IDO Inhibitors Among Immunotherapy Strategies Under Study in Glioblastoma

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.

OncLive: What GBM research do you find most exciting?

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.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.

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

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.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.

Where are we with IDO inhibitors?

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

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.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.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.

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

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.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.

It demonstrated improvement in overall survival in the randomized phase II REACT study for recurrent glioblastoma. However, in the preliminary analyses of the randomized phase III ACT IV clinical trial for newly diagnosed glioblastoma, it did not demonstrate bene t in survival.

That speaks to the idea that timing of the agent may play a role in efficacy. It also speaks to the idea that the second agent we’re using it with—in the ACT IV study, it was temozolomide and in the REACT study, it was bevacizumab—may play a role in potential efficacy.

Is there an understanding about whether or how brain cancer is immunogenic?

I think there’s still a substantial amount that we’ll learn about from that agent, and I think from my perspective, that’s the story that’s the furthest developed. Thus far, with respect to checkpoint inhibitors, we have data that they appear to be safe and they have a unique set of toxicities that most neuro-oncologists hadn’t been used to before.I think we have a clear understanding that there is a locally suppressed immune environment, and there’s also a globally suppressed immune environment. If we look at absolute lymphocyte counts (ALCs) in these patients at time of diagnosis prior to any intervention, we’ll see that they have low ALCs. From a clinician’s perspective, it’s interesting because we don’t really see patients coming to us with opportunistic infections despite having these low ALCs.

We know there is an alteration in the way the immune system works. There are patients who appear to have worsening of their tumor initially, so they’re having these radiographic pseudo-progressions, and then they have a redirection of that and it seems to be associated with a sustained response.

What is the biggest challenge in GBM?

It’s too early to say anything definitively at this point, but I think that the use of immunotherapies is very rational in this patient population, and I think it’s something that is well worth exploring.The short overall survival. Going after improving overall survival and trying to improve the tail end of the curve with people who have prolonged sustained responses—that’s what most of us are chasing. At the same time, we are trying to maintain a good or reasonable quality of life while doing so, which I think we're able to accomplish. The overall survival improvement is where the work needs to be done, so there is a gargantuan need for these types of novel therapies.