Genetically Engineered CD4 T Cells Show Promise Across Cancers

George D. Demetri, MD

Yong-Chen William Lu, PhD

A new treatment consisting of genetically engineered CD4 T cells could have potential in all metastatic cancers, according to Yong-Chen William Lu, PhD.

In an interview with Targeted Oncology, Lu, a fellow in the Surgery Branch of the National Cancer Institute, discusses a phase I dose-escalation study investigating the genetically engineered CD4 T cells ability to target the MAGE-A3 protein, as well as the treatment's potential toxicities and currently ongoing responses in some patients still enrolled in the trial.

TARGETED ONCOLOGY:Can you give us an overview of your study on CD4 T-cell immunotherapy targeting MAGE-A3 in multiple types of metastatic cancer?Lu:I presented the first CD4 genetically modified T-cell therapy against cancer. In this study, which was a first-line trial, we used different doses for the dose escalation to test different doses for the cell. We had 8 patients on dose escalation and another 6 patients on the highest dose, and for that we found 3 patients that responded to all therapy. One patient is a patient with cervical cancer, 1 patient with esophageal cancer, and another one with urothelial cancer. Those 3 patients are still showing an ongoing response and are doing well.

For this trial, we have 2 major questions. The first question is to test whether the CD4 T cell has the response to the cancer in most therapies, similar to CD8 T cell therapy. The second question we wanted to ask is volume, because currently the cancer immunotherapy regimen has been to target melanoma, lymphoma, leukemia, and renal cancer, but the rest of the majority of cancer and those cancer patients did not receive the benefit from that.

This trial tests the hypothesis that T cell therapy can be applied to any type of cancer. We have been treating melanoma cancer patients, breast cancer patients, and cervical cancer patients. So you could potentially apply this to many different types of cancer.

TARGETED ONCOLOGY:What are the next steps going forward?Lu:Our major focus is in the phase II study. For the phase I study, we were confirming that this trial is safe and that we can use the higher dose to do that. In the phase II study, we are going to initially treat 20 patients, then up to 40 patients, for different cancer types. Our major focus will be in melanoma, cervical cancer, esophageal cancer, and urothelial cancer. Hopefully we will understand the effectiveness of this T cell therapy against different types of cancer.

TARGETED ONCOLOGY:What is the mechanism of action for this drug?Lu:It's a very important, but very difficult question, because as we mentioned this is the first CD4 T cell therapy. We know very little about it. So far what we know is that the CD4 T cell is doing the job of helping the CD8 T cell. Other than that, we don't know much. We definitely have lots of work to do, both in human and maybe mice studies. We hope that this trial will stimulate scientists to know more about the CD4 T cell and do more basic research toward the question.

TARGETED ONCOLOGY:What was the safety profile like?Lu:So far the toxicities have been very mild. It's the same as all the other T cell therapies, we have to use chemotherapy to clean out all the T cells that are in the patient, and that will create a space for our modified T cells to expand within the patient. Unfortunately, that is the same as other chemotherapies where you get the same side effects as a chemotherapy regimen.

Other than that, most of the responses have been very mild. The only ones that happened for this particular trial is that 12 of the 14 patients experienced high fever for around 1 to 2 weeks, and that might be the worst thing because as we all know, the immune system needs to be stimulated to fight the cancer cells. It's the same when we have the flu — we might have a fever to fight the disease. Other than that, we haven't seen much toxicities. Only 1 patient at the end of this trial had acute fever and renal injury, but that might have been from a patient-specific issue because we didn't see that in other patients. We couldn't figure out the cause of that, but other than that it's been very safe.

TARGETED ONCOLOGY:What are some of the biggest questions that you hope to answer?Lu: