One goal of our laboratory is to study the peripheral blood from patients with brain tumors undergoing standard-of-care treatment, as well as those individuals that elect to enroll in immunotherapeutic treatment(s). A recent finding from our work highlights an interesting correlation between the kynurenine (Kyn.)/tryptophan (Tryp.) ratio, and overall survival in human glioblastoma (GBM) patients (Figure 1A,B).
Figure 1- Click image to enlarge
These data have multiple implications. First, since the kynurenine/tryptophan ratio is indicative of IDO1 activity and because glioblastoma patients with higher activity show a trend of decreased survival, IDO1 inhibition may be an effective therapeutic modality. The second implication is derived from an unexpected set of findings; rather than IDO1 activity being strongly perturbed just before surgical brain tumor resection (Pre-surg.) or just after surgical brain tumor resection (48h Post-op.), IDO1 activity was most changed at 10 weeks or greater following surgical resection (10w+), suggesting that the time for applying IDO1-targeted therapy may be most relevant to well-after the patient has already returned home, a highly novel concept derived from our laboratory. We are currently following-up these initial observations with increased numbers of patients and increased numbers of time points post-surgery.
Another aspect of our laboratory carries out the analysis of patient brain tumors. Previous work has identified that IDO1 levels, the enzyme that converts tryptophan into kynurenine, is correlated with overall survival in patients with brain tumors (Figure 2). The data are exciting in-so-far as identifying IDO1 as a target for immunotherapeutic inhibition. Through studying IDO1 in human glioblastoma cells in petri dishes, as well as in our laboratory’s mouse models, our group intends to understand 1) how IDO1 is regulated in brain tumors, 2) how it can be targeted in brain tumors and 3) a strategy that studies the impact of IDO1 inhibition on overall survival in brain cancer models. Ultimately, this work is intended to provide tactical insight into the most effective IDO1 inhibitory strategy for patients with incurable brain cancer.
Although each of these aspects within our laboratory is interesting, insightful and important, some of the most exciting work we are currently engaged in applies to the active testing of rational therapeutic combinations for translation into patients. This involves testing various combinations of radiotherapy, chemotherapy, immunotherapy, as well as surgical manipulation, in addition to considering the impact on therapy-induced toxicity, optimal timing for each therapeutic modality and impact of age on therapeutic responsiveness. While combinatorial immunotherapy is a very exciting modality that has been proven to be extremely effective in mouse brain tumor models (Figure 3), studies from patients with incurable melanoma have demonstrated that certain combinations possess high levels of toxicity. Therefore, we are currently pursuing agents (including clinical-grade IDO1 inhibitors), coupled with other forms of therapy, aimed at brain tumor destruction, while limiting the toxic side-effects.
Finally, to gain perspective, to train future scientists and physicians, as well as to push the field of brain tumor immunology forward, all members of our group are required to participate in the review and critique of the literature. This exercise provides an informed context for generating valuable and novel insight with the hope of more effective therapeutic modalities in patients with incurable cancer. Some of these insights can be gained from our recent publications in Clinical Cancer Research and Oncoimmunology (Figure 4).