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

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.