IMMU-34. A BALANCED TRYPTOPHAN DIET LEADS TO MAXIMAL IMMUNOTHERAPEUTIC EFFICACY IN GLIOBLASTOMA MODELS

  • Ladomersky E
  • Zhai L
  • Lenzen A
  • et al.
N/ACitations
Citations of this article
5Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

INTRODUCTION: Immunotherapy has failed to improve glioblastoma (GBM) patient survival in all Phase III clinical trials to-date. A potential mechanism contributing to treatment failure, is based on our recent work showing that, GBM-infiltrating T cells directly increase the intratumoral expression of indoleamine 2,3 dioxygenase 1 (IDO1) (Zhai et al., 2017; CCR): an immunosuppressive enzyme that metabolizes tryptophan (Trp); an essential amino acid only provided to the body by dietary intake. Coincidently, we recently discovered that a substantial proportion of syngeneic mice with intracranial GL261, experience long-term survival when administered radiotherapy (RT) with concurrent PD-1 and IDO1 enzyme inhibitors (Ladomersky et al., 2018; CCR). Since the duration and penetration of pharmacologic IDO1 inhibition is variable, we questioned whether dietary Trp supplementation would influence efficacy of immunotherapy against GBM. METHODS: Mice were placed on ad libitum dietary formulations containing 0%, 25%, 100%, 200%, and 500% normal daily Trp, three days prior to the intracranial-injection (ic.) of 2 × 105 GL261. At fourteen days post-ic., animal subjects enrolled on each diet were treated with: (i) IgG control Ab; or (ii) the simultaneous combination of 2Gy whole brain radiotherapy for five days, four doses of PD-1 mAb (J43) every three days, and 100mg/kg IDO1 enzyme inhibitor (BGB-5777), BID, for four weeks (n=10/group). RESULTS: Mice receiving normal (100%) dietary Trp achieve a long-term survival benefit (3/10; P<0.001). In contrast and unexpectedly, both the depletion and saturation of dietary Trp, has negative effects on immunotherapeutic efficacy. Strikingly, although withholding dietary Trp decreases serological Trp levels (P<0.05), CNS parenchyma Trp concentrations remain stable, regardless of low-absent dietary Trp and peripherally-circulating levels. CONCLUSIONS: These data support that, IDO1-mediated immunosuppression is not overcome by supplementing or depleting the diet of Trp. Moreover, it suggests that a balanced diet, with normal Trp intake, provides maximal efficacy for supporting immunotherapy against malignant glioma.

Cite

CITATION STYLE

APA

Ladomersky, E., Zhai, L., Lenzen, A., Lauing, K., Otto-Meyer, S., Savoor, R., … Wainwright, D. (2018). IMMU-34. A BALANCED TRYPTOPHAN DIET LEADS TO MAXIMAL IMMUNOTHERAPEUTIC EFFICACY IN GLIOBLASTOMA MODELS. Neuro-Oncology, 20(suppl_6), vi128–vi128. https://doi.org/10.1093/neuonc/noy148.537

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free