Pedro Lowenstein

RESEARCH INTERESTS

(i) Self-organization of brain tumors: molecular, physiological, physical, and translational aspects
The current focus of my research program is to discover the cellular, molecular, and mathematical basis underlying the growth patterns of malignant brain tumors, the interactions between cancer cells with the tumor microenvironment in both experimental models and in human patients. In particular, my research program aims to understand how these interactions determine the responses of brain tumors to various types of treatments. To do so, we are probing how brain glioma cells migrate throughout the brain, from the very initial stages of brain tumor formation to later stages, when tumor growth results in the demise of the hosts’ neurons and glial cells. At this time, the tumors become symptomatic. Understanding the precise molecular basis of glioma cells’ growth and invasive behavior will uncover novel therapeutic targets.
My team is using endogenous models of brain tumor models induced by the Sleeping Beauty Transposase system encoding genetic lesions encountered in human gliomas (e.g., PDGF, CDK4, mIDH1, TP53, and ATRX mutations) and fluorescent proteins to determine the earliest growth patterns of models of endogenous brain tumors. We are also implementing these models to study the tumor microenvironment and the migration of immune cells into the macroscopic tumor mass. These models will be used to study the response to novel therapeutic agents. We have now discovered early and late growth patterns of tumors. We believe that understanding the physical and environmental constraints of glioma growth will provide novel therapeutic avenues for their treatment.

(ii) Adaptive immunity against brain tumors: from basic science to translational clinical trials.
In addition, we are uncovering the molecular mechanisms used by cytotoxic T cells to kill glioma cells, and especially, the mechanisms that also limit their clinical effectiveness in effectively eradicating large gliomas. These approaches will be used to develop novel translational therapeutic strategies for implementation in early phase clinical trials. We recently discovered the formation of tumor antigen specific immunological synapses between activated effector T cells and target tumor cells in an intracranial syngeneic brain tumor model; thus, my group has pioneered the development of immunological tools to address the interactions between glioma cells and immune cells and assess effector T cell functions in vivo, in real-time.

(iii) Phase I clinical trial for the treatment of malignant gliomas using a combined cytotoxic and immune-therapeutic approach.
GBM is the most aggressive primary brain tumor with a 5-year survival rate of <5%. Attempts at eliciting a clinically relevant anti-GBM immune response in these patients have met with limited success, due to tumor immune evasion, and a paucity of dendritic cells (DCs) within the brain. In light of the immunosuppressive nature of GBM, I hypothesized that stimulating an immune response directly from within the TME would elicit effective anti-tumor immunity. I showed that increasing the number of brain tumor infiltrating antigen presenting cells [elicited by expressing fms-like tyrosine kinase ligand (Flt3L) within the TME] in combination with the cytotoxic effects of TK (+GCV) induces effective tumor antigen (Ag) uptake, migration of DCs to draining lymph nodes (dLN), and presentation of tumor antigen to naïve T-cells culminating in effective anti-tumor immunity. This led to a Phase I clinical trial: “A non-randomized, open-label dose-finding trial of combined cytotoxic and immune‐stimulatory strategy for the treatment of primary GBM, utilizing Ad-hCMV-TK expressing herpes simplex virus thymidine kinase, and Ad-hCMV-Flt3L expressing fms-like tyrosine kinase ligand” currently ongoing at our institution (IND number BB14574, clinicaltrials.gov number NCT01811992).

In summary, I provide broad scientific expertise, inspired leadership, and high motivation to a multidisciplinary research team to achieve: (i) a thorough understanding of the cellular and molecular basis of gliomagenesis, early tumor growth, and invasion, (ii) a complete understanding of the capacity and limitations of T cells and NK cells to kill brain tumor cells; (iii) the development of novel potential translational therapeutic approaches for the treatment of human malignant brain tumors, and (iv) establish an active program of translational clinical trials at the interface of the Neurosciences and Oncology.