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Immunology 2018
J u l y 0 5 - 0 7 , 2 0 1 8
V i e n n a , A u s t r i a
Page 55
Journal of Clinical Immunology and Allergy
ISSN 2471-304X
1 5
t h
I n t e r n a t i o n a l C o n f e r e n c e o n
Immunology
Check point antibody CTLA-4 and PD-1 act on regulatoryTcells (Treg) to remove their suppression of cytotoxicT lymphocytes (CTL)
that start attacking the tumor. However, treatment of gliomas with combination of these antibodies was not successful because
as other antibodies they do not cross the blood brain barrier (BBB). Upon this treatment, only systemic immune response was
activated. The technology we had developed is focused on engineering and preclinical testing of such nanoimmunotherapeutics to
treat brain cancers which activated both systemic and local brain tumor immune systems. Synthesis of immuno-nanoconjugates:
immuno-nanoconjugates (INC) crossing BBB, P/PEG/msTfR/anti-CTLA-4 and P/PEG/msTfR/anti-PD-1 were synthesized. They
are based on natural polymer, poly β (L-malic acid) (P), and contain anti-transferrin receptor antibody (MsTfR). Physico-chemical,
pharmaceutical, and toxicological parameters of INCs were determined. Brain tumor treatment: syngeneic GL261 glioma cells
(20,000) were intracranially inoculated into C57/BL mice. Six treatment groups were injected with either PBS, anti-PD-1 and
anti-CTLA-4 as a control, or polymer-conjugated anti-PD-1(P/PD-1), anti-CTLA-4 (P/CTLA-4) or a combination of polymers with
antibodies, (P/CTLA-4 + P/PD-1) at 10 mg/kg, 5 times I V. Immuno-nanoconjugates P/CTLA-4 and P/PD-1 significantly improved
survival of brain tumor-bearing mice compared to free anti-CTLA-4 and anti-PD-1 (p<0.04 and p<0.004, respectively). The
combination P/CTLA-4 + P/PD-1 showed the highest survival efficacy compared with CTLA-4, PD-1, and PBS groups (p<0.001,
p<0.04, and p<0.0001, respectively). Flow cytometry analysis of T cell population in the brain tumor revealed reduction of the total
number of CD4+ T-cells in animals treated with P/PD-1 and combination P/CTLA-4 + P/PD-1. The fraction of Tregs (CD4+FOXP3+)
was also reduced by all polymer conjugates compared to free antibodies. Activation of CD8+ T-cells (CD8+IFNγ+ and CD8+CD69+)
was increased by polymer-conjugated anti-CTLA-4/PD-1 and combination therapy. Animals treated with polymer-conjugated anti-
PD-1 and combination treatment showed significant decrease in PD-1 expression by CD8+ cells compared to controls. Multiplex
assay to measure cytokine response to treatment demonstrated significant increase in the expression of IL-1β, IL-2, IL-10, TNFα,
IL-6, IL-12, and IFNγ in the brain and serum after combination therapy.
Conclusion:
Brain tumor treatment with immuno-nanoconjugates that can cross BBB significantly increased animal survival.
Biography
Julia Y Ljubimova is Professor of Neurosurgery and Biomedical Sciences, and Director of Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical
Center, Los Angeles, USA. She has been working in clinical and basic cancer research during her entire career. Her major scientific discoveries are: 1) The cancer biomarkers as
tools for developing new nanomedicine imaging agents and drugs against primary and metastatic tumors and 2) The development of nano imaging and therapeutic agents that
are crossing multiple biological barriers including blood brain barrier (BBB). Nano immunology and nano toxicology are novel important subjects of the fight against tumors and
inflammation, which are currently studied in the Nanomedicine Research Center. Her research is supported by National Institutes of Health/National Cancer Institute, private and
industry grants. She is the author of over 100 publications, reviews and book chapters as well as an inventor on twelve issued patents, and patent applications.
Ljubimovaj@cshs.orgDelivery of checkpoint inhibitors with nano
immunoconjugates for activation of local brain tumor
immune system for glioma treatment
Julia Y Ljubimova
1
, Anna Galstyan
1
, Antonella Chiechi
1
,
Ekaterina Shatalova
1
, Tao Sun
1
, Vladimir A Ljubimov, Keith L
Black
1
, Hui Ding
1
and Eggehard Holler
1,2
1
Cedars-Sinai Medical Center, USA
2
University of Regensburg, Germany
Julia Y Ljubimova et al., Insights Allergy Asthma Bronchitis 2018, Volume: 4
DOI: 10.21767/2471-304X-C1-002