Project Details
Projekt
Bypassing the vaccine factory: creating a lymphoma vaccine in the tumor. In situ vaccination combining intratumoral Flt3L, cytotoxic therapy, and TLR agonists.
Applicant
Dr. Linda Hammerich
Subject Area
Hematology, Oncology
Term
from 2015 to 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 269394022
Lymphoma ranges among the 10 most common cancers and most types are incurable with standard therapies. Existing therapies induce only temporary remissions with patients becoming more debilitated and the disease becoming more aggressive with each subsequent iteration of therapy. In this proposal we will further develop a tumor-targeted vaccine approach already demonstrating efficacy in an early phase clinical trial at our center - in situ vaccination - which consists of 1) intratumoral administration of FMS-related tyrosine kinase 3 ligand (Flt3L), to recruit dendritic cells (DC) to the tumor, 2) cytotoxic therapy to release tumor antigens for DC uptake and presentation, and 3) intratumoral administration of Toll-like Receptor (TLR) agonists to activate antigen-loaded DC. The overall aim of this study is to understand how the immune microenvironment of lymphoma tumors can be manipulated from a tolerogenic to an immunogenic state and what cellular and molecular mechanisms allow or prevent this. Preliminary data demonstrate that Flt3L more effectively recruits DC when administered intratumorally rather than systemically. We will assess which DC subsets most effectively endocytose and present tumor antigens and the impact of different anti-tumor cytotoxic therapies known to induce immunogenic cell death as well as different TLR agonists known to activate these DC subsets. Subsequently, we will determine whether this Flt3L-primed in situ vaccine is even more effective than our previous approach using the TLR agonist alone and which effector T cell subsets mediate the anti-tumor effect. Finally, we will assess rational combinations of the vaccine with systemic immunomodulators being studied in our lab, including T cell stimulants (e.g. common gamma chain cytokines) and checkpoint blockade antibodies (e.g. anti-CTLA-4, anti-PD1, anti-LAG3). The results of these studies will help to identify the optimal in situ vaccination procedure leading to an effective anti-tumoral immune response and regression of the tumors.
DFG Programme
Research Fellowships
International Connection
USA
