully immunocompetent mice. We show how variability in the initial tumor size and the actual amount of virus delivered to the tumor have critical roles on the outcome of therapy. Virotherapy works best when tumors are small, and a robust innate immune response can lead to superior tumor control. Strategies that reduce tumor burden without suppressing the immune response and methods that maximize the amount of virus delivered to the tumor should optimize tumor control in this model system.

Dynamics of multiple myeloma tumor therapy with a recombinant measles virus.

Replication-competent viruses are being tested as tumor therapy agents. The fundamental premise of this therapy is the selective infection of the tumor cell population with the amplification of the virus. Spread of the virus in the tumor ultimately should lead to eradication of the cancer. Tumor virotherapy is unlike any other form of cancer therapy as the outcome depends on the dynamics that emerge from the interaction between the virus and tumor cell populations both of which change in time. We explore these interactions using a model that captures the salient biological features of this system in combination with in vivo data. Our results show that various therapeutic outcomes are possible ranging from tumor eradication to oscillatory behavior. Data from in vivo studies support these conclusions and validate our modeling approach. Such realistic models can be used to understand experimental observations, explore alternative therapeutic scenarios and develop techniques to optimize therapy.

Axillary meristems and the development of epicormic buds in wollemi pine (Wollemia nobilis).

Intact trees of Wollemia nobilis Jones, Hill and Allen (Araucariaceae) routinely develop multiple coppice shoots as well as orthotropic epicormic shoots that become replacement or additional leaders. As these are unusual architectural features for the Araucariaceae, an investigation was made of the axillary meristems of the main stem and their role in the production of epicormic and possibly coppice shoots. Leaf axils, excised from the apex to the base of 2-m-high W. nobilis plants (seedling origin, ex situ grown), were examined anatomically. Small, endogenous, undifferentiated (no leaf primordia, no vascular or provascular connections) meristems were found in the axils from near the shoot apex. In the more proximal positions about half the meristems sampled did not differentiate further, but became tangentially elongated to compensate for increases in stem diameter. In the remaining axils the meristems slowly developed into bud primordia, although these buds usually developed few leaf primordia and their apical 'domes' were wide and flat. Associated vascular development was generally restricted to provascular dedifferentiation of the cortical parenchyma, with the procambium usually forming a 'closed loop' that did not extend back to the secondary vascular tissues. Development of the meristems was very uneven with adjacent axils often at widely differing stages of development into buds. The study shows that, unlike most conifers, W. nobilis possesses long-lived meristematic potential in most, if not all, leaf axils. Unlike other araucarias that have been investigated, many of the meristems in the orthotropic main stem will slowly develop into bud primordia beneath the bark in intact plants. It appears likely that this slow but continued development provides a ready source of additional or replacement leaders and thus new branches and leaves.