Stephen M. Ansell, MD, PhD, discusses overcoming immune evasion in lymphoma.
Stephen M. Ansell, MD, PhD
Immune evasion is one of the biggest obstacles plaguing the implementation of checkpoint inhibitors into the treatment landscape of Hodgkin lymphoma, according to Stephen M. Ansell, MD, PhD.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are currently approved for single-agent use in patients with Hodgkin lymphoma. Nivolumab was granted approval in May 2016 for patients who have relapsed or progressed after autologous hematopoietic stem cell transplantation and posttransplantation brentuximab vedotin (Adcetris). The FDA approved pembrolizumab in March 2017 for the treatment of adult and pediatric patients who are refractory or have relapsed after 3 or more lines of therapy.
Ansell said that although there are good efficacy data for both of these checkpoint inhibitors, many patients progress due to immune evasion. However, combinations of checkpoint inhibitors may offer a solution.
In an interview with OncLive at the 2018 Pan Pacific Lymphoma Conference, Ansell, chair of the Lymphoma Group at Mayo Clinic, discussed overcoming immune evasion in lymphoma.Ansell: One of the big challenges in lymphoma is that many immune cells are present right in the tumor, but somehow those immune cells are not killing the tumor cells. The key question is, how does the tumor hide from the immune system as efficiently as it does? Actually, there are many barriers to a good immune response in lymphoma. The cells that are there are pretty exhausted from being persistently activated, and sometimes there are other cells in the neighborhood that are suppressing their activity.
Also, there are many proteins that are being made on the tumor cell like cytokines, which activate the immune system but then exhaust it over time. With all that going on, plus the immune-suppressive macrophages present in the tumor, the real challenge is working out how to get the T cell to kill the tumor cell efficiently. There are a lot of strategies being tried to test that now.One of the real successful strategies has been to prevent T-cell exhaustion. T cells basically get activated, make proteins such as PD-1 as a receptor on the cell surface, and that then puts them at risk for being suppressed by PD-L1 or PD-L2. Other receptors, such as TIM-3 and LAG-3, are important and those begin to increase as the cell becomes more exhausted. A strategy to keep the immune system engaged is to block these negative signals. Blocking PD-1 has been very successful in lymphoma, but now new trials blocking TIM-3 and LAG-3 are all in progress.
A second strategy that is proving to be very interesting is taking the macrophages, which are “bad boys” that are influencing the immune system in an unfavorable way, and getting them to turn on the tumor. The tumor puts a little protein on the cell surface that signals "don't eat me." The cell is really just telling the immune system that, “It is on their side.” But if you cover that up, the immune system—particularly the macrophages—will provide a lot more scrutiny of that cell and phagocytose it. That is another strategy that is proving to be very exciting and promising at this point.The impact has been pretty profound so far. In Hodgkin lymphoma, blocking PD-1 has proved to be a significant success. Blocking PD-1 in patients who have had all treatments, including transplant or brentuximab vedotin, showed a response rate of at least 65% to 70%. That is now being used earlier in the disease course; in fact, it is even being combined with chemotherapy in the frontline setting. It has been shown that there is a high response rate as a single agent even if it is used before the chemotherapy. These are all ways that these strategies are becoming a reality and benefitting patients directly. The exciting thing is that there are a lot of clinical trials in progress now. I encourage clinicians and patients to participate in trials, because that gives us answers that can impact practice down the road. Clinicians are very familiar with PD-1 blockade. They are using it across a broad spectrum of diseases, including solid tumors. However, the exciting part is the combination approaches—that is where the trials are in progress.
There are a number of organizations to provide all kinds of good information, and I always encourage people to go to those.We are still trying to understand the role of PD-1 blockade compared with antibody-drug conjugates. There are trials now in the relapsed setting where patients are being randomized to those 2 types of treatment. That is a very appropriate trial for patients to be considered for. There are a number of trials now utilizing upfront therapy, and in fact, there are soon-to-be available trials looking at standard treatment compared with these new combinations in the frontline setting.
Another thing is that elderly patients do not tolerate chemotherapy well, so using the antibody-drug conjugate brentuximab vedotin, and PD-1 inhibitor treatment, has been quite promising in older patients for whom chemotherapy is a challenge. These are places where there are a lot of opportunities for patients.When the immune system works, it does a very good job. Therefore, we just need to get the immune system to work well every time and target tumors in a much more efficient fashion. There are a lot of treatments in development that are trying to do that. It is one of those spaces to keep your eye on, which hopefully will result in good outcomes for patients.