Immunotherapy • Glioma - Center Foundation
Most important at this stage:
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the earliest possible implementation of the procedure (effectiveness decreases with the progression of the disease)
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selection of the method depending on the results of tests i.e. correlated with the status of, e.g. HLA-A2, PD-1/PD-L1, CTLA-4, CMV, EGFR. Efficacy of particular methods is not universal and is influenced by individual factors
Results of clinical studies on glioblastoma suggest that most effective are those based on immunotherapy. While in many other programs the advantage (if it occurs) usually covers the period of several months (which is, of course, important as such), with immunotherapy some methods are reported – although cautiously – to bring results which span over several years. For instance, in May 2018 long-awaited results were published of the third (i.e. the last) stage of tests of the DCVax-L vaccine. Clinical trials involved 331 adult patients who underwent surgery and chemoradiation therapy (temozolomide). 232 patients were treated with the tested vaccine coupled with temozolomide, while in the treatment of the remaining 99 patients temozolomide was supplemented with placebo. In the latter group, patients were given the vaccine when progression occurred. In sum, the vaccine was administered to a total of 86.4 percent of group members. The average survival time was 23.1 months from the operation (i.e. less than a year’s prolongation in relation to the standard), but nearly half of all patients reached two years’ survival time and for nearly one third (28.2 percent) survival time was three years. Observation continues (according to the Albert brain Tumor register the standard of three years was recorded for two percent of the total GBM population, and according to MSKCC – for eleven percent). The group included people of different ages, with and without MGMT mutilation, with differing degrees of resection under surgery.
Tests involving another vaccine, ICT-107, demonstrated prolongation of recurrence-free time by nearly sixteen months in HLA-A2- positive patients with MGMT methylation. In the production of the vaccine, dendritic cells are sensitized with six antigens associated with glioblastoma (AIM-2, MAGE-1, TRP-2, gp100, HER-2, and IL-13Ra2). Clinical tests demonstrated higher vaccine efficacy in patients with tumors at least three of the six antigens expression. The third (last) stage of tests was suspended in 2017 because of a lack of financial support.
Research and development of immunology is focused mainly on testing :
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personalized vaccines (produced with biological material from individual patients), e.g. DCvax-L (phase III completed) or Agenus prophage (tests did not go beyond Phase II).
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vaccines based on the antigen(s) associated with the tumor (e.g. ICT-107, SL-701), vaccines targeted at cytomegalovirus (CMV) or, in the same group, Rindopepimut (CDX-110) which is EGFR- targeted, but demonstrates no advantage in tests.
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CTLA-4- and PD-1- targeted drugs at (nivolumab, ipilimumab, pembrolizumab).
Factors that influence vaccine or drug selection
individual patient profile – it has been demonstrated that peptide vaccines (e.g. ICT-107) are much more effective in patients diagnosed as positive in tests for the antigen of HLA-A2 tissue compatibility while such medications as nivolumab or pembrolizumab, which are mononuclear antibodies, have differing efficacy, depending on PD-L1 expression within the tumor. All such information is worth considering before selecting a particular procedure.
availability of material – some vaccines (e.g. DCVax-L) are produced individually for each patient, using a tumor sample. Therefore this method cannot be used if samples are not available.
availability of vaccine or drug – none of the vaccines have yet been considered to enter the standard procedure in glioblastoma treatment (although in many countries nivolumab is registered for melanoma treatment, significantly improving the statistics). For the patient, this means that treatment can be possible either through participation in clinical tests (costs are covered by the sponsor, with all other expenditures being the responsibility of the patient) or by undergoing treatment ion a private clinic. In the case of most clinical trials, an obvious drawback is a risk of being assigned to the placebo group.
Immunotherapy – practical possibilities
Immunotherapy is available either following participation in clinical trials or by undergoing treatment in a private clinic. Before deciding, patients (or their families) should explore available data concerning individual profiles (for instance, it is not advisable to choose peptide vaccine with HLA-A2- negative patients; antigens should be examined if relevant data is available). A promising clinical study which is now recruiting patients (NCT033955876) is available in several clinics in Germany for newly diagnosed adult patients. They should become part of the trial immediately after diagnosis, prior to surgery, since surgical intervention is an integral part of the treatment. The patient is offered a “package”, which includes surgery with the use of 5-ALA acid (for more information, see here), a procedure aimed at selective separation of leukocytes (leukapheresis), radiotherapy with temozolomide and weekly administration of a personalized vaccine, prepared with material obtained in the course of surgery.
Apart from clinical tests, relatively varied possibilities of private treatment are available in Germany. Unfortunately, the costs amount to tens of thousands of euros. Both peptide vaccines and vaccines produced with tumor or blood samples are available. The DCVax-L vaccine is officially approved for glioblastoma patients as the so-called “compassionate use i.e” procedures of humanitarian application of a drug that has not yet been officially registered. The procedure is practiced in a great majority of the UE countries.
In the Cologne clinic, which has a relatively long experience in treating adult and child patients, the integrated procedure includes hypothermia, vaccine and anti-PD-1 medication. The chances of success are higher if treatment begins early. More information about this clinic at
www.iozk.de/en
Oncolytic viral therapy involves the study of, for instance, genetically modified poliovirus (PVS-RIPO), DNX-2401, the Newcastle disease virus, herpes, and parvovirus.