Looking Ahead in T-Cell Lymphoma

There are novel agents that are being explored in peripheral and cutaneous T-cell lymphomas that could possibly lead to an expansion of treatment options, according to Madeleine Duvic, M.D.

Such developments include an open-label phase 1/2 trial exploring the safety and efficacy of a chimeric antigen receptor (CAR)-pNK therapy targeting CD7 in relapsed/refractory patients with peripheral, angioimmunoblastic, extranodal natural killer, enteropathy-type intestinal or hepatosplenic T-cell lymphoma (NCT02742727).

Additionally, the investigational agent E7777 is being tested in patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma in a phase 2 trial (NCT02676778). The primary endpoint of the multicenter, open-label, single-arm study is objective response rate with E7777, which is a fusion protein that combines the interleukin-2 receptor-binding domain with diphtheria toxin fragments.

Why do you think classification is so important?

Are there any new targets being investigated currently?

In an interview with CURE, Duvic, professor of Medicine and Dermatology, Blanche Bender Professorship in Cancer Research, director of the Research Fellowship Program, Department of Dermatology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, shares her insight on classification of T-cell lymphomas, potential treatments in development, and what challenges oncologists are still facing in the field.We are moving toward personalized medicine and targeted therapies, so that if you know what markers a cancer bears on its surface, you can design a toxin-antibody to kill that cell selectively and decrease the toxicity in general. The more we know about the molecular basis for cancer in different people, the more prepared we’ll be to offer effective therapy. Rather than using big guns, we targeted small bullets.Absolutely, there are many new targets being investigated now. One of the most exciting is the CARs, or the chimeric antigen receptors, where if you know there’s a surface molecule, you can send T cells selectively to kill that cell.

However, there are also antibodies that are being developed based on surface markers. There is a whole new area using microRNA inhibitors; microRNAs can control a lot of genes and inhibitors can regulate them. We have a new category of drugs for the peripheral T-cell lymphomas and cutaneous T-cells lymphomas, in that they are very sensitive to histone deacetylase inhibitors [HDAC]. Istodax (Romidepsin) and Zolinza (vorinostat) are approved for peripheral T-cell and cutaneous T-cell lymphomas.

What challenges would you say still exist?

Looking ahead, what do you see happening in this area in the next five to 10 years?

What do you hope the oncology community takes away from all of this?

What are some things that are still unknown?

The T-cell lymphomas are hard because T cells keep you from getting cancer, and they fight off infection and they control the immune system. If they become malignant, they lose their ability to be killed. Then, they are the only kids left on the block or the malignant cells after we have decimated all the other T cells. Treating a peripheral T-cell lymphoma or cutaneous T-cell lymphoma leaves the patient immunosuppressed almost to the extent of a patient with AIDS. We have to find ways to be more selective in killing only the specific malignant T cells and not all of the T cells.It is my hope that we will create therapies that are less toxic and more effective. The drugs that we have now for these diseases have overall response rates in 20 percent to 35 percent, and we need drugs that have 90 percent efficacy. All of that happens through targeting and through basic science research.[I hope that they have] an appreciation that T-cell lymphomas are quite heterogeneous, and that not one shoe fits all. You can’t just use CHOP and then be done with it. This is because, although CHOP is effective initially, patients almost always relapse. Additionally, we are only curing a few patients with allogeneic stem cell transplant. The rest of the patients with advanced T-cell lymphomas will probably die of their disease. Therefore, we need a lot of better therapies. We need to know more about who should get what therapy.I believe that the oncologists don’t know a lot about cutaneous T-cell lymphomas and how to diagnose them. This is because they are very subtle when they appear; they look like ringworm, cirrhosis, or even eczema. Oftentimes, that results in a delay of diagnosis, which means that the patients are sicker when they first present and are harder to control.

Most cutaneous T-cell lymphomas fall into the category of mycosis fungoides, or Sézary syndrome. Patients with early onset mycosis fungoides can be treated very conservatively. They don’t need chemotherapy. In fact, if you give chemotherapy they get worse, because you are knocking out a patient’s innate immune system that can control it. Therefore, we manage it early enough with topical steroids, with phototherapy, and topical nitrogen mustard (Mustargen)—just topical agents will control them and often put them in remission for a long time.