Brain tumors are the first cause of cancer mortality in children and the 3rd cause in
young adults. The most frequent brain tumors are gliomas and among them the most common
type is astrocytoma. The most malignant astrocytoma is Glioblastoma (GBM). Standard
therapy of newly diagnosed GBM patients includes surgery, irradiation and temozolomide
(TMZ) chemotherapy with 1-year and 5-year survival rates at 30% and 3%, respectively. For
the treatment of recurrent GBM, TMZ is widely used even if the optimal dosing schedule
and the minimal time interval from first line are unknown. Other appropriate therapeutic
options include Lomustine, an alkylating drug, and Bevacizumab, an anti-angiogenic agent
targeting VEGF-A, approved only in selected countries (i.e. North America, Switzerland).
Controlled trials are rare for recurrent glioblastoma, consequently therapeutic decisions
are mostly based on low-level evidence.
Amongst innovative strategies, immunotherapy is considered as one of the most promising.
Immunotherapy stimulates the natural properties of the immune system to protect against
cancer growth. Therapeutic vaccines (active immunotherapy) are expected to elicit a
cytotoxic immune response to tumor-associated antigens, destroying malignant cells
without harming normal cells. The cells involved in this response are T lymphocytes,
which can sense abnormal peptides at the tumor cells surface. One critical step towards
the development of therapeutic vaccines was the identification and validation of glioma
antigens. This is an obstacle the investigators have circumvented with the
characterization of several immunogenic glioma peptides by screening the peptidome of ex
vivo human glioma samples. This led to the development of a multipeptide vaccine called
IMA950.
IMA950 is composed of 9 synthetic tumor-associated HLA-A2-restricted peptides (TUMAPs),
two MHC class II-binding peptides and one HLA-A2-restricted HBV-derived peptide, the
latter used as marker of vaccine immunogenicity. The HLA-A2 allele is expressed by
approximately 45% of the Swiss population. As the interactions between peptides and their
corresponding HLA molecule are highly specific, only HLA-A*02 positive patients will be
included in this trial. The reasons why this set of peptides is very promising for
vaccination are as follows:
1. Tumor peptides have been isolated from ex vivo samples:
2. They are over-expressed in glioma (compared to normal tissues)
3. They are derived from proteins involved in the malignant process. 4. They are immunogenic in vitro in healthy donors and in glioma patients. 5. This is a MULTI-peptide vaccine IMA950 was investigated in a monocentric phase I/II
trial for newly diagnosed glioblastoma and WHO grade III gliomas using poly-ICLC as
adjuvant (PI: P-Y. Dietrich, NCT01920191, study completed, final results in
preparation for publication). A total of 19 patients (16 with GBM and 3 with
anaplastic astrocytoma) were included, with a median number of 9 injections received
per patient (range: 4-11). The multipeptide vaccine did not show any serious safety
issues, apart from some mild inflammatory reactions at the injection site,
peritumoral or resection cavity edema/tumor flare manageable with steroids, as well
as peri-vaccinational transient mild headache, fatigue and flu-like syndrome (grade
3 events: 42.1%, grade 4 events: 21%, no grade 5 events). Regarding vaccine
immunogenicity, CD4 T-cell responses were detected in the majority of patients (58%)
and were usually sustained. The CD8 T-cell responses were detected in 63% of
patients, with 37% of them being multi-TUMAP responders. Median overall survival
from date of surgery was 21 months (range: 10
- - 41 months) for the overall cohort,
with a 19 months survival for the GBM-only cohort (range: 10-41 months), which
compares favorably with the reported median survival of 15 months with the reference
treatment of temozolomide-based chemoradiation.
PFS was 93% and 56% at 6 and 9
months respectively.
Despite the T cell ability to detect tumor peptides that are naturally presented by tumor
cells, these T cells do not normally become activated and do not protect the body against
the cancer, as tumor cells on their own are only poorly immunogenic. For effective T cell
activation, the help of co-stimulatory molecules, which are expressed on activated
professional APCs, e.g. dendritic cells, is required. During infections, the activation
of APCs is triggered by molecular patterns common to all pathogens of a class (e.g. RNA
viruses). These patterns, also referred to as "danger signals", are not provided by
peptides themselves. Consequently, artificial danger signals have to be provided with a
tumor vaccine to induce the required co-stimulation on APCs. In combination with a
vaccine, such substances with a non-specific immunostimulatory effect are called
adjuvants. Poly-ICLC, (Hiltonol®, Oncovir) is a synthetic double-stranded ribo-nucleic
acid (dsRNA) mimicking viral pathogen associated molecular patterns (PAMP) that activates
multiple elements of innate and adaptive immunity.
The importance of intact immune surveillance in controlling outgrowth of neoplastic cells
has been known for decades. The PD-1 receptor-ligand interaction is a major pathway
hijacked by tumors to suppress immune control. The normal function of PD-1, expressed on
the cell surface of activated T-cells under healthy conditions, is to down-regulate
unwanted or excessive immune responses, including autoimmune reactions. Binding of PD-1
ligands (PD-L1 and PD-L2) to the PD-1 receptor inhibits T-cell activation triggered
through the T-cell receptor. Pembrolizumab (Keytruda™) is a potent and highly selective
humanized monoclonal antibody (mAb) designed to directly block the interaction between
PD-1 and its ligands. Impressive response rate and prolonged survival were first observed
for metastatic melanoma, but the clinical benefit of this mAb was recently shown to
extend to several other cancer types. There is a strong rationale to investigate the role
of PD-1/PD-L1 blockade in malignant glioma, since (i) we and others have previously
reported that PD-L1 expression by glioma cells may contribute to tumor-related
immunoresistance; (ii) PD-L1 is also expressed by tumor-infiltrating macrophages and
circulating monocytes; (iii) expression of PD-L1 on circulating monocytes was shown to
correlate with worsened survival in patients who received the HSPPC-96 vaccine for newly
diagnosed and recurrent GBM. The 200 mg Q3W dose will maintain individual patient
exposures within the exposure range demonstrated to be well tolerated, safe and
established in melanoma as associated with maximal efficacy response. A fixed dose
regimen simplifies the dosing regimen so as to be more convenient for physicians and to
reduce the potential for dosing errors.
The combination of pembrolizumab with a vaccine therapy is currently being tested in
several trials for different tumors, such as melanoma, bladder, colorectal and prostate
cancer (NCT02574533, NCT02054520, NCT02432963, NCT02499835, NCT02515227). Here the
investigators postulate that Pembrolizumab may improve the immunogenicity of the IMA950
vaccine and the function of vaccine-induced glioma-specific T cells, and that the
multipeptide vaccine may help to focus the immune response against antigens overexpressed
by glioma, leading together to an optimization of the antitumor immune effect whilst
reducing the risk of collateral damage to the brain.
The study aims to answer questions regarding safety (for the future clinical development
of this strategy), immunogenicity (synergy between multipeptide vaccine and
pembrolizumab) and clinical outcome. Ancillary translational research should help to
identify possible correlation between neo-epitopes, methylation status, immune response
and clinical outcome.
