Lunch & Poster Display session Poster Display session

106P - A single dose of local IL-12 promotes anti-tumor effect of anti-EGFRvIII-CAR-T cells in a syngeneic murine model of glioblastoma

Presentation Number
106P
Lecture Time
12:15 - 12:15
Speakers
  • A. Liuzzi (Zurich, Switzerland)
Session Name
Lunch & Poster Display session
Location
Room B, Geneva Palexpo, Geneva, Switzerland
Date
12.12.2019
Time
12:15 - 13:15
Authors
  • A. Liuzzi (Zurich, Switzerland)
  • G. Agliardi (CH-, Switzerland)
  • B. Becher (Zurich, Switzerland)
  • M. Pule (London, Switzerland)

Abstract

Background

Glioblastoma multiforme (GBM) is one of the most devastating brain tumors with poor prognosis and high mortality. Immunotherapy with chimeric antigen receptor (CAR) T cells is gaining attention as a promising strategy to treat this disease. An ideal candidate to target with CAR T cells is the tumor specific variant III of the epidermal growth factor receptor (EGFRvIII), which represents a mutation found in more than 30% of glioblastoma patients. However, anti-EGFRvIII-CAR modified T cell therapy has shown only limited effects in GBM patients, in all likelihood due to the immunosuppressive microenvironment that CAR T cells encounter in the tumor microenvironment (TME) of gliomas. To make gliomas susceptible to CAR T cell therapy, combinatorial approaches to convert the TME are required.

Methods

Mice received 5Gy TBI on day 15 post implantation, followed by intra-tumoral injection of IL-12:Fc on day 20 and infusion of EGFRvIII-directed CAR or non-transduced T cells on day 21. To perform functional analysis, we adopted high-parametric flow-cytometric characterization of the TME using 23 independent parameters 8 days after CAR T cells injection. We utilized unsupervised validated clustering approaches (FlowSOM and CellCNN) to discriminate between different cell populations.

Results

Here, we demonstrate that the combination of a single dose of local IL-12 with anti-EGFRvIII-CAR T cells synergizes to increase long-term survival in a syngeneic mouse model of GBM. IL-12 not only boosted the pro-inflammatory and cytotoxic activity of anti-EGFRvIII-CAR T cells, but also induced a complete remodelling of the tumor microenvironment (TME) with strong endogenous anti-tumor immune T cell responses. These findings highlight the capacity of IL-12 to induce an immunologically “cold” tumor such as GMB to acquire responsiveness to CAR T cells therapy.

Conclusion

This study demonstrates the capacity of IL-12 as local “adjuvant” therapy to boost the efficacy of CAR T cells and to awake the endogenous anti-tumor T cell responses.

Legal entity responsible for the study

University of Zurich.

Funding

University Research Priority Project and Advanced T-cell Engineered for Cancer Therapy.

Disclosure

M. Pule: Honoraria (self), Honoraria (institution): Autolus LTD. All other authors have declared no conflicts of interest.

Collapse