First Report of Parkinsonism Associated With Indoximod, an Immune-Modulating Agent

Floyd, Mark; Osta, Badi El; Tang, Shou‐Ching

doi:10.1200/jgo.2016.007492

Cited by 7 publications

(4 citation statements)

References 5 publications

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“…In these patients, stable disease >6 months was observed, encouraging the notion that indoximod can reactivate latent T cell immunity in cancer patients. In the initial trials of indoximod, its relative apparent safety is notable given comparisons to the acute side-effects of immune checkpoint therapy, however, a case of Parkinsonism was reported recently in a patient receiving indoximod treatment ( 52 ). While safety studies were not able to identify a maximum tolerated dose (MTD) for indoximod, pharmacokinetic analysis indicated that 1,200 mg twice daily (BID) was the maximum exposure that could be achieved in a patient based on a plateau that occurred in plasma AUC and Cmax beyond this dose.…”

Section: Clinical Evaluation Of Indoximodmentioning

confidence: 99%

Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer

et al. 2018

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Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1 enzyme. However, clinical development focused on D-1MT (now termed indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, a convergent effector signaling molecule for all IDO/TDO enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique biological and mechanistic features of indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of cancer therapy, including chemotherapy, chemo-radiotherapy, vaccines, and immune checkpoint therapy. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease.

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Section: Clinical Evaluation Of Indoximodmentioning

confidence: 99%

Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer

et al. 2018

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“…DAT-SPECT revealed a decreased radiotracer uptake in the right basal ganglia in our patient, which might correspond to his symptoms of left-dominant involuntary movement. Floyd et al reported that DAT-SPECT showed normal dopamine transporter uptake in a patient with ICI-induced parkinsonism (10). Although drug-induced parkinsonism generally causes no abnormalities that are visible on DAT-SPECT, whether or not parkinsonism in patients with irAEs results in similar DAT-SPECT findings is unclear.…”

Section: Discussionmentioning

confidence: 99%

Steroid-responsive Nivolumab-induced Involuntary Movement with Anti-thyroid Antibodies

et al. 2019

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We herein report a 68-year-old man with neurologic immune-related adverse events (irAEs) who exhibited nivolumab-induced steroid-responsive progressive ataxia, tremor, and anti-thyroid antibodies. His symptoms matched abnormalities on N-isopropyl-p-(123I)-iodoamphetamine single-photon emission computed tomography (SPECT) and dopamine transporter SPECT. Based on these clinical findings, we diagnosed the patient with a condition similar to the cerebellar type of Hashimoto's encephalopathy with nivolumab-induced antithyroid antibodies. Neurologic irAEs can be difficult to diagnose due to their varied clinical courses and lack of specific examinations. Therefore, a comprehensive approach, including assessments of autoantibodies and functional imaging, might be important for the diagnosis of neurologic irAEs.

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“…Indoximod is a methylated TRP that inhibits IDO to maintain or elevate TRP levels important to T cell function. Interestingly, a case study reported that indoximod induced parkinsonism in a patient treated for metastatic breast cancer [101]. Recently, an IDO1 inhibitor (1-Methyltryptophan) was tested in murine model of PD, and the results showed improved locomotor activities, reduced level of neuroinflammatory and neuronal apoptotic markers.…”

Section: Damentioning

confidence: 99%

Single Nucleotide Polymorphisms of Indoleamine 2,3-Dioxygenase 1 Influenced the Age Onset of Parkinson's Disease

Török¹,

Maszlag-Török²,

Molnár³

et al. 2022

Front. Biosci. (Landmark Ed)

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Background: Earlier studies reported alterations of the kynurenine (KYN) pathway of tryptophan (TRP) metabolism in Parkinson's disease (PD). The first rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan dioxygenase were observed upregulated, resulting elevated KYN/TRP ratios in the serum and cerebrospinal fluid samples of patients with PD. More and more single nucleotide polymorphisms (SNPs) have been identified in a population of PD. However, little is known about the impact of genetic variations of the IDO on the pathogenesis of PD. Methods: SNP analysis of IDO1 was performed by allelic discrimination assay with fluorescently labelled TaqMan probes and a subgroup analysis was conducted according to the age of PD onset. The frame shifts variant rs34155785, intronic variant rs7820268, and promotor region variant rs9657182 SNPs of 105 PD patients without comorbidity were analyzed and compared to 129 healthy controls. Results: No significant correlation was found in three SNPs between PD patients and healthy controls. However, the subgroup analysis revealed that A alleles of rs7820268 SNP or rs9657182 SNP carriers contribute to later onset of PD than non-carriers. Conclusions: The study suggested that SNPs of IDO1 influenced the age onset of PD and genotyping of SNPs in certain alleles potentially serves as a risk biomarker of PD.

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First Report of Parkinsonism Associated With Indoximod, an Immune-Modulating Agent

Cited by 7 publications

References 5 publications

Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer

Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer

Steroid-responsive Nivolumab-induced Involuntary Movement with Anti-thyroid Antibodies

Single Nucleotide Polymorphisms of Indoleamine 2,3-Dioxygenase 1 Influenced the Age Onset of Parkinson's Disease

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