A new experimental vaccine, called IDH1-vac, has shown promise in combating aggressive gliomas with the IDH1 mutation. In an initial study, the vaccine was safe and stimulated immune responses in 93% of patients, helping to control tumor progression in many cases and prolonging survival. These results indicate that the vaccine may be an effective approach to strengthening the immune system against this specific type of brain cancer.
Falling Walls is the unique global hub connecting science, business, and society. They shape the future of humanity through impact-driven ideas and discoveries, driven by each other’s shared dedication to creating breakthroughs across borders and disciplines.
The winner of the prestigious Falling Walls Science Breakthrough Prize, held on November 9, 2024, in Berlin, was Dr. Michael Platten, a neurologist at Mannheim Medical University and the German Cancer Research Center, who has achieved a breakthrough in cancer immunotherapy.
His groundbreaking research targets gliomas, including aggressive glioblastomas, using immune system strategies.
Platten and his team have developed an experimental vaccine for a type of brain cancer called glioma, which occurs in aggressive and difficult-to-treat forms. This type of tumor often has a mutation in a protein called IDH1, which creates a specific “target” for the immune system.
The vaccine, called IDH1-vac, is designed to stimulate the immune system to recognize and attack tumor cells that have this mutation.
In an initial study of 33 patients, published in Nature in 2021, the vaccine was shown to be safe and free of serious side effects. For most patients (93%), the vaccine was able to activate immune system responses.
Three years after starting treatment, approximately 63% of patients had no disease progression, and about 84% were still alive. Among patients who responded well to the vaccine, survival rates were even higher.
The study also showed that after receiving the vaccine, some patients experienced a reaction called pseudoprogression, where the immune system causes inflammation at the tumor site, which can be mistaken for tumor growth.
However, this inflammation was a positive sign, indicating that the vaccine was working and that the immune system was responding to the tumor.
Most patients in the study had already undergone conventional treatments, such as radiation or chemotherapy, before receiving the vaccine. These treatments combined with the vaccine can boost the immune response against the tumor.
However, patients who did not have a strong immune response to the vaccine showed progression of their cancer within two years.
The study suggests that the IDH1-vac vaccine may be a promising new approach to combating brain tumors with the IDH1 mutation, specifically by stimulating the immune system to target and effectively attack tumor cells.
a) Diagram representing disease progression and interventions for each patient in SDS (n = 32 patients). b) Diagram of overall and progression-free survival probabilities according to time-dependent IDH1-vac-induced immune response in IDS (n = 30 patients). The x-axes show time since first diagnosis, red line (with immune response) and blue line (without immune response). c) Exemplary recovery sequences. d) Frequencies of PsPD, stable disease (SD), and progressive disease (PD) according to T cell response types for patients in IDS. e) Magnitude of best T cell response defined by maximum specific count. f) Mutation specificity scores and molecular profile of each patient in IDS (n = 30 patients). g) Graph of overall and progression-free survival probabilities.
READ MORE:
A vaccine targeting mutant IDH1 in newly diagnosed glioma.
Platten M, Bunse L, Wick A. et al.
Nature 592, 463–468 (2021).
Abstract:
Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma1,2,3. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II4,5. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+ tumors in syngeneic MHC-humanized mice4,6,7,8. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H)+ astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG+ and CXCL13+ T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.
Comentários