Abstract
A vaccine targeting IDH1 in patients with newly diagnosed diffuse glioma may be worth pursuing, researchers say. In a phase I trial, the vaccine was deemed safe, and it induced an immune response—including clonal expansion of CD4 T cells—in 93.3% of patients.
Researchers have long been interested in developing a vaccine to treat glioma, but progress has been limited. Now, results of a phase I trial suggest that a vaccine targeting IDH1 in patients with newly diagnosed diffuse glioma may be worth pursuing: The vaccine was safe and induced an immune response, including clonal expansion of CD4 T cells, in nearly all trial participants (Nature 2021;592:463–8).
Diffuse glioma is difficult to treat surgically, and it often recurs after radiotherapy and/or chemotherapy. However, a subset of gliomas has an IDH1 driver mutation that represents an appealing therapeutic target because it is highly specific to, and uniformly expressed in, tumor cells.
Lead author Michael Platten, MD, of the German Cancer Research Center in Heidelberg, and his team began with a simple question: “Is this mutation immunogenic?” Initial experiments revealed that the most common IDH1 mutation in glioma contains an immunogenic epitope presented on the MHC class II complex. Using this information, researchers developed an IDH1-specific peptide vaccine that induced CD4 T-cell responses in MHC humanized mice and resulted in control of IDH1-mutant tumors (Nature 2014;512:324–7). “Very early on we thought, this is something that we should translate into a clinical trial,” Platten says.
For the trial, researchers enrolled 33 patients newly diagnosed with grade 3 or 4 IDH1-mutant astrocytoma, all of whom received between four and eight doses of the vaccine with radiotherapy and/or chemotherapy; 29 patients had surgery to remove some or all of their tumors. Overall, the vaccine was safe, with adverse events—most commonly pain or inflammation at the injection site—limited to grade 1. Twenty-eight of 30 evaluable patients (93.3%) had vaccine-specific immune responses starting as early as 4 weeks after the first dose, and responses occurred across MHC alleles. Twenty-six patients had T-cell immune responses, and 28 had B-cell responses. Further analysis revealed that patients exhibited clonal expansion of CD4 T cells that were reactive to mutant IDH1. Additionally, 12 patients experienced pseudoprogression, a transient inflammatory reaction associated with a T-cell response. At 3 years, 63% of patients had not experienced disease progression, and 84% were still alive.
The findings provide evidence “that we can induce mutation-specific T cells that home into the brain tumor tissue,” Platten says, although more work is needed to confirm the vaccine's efficacy. To this end, the researchers are planning a randomized phase II trial in a similar group of patients. They are also testing the vaccine with the PD-L1 inhibitor avelumab (Bavencio; EMD Serono) in a phase I trial of recurrent glioma.
“It's an interesting paper, and a lot of it makes biological sense,” says Donald O'Rourke, MD, of the University of Pennsylvania in Philadelphia, who was not involved in the research. However, researchers should not draw definitive conclusions about response to the vaccine without an analysis of tumor tissue after treatment to see if IDH1 expression is lost or reduced, he says. “I think it's something to build on.”
Michael Lim, MD, of Stanford University School of Medicine in Palo Alto, CA, who was not involved in the study, says the presence of CD4 T cells and the occurrence of pseudoprogression are encouraging preliminary signs of an immune response to the vaccine. Also, “the fact that immune response is independent of the MHC allele suggests a more universal application of this technology.” A larger trial, he says, will allow researchers to look at grade 3 and 4 gliomas separately while gaining insight into survival. “I think it's an original and exciting idea in an area of big need,” he concludes. –Catherine Caruso
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