Alicia Lenzen

IDO1 Inhibition Synergizes with Radiation and PD-1 Blockade to Durably Increase Survival Against Advanced Glioblastoma

Purpose: Glioblastoma is the most aggressive primary brain tumor in adults with a median survival of 15–20 months. Numerous approaches and novel therapeutics for treating glioblastoma have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, nivolumab (anti-PD-1), which failed to improve recurrent glioblastoma patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for glioblastoma, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents. Experimental Design: Here, we investigated immunocompetent orthotopic mouse models of glioblastoma treated with the potent CNS-penetrating IDO1 enzyme inhibitor, BGB-5777, combined with anti-PD1 mAb, as well as radiotherapy, based on our recent observation that tumor-infiltrating T cells directly increase immunosuppressive IDO1 levels in human glioblastoma, the previously described reinvigoration of immune cell functions after PD-1 blockade, as well as the proinflammatory effects of radiation. Results: Our results demonstrate a durable survival benefit from this novel three-agent treatment, but not for any single- or dual-agent combination. Unexpectedly, treatment efficacy required IDO1 enzyme inhibition in non-glioblastoma cells, rather than tumor cells. Timing of effector T-cell infiltration, animal subject age, and usage of systemic chemotherapy, all directly impacted therapy-mediated survival benefit. Conclusions: These data highlight a novel and clinically relevant immunotherapeutic approach with associated mechanistic considerations that have formed the basis of a newly initiated phase I/II trial for glioblastoma patients. Clin Cancer Res; 24(11); 2559–73. ©2018 AACR.

Improving vaccine efficacy against malignant glioma

ABSTRACT The effective treatment of adult and pediatric malignant glioma is a significant clinical challenge. In adults, glioblastoma (GBM) accounts for the majority of malignant glioma diagnoses with a median survival of 14.6 mo. In children, malignant glioma accounts for 20% of primary CNS tumors with a median survival of less than 1 y. Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored. We conclude by proposing new strategies that are built on current vaccine technologies and improved upon with novel combinatorial approaches.

IDO1 in cancer: a Gemini of immune checkpoints

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan (Trp) into downstream catabolites known as kynurenines. Coincidently, numerous studies have demonstrated that IDO1 is highly expressed in multiple types of human cancer. Preclinical studies have further introduced an interesting paradox: while single-agent treatment with IDO1 enzyme inhibitor has a negligible effect on decreasing the established cancer burden, approaches combining select therapies with IDO1 blockade tend to yield a synergistic benefit against tumor growth and/or animal subject survival. Given the high expression of IDO1 among multiple cancer types along with the lack of monotherapeutic efficacy, these data suggest that there is a more complex mechanism of action than previously appreciated. Similar to the dual faces of the astrological Gemini, we highlight the multiple roles of IDO1 and review its canonical association with IDO1-dependent tryptophan metabolism, as well as documented evidence confirming the dispensability of enzyme activity for its immunosuppressive effects. The gene transcript levels for IDO1 highlight its strong association with T-cell infiltration, but the lack of a universal prognostic significance among all cancer subtypes. Finally, ongoing clinical trials are discussed with consideration of IDO1-targeting strategies that enhance the efficacy of immunotherapy for cancer patients.

The Kynurenine/Tryptophan Ratio and Glioblastoma Patients Treated with Hsppc-96 Vaccine

The discovery that immunotherapy is a clinically-relevant approach for the treatment of malignant tumors is revolutionizing patient care. In adults diagnosed with glioblastoma (GBM), an aggressive and incurable primary brain tumor, autologous HSPPC-96 vaccination provides a significant increase in overall survival. However, all GBM patients eventually succumb to their disease, providing rationale for discovering new methods that proactively identify individuals that will respond, optimally. Of the immunosuppressive mediators that contribute to the inhibition of productive tumor immunity, indoleamine 2,3 dioxygenase 1 (IDO1), a rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn), has been demonstrated to be expressed at elevated levels in patients with malignant glioma. Recently, our group determined that a correlation exists between peripheral blood Trp and Kyn levels in GBM patients and the association with overall survival after HSPPC-96 treatment. Our findings indicate that the Kyn/Trp ratio may be a useful benchmark for identifying GBM patients with a higher likelihood to survive longer after vaccination. The relevance to future clinical trials, the limitations of brain tumor models to address these findings and the role of IDO1 versus tryptophan dioxygenase (TDO) in the maintenance of peripheral Trp and Kyn levels, is discussed.