4 Feb 2016 mRNA- and peptide-based anticancer immunotherapies EMA – CDDF Joint Meeting, London Michael Platten Neurology Clinic, University Hospital Heidelberg National Center for Tumor Diseases CCU Neuroimmunology and Brain Tumor Immunology German Cancer Research Center, Germany
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4 Feb 2016
mRNA- and peptide-based anticancer immunotherapies
EMA – CDDF Joint Meeting, London
Michael Platten Neurology Clinic, University Hospital Heidelberg National Center for Tumor Diseases CCU Neuroimmunology and Brain Tumor Immunology German Cancer Research Center, Germany
COI-disclosure
Patent „Means and methods for treating or diagnosing IDH1 R132H mutant-positive cancers“; WO 2013/102641 A1, PCT/EP2013/050048
Challenges in anti-cancer vaccines
Target Antigen
Microenvironment
Tolerance Exhaustion
Challenges in target selection
Target Antigen TAA
TA • Specific immune responses • Mostly mutated antigens • Mostly private antigens • Often minor antigens • Mostly CD4 epitopes • Often low expression
• Shared Antigens • Low immunogenicity • Side effects • Dependent on HLA-Type
Individualized concepts
Classic trial concepts warehouse concepts
Tumor-associated antigens
Target Antigen TAA • Shared Antigens • Low immunogenicity • Side effects • Dependent on HLA-Type
Classic trial concepts warehouse concepts
Failure of classic vaccines targeting TAAs
Hodi et al., NEJM 2009
Identification of shared antigens
Glioblastoma (n= 144) Normal brain (n= 50)
RNA sequencing data Glioblastoma (n= 66) Normal brain (n= 21)
quantitative real-time PCR data
Vaccine warehouse targeting shared antigens
BioNTech
(Mutated) Tumor antigens
Target Antigen
TA • Specific immune responses • Mostly mutated antigens • Mostly private antigens • Often minor antigens • Mostly CD4 epitopes • Often low expression
Individualized concepts
CI unmask T cell responses to mutated antigens
Snyder, NEJM 2014
Mutational load predicts response to CI
Melanoma NSCLC Bladder
glioblastoma
pilocytic astrocytoma
TCGA, Nature 2013
low grade glioma
The frequency of immunogenic neoepitopes is 1-5%
Schumacher and Schreiber, Science 2015; Tran et al, Science 2015
Immunogenic neoepitopes
1-3 10-30
IDH1R132H – a shared mutated epitope
uniform (R132H) specific (no tolerance) common (up to 80%) wide variety of tumors oncogenic early routine diagnostic marker
vacc
sham vacc - CD4
IDH1R132H
IDH1R132H IDH1wt0
50
100
150
200
250
300
IFN γ
spo
ts (-
bac
kgro
und)
IDH1wt
IDH1R132H IDH1wt0
50
100
150
200
250
300
IFN γ
spo
ts (-
bac
kgro
und)
Schumacher et al., Nature 2014; Bunse et al., JCI 2015 WO 2013/102641 A1, PCT/EP2013/050048, EPA 14190538.0
Vaccines targeting mutated epitopes require patient-specific identification and manufacturing as most neoepitopes are private
mRNA vaccines may offer advantages over peptide vaccines in efficacy and manufacturing
Current research addresses the mechanims of action (CD4 / CD8) and antigen spreading / escape machanisms
Combination of neoepitope vaccines with checkpoint blockade may increase efficacy
CCU Neuroimmunology and Brain Tumor Immunology Simon Becker Lukas Bunse Theresa Bunse Katrin Deumelandt Edward Green Melanie Keil Katharina Ochs Iris Oezen Christiane Opitz Martina Ott Katharina Rauschenbach Felix Sahm Khwab Sanghvi Jana Sonner
University Hospital Heidelberg and National Center for Tumor Diseases Neurooncology Neurology Neuropathology Neurosurgery Neuroradiology Immunology Hematology Trial Center Immune Monitoring
DKFZ Heidelberg Cancer Immunotherapy Program
University of Tübingen DKTK partner sites TRON, BioNTech Immatics, Agios, Adaptive, CureVac