Advancing treatment and understanding of immunotherapy in glioblastoma

SUMMARY/ABSTRACT
Immunotherapy holds great promise for the treatment of glioblastoma; still, certain characteristics of glioblastoma
present inherent therapeutic challenges. Herein, two experienced interdisciplinary laboratory and clinical teams
at UCSFs Helen Diller Family Comprehensive Cancer Center and Northwestern University's Robert H. Lurie
Comprehensive Cancer Center join efforts to develop innovative immunotherapy approaches against
glioblastoma. This proposal leverages industry and institutional support to address three specific objectives: 1)
to improve our understanding of the role of immunotherapy approaches in glioblastoma; 2) to improve our
understanding of how to overcome the limitation the blood brain barrier and 3) to develop innovative
immunotherapy treatments for glioblastoma, with associated early clinical trials focused on patients suffering
from recurrent glioblastoma.
Project 1, coordinated from Northwestern, will build on the team's preclinical results in mouse brain tumor models
demonstrating an immunomodulatory and sensitization effect when immune checkpoint inhibitor therapy is
preceded by a immunogenic dose of doxorubicin, an effect that can be further enhanced by ultrasound-based
BBB opening. Support by innovative biotech companies (Agenus, AstraZeneca, Carthera) provide drugs or
devices for preclinical and clinical investigation as well as specific expertise, assays and technology for
investigations at both institutions, making this collaboration a very powerful consortium. The ensuing clinical trial
will investigate the novel anti-PD1 checkpoint inhibitor balstilimab in conjunction with doxorubicin, with and
without sonication for BBB opening. By administration of immune therapy prior to surgery (induction therapy,
neoadjuvant treatment) the immune effect enables us to evaluate in vivo immune response in the resected brain
tissue. We have previously identified pERk/MAPK activation as a biomarker for benefit from anti-PD1 treatment
in recurrent glioblastoma; this and other markers will be explored furthermore. Four prospectively treated cohorts
will be treated with and without induction therapy, and with and without BBB opening. Translational endpoints
include immune response (tumor tissue, peripheral) and drug tissue concentration.
Project 2, coordinated from UCSF, is a study based on the exciting novel synthetic Notch “synNotch” receptor
CART system and pioneering T cell circuits that recognize tumor cells based on a “prime-and-kill” strategy. In
this system, the first antigen, which is expressed exclusively on GBM cells (EGFRvIII), primes the T cells to
induce expression of a CAR that recognizes IL-13Rα2 and EphA2, thereby eradicating GBM cells expressing
either EphA2 or IL-13α2. Project 2's team hypothesizes that synNotch CART cells can revolutionize the CART
therapy for glioblastoma by overcoming the challenges of off-tumor toxicity, antigen heterogeneity, and CART
cell exhaustion. Thus, these synNotch-CART cells are hypothesized to be significantly more efficacious than
conventional, constitutively expressed IL-13Rα2/EphA2 CART cells. Investigators will optimize the efficacy of
the lead agent and test this hypothesis in the first in human clinical trial of this new class of agents in glioblastoma
patients.
This U19 proposal also has set aside funds for support of the distinctly important trans-GTN pilot projects, and
for two cores (Administrative, Immune Monitoring & Biospecimen) that will support the efforts of the two projects.
By addressing the overall specific objectives described, the research proposed in this U19 application has a high
likelihood of changing the way immunotherapy is understood and utilized in glioblastoma. The innovative
research described in this proposal will take advantage of the exceptional resources assembled by the well-
established, collaborative group of clinical and basic scientists at UCSF and Northwestern.

Grant Number: 5U19CA264338-05
NIH Institute/Center: NIH
Principal Investigator: Nicholas Butowski