Author: Bozza, Matthias ; Oezen, Iris ; Alansary, Dalia ; Marsh, Kelly ; Dorsch, Marion ; Green, Edward ; Schrimpf, Daniel ; Cahill, Daniel P ; Kilian, Michael ; Bunse, Lukas ; Zhu, Dongwei ; Hänggi, Daniel ; Platten, Michael ; Ratliff, Miriam ; Sanghvi, Khwab ; Herold-Mende, Christel ; Al-Ali, Ruslan ; Kramer, Magdalena ; Harter, Patrick N ; Nicolay, Brandon ; Bieback, Karen ; Wick, Wolfgang ; Benner, Axel ; Uhlig, Stefanie ; Bunse, Theresa ; Poschet, Gernot ; Preusser, Matthias ; von Landenberg, Anna ; Wiestler, Benedikt ; Friedrich, Mirco ; Deumelandt, Katrin ; Meyer, Jochen ; Burger, Michael C ; Kaulfuss, Stefan ; Nadji-Ohl, Minou ; Steadman, Mya ; Plate, Karl H ; Neftel, Cyril ; Weller, Michael ; Hess-Stumpp, Holger ; Thon, Niklas ; Habel, Antje ; Niemeyer, Barbara A ; Sonner, Jana K ; Harbottle, Richard ; Okun, Jürgen ; Turcan, Sevin ; Berghoff, Anna S ; Pusch, Stefan ; Breckwoldt, Michael O ; Sahm, Felix ; Kessler, Tobias ; Suvà, Mario L ; Karcher-Bausch, Simone ; Eisel, Jessica ; von Deimling, Andreas

The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell-derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment.

Blood and Lymphatic Cancer: Targets and Therapy

<p>IDH1-mutated relapsed or refractory AML: current challenges and future prospects</p>

Review

Author: Megías-Vericat, Juan Eduardo ; Montesinos, Pau ; Ballesta-López, Octavio ; Barragán, Eva

The prognosis of patients with relapsed or refractory acute myeloid leukemia (R/R AML) is discouraging with salvage standard approaches. Mutations of isocitrate dehydrogenase 1 (IDH1 ^mut ), present in 7-14% of AML patients, have been discovered recently, opening the door to targeted agents aiming to improve the outcomes in this setting. Several oral selective IDH1 ^mut inhibitors are under investigation, ivosidenib being the first approved for R/R AML. We performed a systematic review to analyze the clinical outcomes and safety reported with IDH1 ^mut inhibitors and other agents in adult patients with IDH1 ^mut R/R AML. Ivosidenib in monotherapy achieved complete remission (CR) of 24%, overall response of 42%, and median overall survival of 9 months in R/R AML, and promising outcomes were reported with IDH305 and FT-2102. IDH1 ^mut inhibitors were generally well tolerated, but some therapy-related toxicities should be monitored, including IDH-differentiation syndrome, prolongation of the QT interval, and leukocytosis, all manageable and reversible. Also, venetoclax, CB-839, PARP inhibitors, and IDH1 peptide vaccine are being studied in IDH1^mut AML. The results of the ongoing and upcoming clinical trials will bring new evidence to establish the role of IDH1 ^mut inhibitors in therapeutic strategies of AML.

100 Deals associated with IDH1 peptide vaccine(Deutsches Krebsforschungszentrum, Dkfz)

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Indication	Highest Phase	Country/Location	Organization	Date
Glioma	Phase 1	-	German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)	-

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IDH1 peptide vaccine(Deutsches Krebsforschungszentrum, Dkfz)

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