Immunotherapy in Refractory DLBCL

Transcript:Ian W. Flinn, MD: Let’s talk about large-cell lymphoma. There are data recently presented, the SCHOLAR-1 study, by Michael Crump, looking at basically a retrospective analysis of multiple different clinical trials and the expected outcome for patients that have refractory large-cell lymphoma. And it’s pretty dismal: there’s 20% to 30% response rate. The median survival is 6 months or less, and so there’s clearly a need for new drugs in that arena. One place that PD-1 inhibitors have been tried is in the post-autologous stem cell transplant space. So, with pidilizumab, there’s a study with that that was published a number of years ago trying to use the drug there. Krishna, what’s your take on that? Do you think that’s a good idea?

Krishna V. Komanduri, MD: Yes, that’s an interesting concept. Philippe Armand did a study that was published in the JCO in 2013 using pidilizumab, giving three doses of it after autologous transplantation. After autologous transplant, there are a number of very interesting things relevant to how immunotherapy may work and where it may best work. You’ve just had the patients get high doses of cytotoxic chemotherapy so that the disease burden has gone from modest to high in these patients who had always relapsed, and, of course, we’re often getting salvage therapy. Most of those patients had measurable disease at the time of transplant.

First, their disease burden had been reduced, so to the point where an immune response could perhaps finish off the malignancy. The second thing is that the post-autotransplant period, in terms of how the immune system is—and this is a bit of focus in my lab, in both the auto and the allogeneic transplant settings—we know that there’s lymphopenia. If you can expand an antigen-specific immune response against the tumor, it may have a relative advantage in terms of competing other cells out that would normally be competing for cytokines and other things that drive the growth of T cells. And the third thing is that in the post transplant setting, lymphopenia-induced expansion of T cells tends to push them toward the late memory stage that we think actually can be disinhibited by these checkpoint inhibitors. So, that immune remodeling in the post transplant setting is exciting.

What Philippe did was basically give a group of patients pidilizumab in that setting, and I think that there are a couple of relevant things. Fifty percent of those patients had some measurable disease even after transplant, and in those patients, one- third of the patients treated with pidilizumab post transplant actually converted to a CR. Despite the fact that many patients had measurable disease at the time of transplant, the responses were good. This was not a randomized controlled trial, so there was no control group that was treated without pidilizumab. They looked at historical controls, but at least with respect to historical controls, response rates appeared to be favorable. And, again, there was this conversion that we wouldn’t, at least, intellectually, expect between patients who had measurable disease to unmeasurable disease.

Ian W. Flinn, MD: There’s also the patients. A good one-third of the patients who went on this trial were PET-positive going into the transplant, and that’s a group that we think have historically very bad outcomes; about 70% survival at 16 months.

Andre Goy, MD, MS: This was a high-risk population, and this is a small number of patients, but the signal is really there. And based on some of these data and others, we actually initiated a study in our center post autotransplant in high-risk patients who had relapsed within a year with large-cell lymphoma, primarily with failures, as well. And then we give them the ipilimumab/nivolumab combination post autologous in a dose-escalation fashion because we have to be careful at the beginning. To your point, this is a perfect immunological milieu. Post transplant, when you try to do immunotherapy, you reset the clock because you might have less of this immunosuppression that is induced by the clone. So, I think this is really exciting, as we can revisit and reinvent auto-transplant.

Krishna V. Komanduri, MD: In that group of patients that you just talked about that has a relapse within 1 year of transplant, we know…

Andre Goy, MD, MS: They do very poorly.

Krishna V. Komanduri, MD: Very poorly, and I think that’s an ideal place to test these concepts.

Transcript Edited for Clarity