Researchers Investigating TCR Therapy in NSCLC

Jeffrey P. Ward, MD, PhD

A single-arm, phase I clinical trial is exploring the safety and tolerability of a T-cell receptor therapy for patients with advanced non—small cell lung cancer (NSCLC).

NY-ESO-1 TCR (TAEST16001) engineered autologous T-cell therapy is being administered in patients with NSCLC whose tumors have NY-ESO-1 antigen expression and who have received at least 1 standard therapy (NCT03029273). NY-ESO-1 is expressed on 10% to 50% of cells in melanoma, lung cancer, ovarian cancer, liver cancer, esophageal cancer, breast cancer, prostate cancer, and bladder cancer cases.

In the study, an estimated 20 patients will receive treatment with cyclophosphamide 3 days prior to treatment with NY-ESO-1 therapy at 1 g daily for 2 days. After NY-ESO-1 treatment, which will be a single intravenous dose of 5 x 10⁹ anti-NY-ESO-1 TCR transduced T cells, patients will remain in the hospital for safety monitoring and frequent follow-up will be conducted. Subcutaneous injections of interleukin-2 will also be administered concomitantly for 14 days.

This trial is 1 of several that are testing the potential of T-cell therapy beyond hematologic malignancies and into solid tumors, such as NSCLC.

OncLive: Please provide an overview of your presentation at the State of the Science Summit.

There has been a lot of research on immunotherapy in cancer. Is there anything with the immune system and how it works that we still don’t know?

Specifically, what are some obstacles in the field we can overcome in the near future?

Jeffrey P. Ward, MD, PhD, an instructor in the Department of Medicine, Oncology Division, Medical Oncology, Washington University School of Medicine in St. Louis, lectured on immunotherapy and vaccines in NSCLC during the 2017 OncLive^® State of the Science Summit on Advanced Non—Small Cell Lung Cancer. In an interview, he discussed the questions researchers still face about targeting the immune system and exactly what role TCR therapy could play in the treatment of patients with NSCLC.Ward: Cancer immunotherapy is really the next generation of treatments that will be really effective for patients with lung cancer. I gave an overview of how the immune system works—a really nuts-and-bolts talk—and of some novel therapies that are either in clinical practice or in clinical trials, or in the next generation of things that are coming. Honestly, there is probably more that we don't know than we do at this point. We think we understand a lot of small details, but we are constantly surprised. The thing to understand about PD-L1 is that it is still a big, moving target. There is a lot of controversy and it is 1 of the biggest topics we talk about as oncologists, as we define who is going to respond and who is not going to respond. PD-L1 is 1 piece of the puzzle, but as I talked about, there are multiple different subpoints that decide whether the immune system is going to do something or if it is going to remain inert. designing a targeted therapy, designing a vaccine that we can then vaccinate a patient with after they progress on other therapies.

Basically, there are certain characteristics of a patient’s tumor, or immune system, that might be linked with therapeutic response?

What ongoing clinical trials are interesting to you right now?

I envision, in the future, that there is going to be more than 1 biomarker that is going to define who will respond. If you look at breast cancer, they have these large, 50- to 60-gene panels; we don’t have anything like that in lung cancer. Perhaps that time will come. PD-L1 testing tries to break that down into a simplistic, “yes.” However, what we really gain to understand is that it is probably a little bit too simplistic. There is more to a T cell and how a T cell decides whether to seize the antigen-presenting cell, migrate the tumor, and respond against an antigen or not. There are probably more molecules that we have not even discovered that may help guide that in the future. We were talking about the science: what decides some of these treatments and what is going to work and not work. In hematologic malignancies, we have been using CAR T cells and try to pick out a molecule that we can then educate our patients’ own T cells. Then, we can retransfuse them into patients and have them respond. We are doing similar approaches in lung cancer; we have identified some good targets that are available on lung cancer cells. [We are trying to see] if we can educate T cells to target them directly at the lung cancer. One of these studies is now available at Washington University School of Medicine, and we will see if that is as good of an approach in lung cancer as it is in leukemias and lymphomas.

Another one of our strengths at Washington University School of Medicine is doing genomic sequencing and identifying mutations in cancers. We have a very wealthful knowledge of that, and we have used that in clinical trials of targeted therapies. Now, we are trying to do some similar approaches where we sequence tumors, identify what is unique about a patient’s tumor and, instead of designing a targeted therapy, designing a vaccine that we can then vaccinate a patient with after they progress on other therapies.

What potential do you see TCR therapy having in lung cancer?

This can even be done to reinvigorate or rechallenge their immune system to go after their cancer. That is another set of clinical trials that we have available. Hopefully, in the next 5 years, we will be talking about these approaches, or even better than what we are doing now. One of the studies I talked about is a pharmaceutical company’s trial targeting the molecule NY-ESO-1. We have data in very small studies coming from the NCI in other cancer types, and there are some preliminary data now in lung cancer. It is a little too early to know how efficacious of an approach this is going to be, but part of the challenge in using these therapies in solid tumors has always been that perhaps the environment of the tumor is not really conducive to them responding and giving us the efficacy that we like. We are going to learn a lot by trying to advance these studies.