Brain cancer: Mutant protein vaccine shows safe and effective

Brain cancer: Mutant protein vaccine shows safe and effective.  The first case of brain cancer patient vaccinated with mutant protein vaccine shows safe and effective.

Among fully vaccinated patients, the three-year survival rate after treatment was 84%, and 63% of patients had no progression of tumor growth during this period.

Surgical resection is one of the main methods of clinical tumor treatment, and residual micro tumor tissue or circulating tumor cells can cause tumor recurrence or metastasis, which is also a major challenge for tumor treatment. Tumor vaccines can inhibit tumor recurrence and metastasis by activating continuous anti-tumor immune protection effects, and have great potential in tumor postoperative treatment.

Doctors and cancer researchers from Heidelberg and Mannheim have conducted a clinical trial for the first time to test a mutation-specific vaccine against malignant brain tumors. The study was published in the journal Nature, and the results show that the vaccine is safe and triggers the required immune response in tumor tissues.

Diffuse gliomas are usually incurable brain tumors that spread to the entire brain and are difficult to completely remove by surgery. Chemotherapy and radiotherapy often have limited effects. In many cases, diffuse gliomas have a common feature: in more than 70% of patients, tumor cells have the same genetic mutation. The same error in the DNA causes a single, specific protein building block to be exchanged in the IDH1 (isocitrate dehydrogenase 1) enzyme. This creates a new protein structure, the so-called neo-epitope, which can be recognized as a foreign body by the patient’s immune system.

The researchers said, “Our idea is to support the patient’s immune system and use vaccines as a targeted way to alert it to tumor-specific new epitopes. The IDH1 mutation is a particularly suitable candidate because it Gliomas are highly specific and do not occur in healthy tissues. In addition, IDH1 mutations are the reason for the development of these gliomas, which means that vaccines against mutant proteins can fundamentally solve the problem.”

The study included 33 patients, and one patient (ID16) was not vaccinated due to an adverse event (fever of unknown cause) before vaccination. Therefore, 32 patients received treatment and were included in the safety data set (SDS). Twenty patients (62.5%) were males and 12 (37.5%) were females, with an average age of 40.4±8.95 years.

According to the standard of care (SOC) treatment the patients received before enrollment, the test subjects were divided into three treatment groups (TG1-TG3): radiotherapy alone (RT, TG1), TMZ three-cycle chemotherapy (single TMZ, TG2) or TMZ Combined radiotherapy and chemotherapy (RT+cTMZ, TG3). Most patients received both radiotherapy and chemotherapy and TMZ before IDH1 vaccination (n = 23, 71.9%); 3 (9.4%) received TMZ alone, and 6 (18.8%) received radiotherapy alone. Of the 32 patients, 21 (65.6%) had World Health Organization (WHO) grade 3 astrocytoma, and 11 (34.4%) had grade 4 astrocytoma.

Patient characteristics at baseline and SOC treatment

Thirty of the 32 patients in SDS (93.8%) and 28 of the 30 patients in the immunogenicity dataset (IDS; 93.3%) reached the end of treatment (EOT). The maximum treatment time is 23 weeks. The median follow-up time for SDS (as of June 2020) was 46.9 months (95% confidence interval (CI): 45.2-49.2 months), and IDS was 47.1 (45.2-49.2) months.

29 out of 32 patients in the SDS group (90.6%) and 27 out of 30 patients in the IDS group (90.0%) received 8 vaccinations; one patient received 7 vaccinations, one received 6 vaccinations, and one The name was vaccinated 4 times. Treatment-related adverse events occurred in 29 of 32 patients (90.6%), but they were not serious. One patient (3.1%) had a treatment-related serious adverse event, and one patient (3.1%) was suspended due to a treatment-related adverse event.

Cellular and humoral immunogenicity of IDH1-vac

In SDS, 12 of 32 patients (37.5%) developed pseudo-progression (PsPD), while 10 of 60 patients (16.7%) in the molecularly matched control cohort developed pseudo-progression. Contrast-enhanced PsPD diagnosed by brain imaging is an indicator of intracavitary inflammation. There was no significant correlation with age, extent of resection, SOC treatment or WHO grade. The longer median observation period (7.3 years) in the matched cohort resulted in a bias towards detecting more PsPD.

Efficacy, pseudo-progression and T cell response of IDH1-vac

Among PsPD patients, only ID08 patients underwent lesion resection. Single-cell RNA sequencing (scRNA-seq) found three CD4+T cell clusters in the PsPD lesions of ID08 patients: regulatory T cells, activated CD40LG+CD4+T cells and CXCL13+CD4+T cells. According to reports, CXCL13+CD4+ T cells are important for anti-tumor immunity. By combining scRNA-seq and TCR sequencing, the researchers found that the CD40LG+CD4+ and CXCL13+CD4+ T cell populations are all dominated by a TCR (TCR14).

Molecular T cell phenotype of IDH1-vac-related PsPD

All in all, no serious side effects have been observed in patients who have been vaccinated. In 93% of patients, the immune system showed a specific response to vaccine peptides. Regardless of the patient’s genetic background, HLA protein, an important presentation molecule of the immune system, would have a specific response.

In a large proportion of vaccinated patients, doctors have observed pseudo-progression, which is tumor swelling caused by a large number of invading immune cells. Single-cell sequencing showed that there are a large number of helper T cells in the blood of these patients, and their immune receptors specifically respond to vaccine peptides. The researchers said that the results of the study also proved that activated mutation-specific immune cells have invaded brain tumor tissue.

Among fully vaccinated patients, the three-year survival rate after treatment was 84%, and 63% of patients had no progression of tumor growth during this period. Among the patients whose immune system had a specific response to the vaccine, a total of 82% of patients had no tumor progression within three years.

The researchers are also preparing to conduct a phase II study to check whether the IDH1 vaccine produces a better therapeutic effect than standard treatment alone.

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