IDO Inhibitors Among Immunotherapy Strategies Under Study in Glioblastoma

Shannon Connelly
Published: Wednesday, Nov 30, 2016
Rimas V. Lukas, MD

Rimas V. Lukas, MD

The concept of using immunotherapies to treat patients with glioblastoma multiforme is gaining ground among researchers who are interested not only in evaluating checkpoint blockade agents that have proved effective in other tumor types but also in exploring novel targets, according to Rimas V. Lukas, MD.

Lukas, an associate professor of Neurology and director of Medical Neuro-Oncology at The University of Chicago Medicine, recently spoke with OncLive about developments in the field, particularly those concerning the indoleamine 2,3-dioxygenase (IDO) pathway.

OncLive: What GBM research do you find most exciting?

Lukas: As with the rest of oncology, the use of immunologic therapies is what has a substantial proportion of the neuro-oncologists fairly excited. I think that following in the footsteps of our colleagues in melanoma and other related disorders, immunotherapies such as PD-1 antibodies are of particular interest.

Right now we’re excited to have recently opened up a trial using the PD-1 antibody nivolumab (Opdivo) in newly diagnosed glioblastoma. We’ve had the opportunity to utilize the PD-L1 antibody atezolizumab (Tecentriq) in recurring glioblastoma as well, so I think those are 2 very exciting things.

The other areas that we are particularly interested in, and that have a lot of promise are upstream from the PD-1/PD-L1 access: IDO and targeting IDO inhibition. I think the field of glioblastoma clinical research is at the forefront in the sense that it’s looking at the next steps after PD-1/PD-L1 blockade once we’ve investigated that fully.

I think what many people are substantially interested in is going to be the utilization of not just blocking one checkpoint, but thinking about blocking multiple (checkpoints) and what the best combinations are, or using checkpoint blockade in conjunction with either traditional cytotoxic chemotherapies or antiangiogenic therapies.

Are there specific challenges that come with using immunotherapies in GBM?

In neuro-oncology, in particular, we worry about cerebral edema, and when we’re using immunotherapies, that becomes a substantial concern, so our radiographic endpoints become difficult to interpret. In addition, from a clinical care perspective, patients develop significant symptoms once they have cerebral edema, and that’s different than I think in many of our other oncologic specialties, where they have to worry about that to a lesser degree.

We utilize steroids, oftentimes dexamethasone, to decrease cerebral edema, which in theory, at least, is counterproductive to the use of immunotherapies. So, one could imagine whether using antiangiogenic therapies in conjunction with immunotherapy may make reasonable sense. Those are questions that are being actively explored right now and it will be exciting to hear those answers.

Where are we with IDO inhibitors?

Right now, those are in phase II clinical trials. The agent that we’re exploring here is indoximo; that is an oral IDO inhibitor. It appears to be very well tolerated thus far. Hopefully, we’ll get some sort of efficacy signal readout in the relatively near future.

What are the differences between IDO inhibition and the checkpoint blockade approach?

IDO is an enzyme that converts tryptophan to kynurenines. Kynurenines help facilitate the immunosuppressive microenvironment and so they’re associated with a higher amount of PD-L1 expression on the tumor cells; they’re associated with a larger amount of Tregs (regulatory T cells) within the tumor itself, and they’re associated with a smaller amount of CD8-positive cells.

So from my perspective, they’re the upstream element that plays a role in creating that environment. It’s a very attractive target because of that, as opposed to PD-1 or PD-L1, which is dealing with those immune cells or the tumor itself.

Are there any immuotherapy trials thus far that seem promising in GBM?

One of the most interesting and complicated stories right now is the EGFRvIII vaccine rindopepimut (Rintega), an agent with which we’ve participated in a number of clinical trials here.

It’s a very well-tolerated agent. It takes the external domain tumor-specific epitope, tags it on to keyhole limpet hemocyanin (KLH), something that ramps up the immune activity, and is administered intradermally along with GM-CSF, which further stimulates immune activity. The immune system then reads it outside the nervous system and recognizes that this is something similar to what we have going on inside the nervous system within the tumor itself, and then ideally allows the immune system to do its job.

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