Indoximod [Neurosurgery Wiki]

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====== Indoximod ======

A methylated [[tryptophan]] with [[immune checkpoint inhibitor]]y activity. Indoximod inhibits the enzyme indoleamine 2,3-dioxygenase ([[IDO]]), which degrades the essential amino acid [[tryptophan]], and may increase or maintain tryptophan levels important to [[T cell]] function. Tryptophan depletion is associated with [[immunosuppression]] involving T cell arrest and [[anergy]]. 
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Pre-treatment and on-treatment α-[[[11C]]]-[[methyl]]-L-Trp ([[AMT]]) [[positron emission tomography]] ([[PET]]) with co-registered [[MRI]] was performed on patients with [[recurrent glioblastoma]] treated with the [[IDO1]] pathway inhibitor [[indoximod]] (D1-MT) and [[TMZ]].

Regional intratumoral variability of AMT within enhancing and non-enhancing tumor was noted at baseline. On treatment imaging revealed decreased regional uptake suggesting IDO1 pathway modulation with treatment.

Lukas et al. from the Northwestern University, [[Chicago]] validated the ability to use PET of the Trp probe, AMT, for use in visualizing and quantifying intratumoral Trp uptake in GBM patients treated with an IDO1 pathway inhibitor. These data serve as rationale to utilize AMT-PET imaging in the future evaluation of GBM patients treated with IDO1 enzyme inhibitors
((Lukas RV, Juhász C, Wainwright DA, James CD, Kennedy E, Stupp R, Lesniak MS.
Imaging tryptophan uptake with positron emission tomography in glioblastoma
patients treated with indoximod. J Neurooncol. 2018 Nov 10. doi:
10.1007/s11060-018-03013-x. [Epub ahead of print] PubMed PMID: 30415456.
)).
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Phase 1b/2 single-arm trials in adult and pediatric brain cancers are being conducted in which indoximod is combined with chemotherapy or chemo-radiotherapy, with some early but intriguing efficacy data being reported. A preclinical treatment rationale was established in a robust orthotopic model of malignant brain cancer (glioblastoma), where the synergistic effects of indoximod were demonstrated in combination with temozolomide (TMZ) and radiation as a cooperative DNA damaging modality
((Li M, Bolduc AR, Hoda MN, Gamble DN, Dolisca SB, Bolduc AK, Hoang K, Ashley C,
McCall D, Rojiani AM, Maria BL, Rixe O, MacDonald TJ, Heeger PS, Mellor AL, Munn 
DH, Johnson TS. The indoleamine 2,3-dioxygenase pathway controls
complement-dependent enhancement of chemo-radiation therapy against murine
glioblastoma. J Immunother Cancer. 2014 Jul 7;2:21. doi: 10.1186/2051-1426-2-21. 
eCollection 2014. PubMed PMID: 25054064; PubMed Central PMCID: PMC4105871.
)).

In the latest report from the adult trial (NCT02052648) 
(( Colman H, Mott F, Spira AI, Johnson TS, Zakharia Y, Vahanian NN, et al. A phase 1b/2 study of the combination of the IDO pathway inhibitor indoximod and temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors: Safety analysis and preliminary efficacy of the phase 1b component. J Clin Oncol. (2015) 33:2070 10.1200/jco.2015.33.15))
, 12 patients who had progressed on standard of care therapy with TMZ were enrolled in a traditional 3+3 dose escalation study of indoximod (600, 1,000, or 1,200 mg twice daily). No dose-limiting toxicity was encountered nor did indoximod cause a delay or reduction in TMZ dosing in any patient. The best responses documented were 1 patient with partial response per Response Assessment in Neuro-Oncology (RANO) criteria at 15 months and 4 patients with stable disease lasting between 4 and 11 months 
((Zakharia Y, Colman H, Mott F, Lukas R, Vahanian N, Link C, et al. IMCT-21 updates on phase 1b/2 combination study of the IDO pathway inhibitor indoximod with temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors. Neuro-Oncology (2015) 17:v112 10.1093/neuonc/nov218.21)).

A phase 2 expansion of the study is ongoing at the 1,200 mg twice daily dose in combination with TMZ, bevacizumab and ateriotactic radiation (SRS) (NCT02052648).

In the pediatric brain cancer trial (NCT02502708) 
((Johnson TS. Radio-chemo-immunotherapy using the IDO-inhibitor indoximod for childhood brain cancer. In: 2017 International Pediatric Neuro-oncology Conference. (Houston TX, Texas Children's Hospital) (2017).))
, the first trial to evaluate indoximod both in children and in the context of radiotherapy, 17 patients from an original cohort of 29 heavily pretreated patients in the dose escalation phase 1b study who were eligible to receive further treatment were administered indoximod and radiotherapy followed by standard of care cycles of TMZ with indoximod as maintenance therapy. The other 12 patients received only indoximod and TMZ. Both treatments were well tolerated with minimal toxicity attributed to indoximod. Overall, at the time of the report, 29 patients in the dose-escalation phase of the study exhibited a median PFS of 6.2 months and median time to regimen failure (TTRF) of 11.7 months, which compares favorably with historical controls. Notably, patients receiving radiotherapy appeared to benefit significantly when indoximod was added, with a median TTRF of 12 months observed vs. 3.2 months without radiotherapy (p = 0.04). These data suggested a dose-sparing effect of indoximod on conventional chemo-radiotherapy, potentially extending efficacious responses. The notion that targeting the IDO pathway may improve chemo-radiotherapy is supported a recent study in lung cancer 
((Wang W, Huang L, Jin JY, Jolly S, Zang Y, Wu H, Yan L, Pi W, Li L, Mellor AL, 
Kong FS. IDO Immune Status after Chemoradiation May Predict Survival in Lung
Cancer Patients. Cancer Res. 2018 Feb 1;78(3):809-816. doi:
10.1158/0008-5472.CAN-17-2995. Epub 2017 Nov 8. PubMed PMID: 29118088; PubMed
Central PMCID: PMC5811356.
)).
Encouraged by these response data, the same regimen is now being tested in patients with diffuse intrinsic pontine glioma (DIPG), a dismal disease with no effective treatment option. Thus far, 3/6 patients enrolled are reported to have achieved good symptomatic and radiographic response
((Fox E, Oliver T, Rowe M, Thomas S, Zakharia Y, Gilman PB, Muller AJ,
Prendergast GC. Indoximod: An Immunometabolic Adjuvant That Empowers T Cell
Activity in Cancer. Front Oncol. 2018 Sep 11;8:370. doi: 10.3389/fonc.2018.00370.
eCollection 2018. Review. PubMed PMID: 30254983; PubMed Central PMCID:
PMC6141803.
)).