Vaccination of MSI-H colorectal cancer ... - ORYX Medicine
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Vaccination of MSI-H colorectal cancer patients with frameshift peptide antigens – a phase I/IIa clinical trial Matthias Kloor1), Miriam Reuschenbach1), Julia Karbach2), Reza Rafiyan2), Salah-Eddin Al Batran3), Claudia Pauligk3), Elke Jäger2), Magnus von Knebel Doeberitz1)
1 Department of Applied Tumour Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany and Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany, 2 Oncology and Hematology, Krankenhaus Nordwest, Frankfurt, Germany, 3 Institute for Clinical Research, Krankenhaus Nordwest, Frankfurt, Germany
Background
Colorectal cancer is a heterogeneous tumor type. Whereas the majority of colorectal cancers show
chromosomal instability, a subset of about 15% of colorectal cancers (CRC) have a deficient DNA
mismatch repair (MMR) system and accumulate small mutations at repetitive DNA sequences, a
phenotype termed high level microsatellite instability (MSI-H). MSI-H cancers are particularly
characteristic for individuals with the inherited HNPCC (hereditary non-polyposis colorectal cancer) or
Lynch syndrome, which is caused by germline mutations of the MMR genes. Mutation carriers have a
high lifetime risk for the development of MSI-H cancers. Dense infiltration with lymphocytes is
commonly observed in MSI-H CRC lesions. These pronounced immune responses may be explained
by the generation of defined MMR deficiency-induced antigens (frameshift peptides, FSP).
We here report the results of a phase I/IIa peptide vaccination trial (Micoryx, NCT01461148) that
evaluates FSP vaccination in patients with MSI-H colorectal cancer
FSP antigens can be recognized by the immune system as foreign. MSI-H cancer
cells produce FSP antigens as the result of insertion/deletion mutations at cMS
sequences (arrows). Mutant genes, which are translated, can give rise to non-
functional proteins. These proteins encompass an N-terminal wild type amino acid
sequence (gray) and a C-terminal neopeptide or frameshift peptide sequence (red,
blue). Through processing via the HLA class I and HLA class II antigen processing and
presentation machinery, epitopes derived from FSP antigens can be presented on the
surface of MSI-H cancer cells. Antigens presented by HLA class I antigens can be
targets of CD8-positive T cell attack, whereas antigens presented by HLA class II
antigens can be recognized by CD4-positive T cells.
Methods
The Vaccine We developed a vaccine (Micoryx) to strengthen these immune responses and to potentially treat or prevent the formation of MSI-H CRC. For the Micoryx FSP vaccine, three coding microsatellite instability-derived FSP antigens were selected (AIM2(-1), HT001(-1), TAF1B(-1)). These antigens are highly promising targets, because
1. They are shared among the majority of MSI-H CRC and other MSI-H cancers, so that a combination vaccine of these three FSPs covers about 98.5% of MSI-H CRCs,
2. they encompass long immunogenic neo-antigen peptide stretches, which allow induction of immune responses against multiple epitopes, independent from the patients‘ HLA type,
3. the FSPs are directly derived from functionally relevant driver mutations, so immune escape by loss of the antigens is unlikely.
Study Design Phase I/IIa study of immunization with frameshift peptides administered with Montanide® ISA-51 VG in patients with advanced MSI-H colorectal cancer (MICORYX)
EudraCT No.: 2011-000765-12 Sponsor: Oryx GmbH & Co. KG
clinicaltrials.gov/show/NCT01461148
Study size: 22 patients
Inclusion criteria: History of MSI-H colorectal cancer, UICC
stage III or IV, after completion of standard chemotherapy
Study end points: Safety, immunological efficacy, clinical
response
Vaccination scheme:
Peptide ELISA IFN-gamma ELISpot
Results
• The Micoryx vaccine strongly induced T cell (mainly CD4-positive) and humoral immune
responses in all patients vaccinated per protocol
• No FSP antigen-associated severe adverse events have been observed.
• The majority of patients included were tumor-free and had history of MSI-H CRC (UICC stage
III).
Conclusions M S I - H C R C a r e h i g h l y immunogenic tumors that occur sporadically (15% of CRC) or in the context of Lynch syndrome.
Preliminary evaluation of Micoryx demonstrates that vaccination with FSPs is safe and induces strong humora l and ce l lu la r immune responses in vaccinated patients
FSP vaccination holds high potential as a novel adjuvant treatment option in MSI-H colorectal cancer patients, and for cancer prevention in Lynch syndrome mutation carriers
The immunogenicity of MSI-H CRCs is associated with the generation of mismatch repair deficiency-induced neopeptides (FSPs).
References • Kloor M, Michel S, Buckowitz B, et al. Beta2-microglobulin mutations in microsatellite unstable colorectal tumors. Int J Cancer. 2007 Jul 15;121(2):454-8. • Schwitalle Y, Kloor M, Eiermann S, et al. Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology. 2008 Apr;134(4):988-97. • Surmann EM, Voigt AY, Michel S, et al. Association of high CD4-positive T cell infiltration with mutations in HLA class II-regulatory genes in microsatellite-unstable colorectal cancer. Cancer Immunol Immunother. 2015 Mar;64(3):357-66. • Reuschenbach M, Dörre J, Waterboer T, et al. A multiplex method for the detection of serum antibodies against in silico-predicted tumor antigens. Cancer Immunol Immunother. 2014 Dec;63(12):1251-9.
Abstract #3020 miriam.reuschenbach@med.uni-heidelberg.de matthias.kloor@med.uni-heidelberg.de
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