Although immunotherapy has dramatically improved lung cancer responses over the past decade, substantially less than half of all treated patients see a significant improvement in survival, even with combination therapies. A large new phase II clinical trial and separate phase I trial, both led by multidisciplinary teams at NYU Langone Health, could point the way toward boosting that response rate through novel approaches that aim to alter the tumor microenvironment and sensitize the malignant cells to immunotherapy.

Within the tumor microenvironment, specific cellular components and products may prevent malignant cells from appropriately responding to immunotherapy. Daniel H. Sterman, MD, the Thomas and Suzanne Murphy Professor of Pulmonary and Critical Care Medicine and director of the Division of Pulmonary, Critical Care, and Sleep Medicine at NYU Langone, says manipulating that microenvironment by injecting a compound directly into the tumor could yield a much better response rate.

A phase II clinical trial known as LuTK02 is testing that concept using a therapy called gene-mediated cytotoxic immunotherapy (GMCI) and has begun treating patients, with a goal of enrolling 111 people in about a dozen medical centers nationwide. The trial is recruiting patients with lung cancer who tolerate their existing immunotherapy but are not responding to it; their cancer is either stable, rebounding after an initial response, or growing unabated. Dr. Sterman says the academicindustry sponsorship with Advantagene, Inc. (Candel Therapeutics) represents the culmination of a long collaboration with the companys research in thoracic malignancies. It is one of the first clinical trials delivering immunotherapy directly into patients lung tumors, and we are excited about this new modality, he says.

As the trials lead site, NYU Langone is managing multiple aspects of the effort, including the immunological analysis of all blood and tumor tissue samples. Its a really important initiative of our new Lung Cancer Center at Perlmutter Cancer Center and highlights the multidisciplinary nature of the Lung Cancer Center, Dr. Sterman says. The clinical research, he adds, is drawing on the extensive expertise of collaborators in the divisions Interventional Pulmonology Program, as well as NYU Langones Precision Immunology Laboratory and Division of Thoracic Imaging and Perlmutter Cancer Centers Thoracic Oncology Disease Management Group. Its a wonderful collaboration of all of these different elements and a really exciting paradigm in which NYU Langone can take a lead role in the logistics and the biological analysis of large trials, Dr. Sterman says.

For lung cancer, researchers have developed two minimally invasive ways to deliver GMCI. One strategy is to use bronchoscopy for the intra-tumor delivery; the other is via a percutaneous injection directly into the tumor mass, guided by CT or ultrasound imaging. Both methods are being used in the LuTK02 trial. We have been working on this concept for several years here at NYU Langone, and this is the first time that we have actually implemented it in lung cancer patients who are refractory to immunotherapy, Dr. Sterman says.

GMCI is a combination biologic that uses a recombinant viral vector, a replication-incompetent adenovirus, to deliver the herpes simplex virus thymidine kinase gene, HSVTK, to the tumor cells. HSVTK gene expression in lung tumor cells may spur a mild immune response on its own, but the effect is dramatically heightened by subsequent treatment with the antiherpes simplex drug valacyclovir.

When you give the patient valacyclovir for two weeks by mouth, the drug in the tumor site is converted into a toxic metabolite that kills tumor cells and activates, together with the thymidine kinase gene, a robust immune response, Dr. Sterman says. It acts not only locally where you do the injection, but anywhere in the body where tumor cells may be. After their first course of GMCI therapy and two weeks of valacyclovir, the trial participants receive a second round five to seven weeks later. Imaging every nine weeks, biopsies, and a battery of immunological tests will allow the collaborators to look for signs of tumor response at local and distant sites.

For me, this has certainly been the culmination of a lot of collaborative work that we have been doing over the last 20 years, Dr. Sterman says. The great hope is that we will have less invasive, safer, and more effective ways of treating lung cancer in the future.

In a separate clinical trial, Dr. Sterman and colleagues are testing another method for delivering immunotherapy directly to lung tumor cells. The phase I feasibility study of bronchoscopic cryo-immunotherapy (BCI) in peripheral lung tumors, funded by the National Cancer Institute, is enrolling 15 patients with advanced non-small cell lung cancer. The collaboration, Dr. Sterman says, includes NYU Langones Section of Interventional Pulmonology, Division of Thoracic Surgery, and Precision Immunology Laboratory.

To perform BCI, clinicians advance a flexible cryoprobe through a bronchoscope to reach a peripheral tumor and freeze a portion of the lesion. Preclinical data suggest that the procedure activates a local and systemic immune response. We are the first in the world to investigate this novel form of cancer immunotherapy, which is conducted in patients undergoing standard-of-care bronchoscopy for known or suspected advanced lung cancer, Dr. Sterman says. Blood samples taken before and after the procedure will allow the clinicians and scientists to assess antitumor activation signals within the patients lymphocytes.

In effect, Dr. Sterman says, using BCI or GMCI is a way of vaccinating patients against their own tumor via a minimally invasive procedure. These techniques may serve as in situ vaccines, he says. The strategy, if successful, could open the door to more combinational approaches. Maybe we can kill some tumor cells by freezing them and then even in the same procedure inject into them a substance that will further activate the immune response, he says. If given in addition to systemic therapy, surgery, or radiation, the multistep scheme could offer an important new method for controlling or reversing tumor growth.

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New Clinical Trials Focus on Boosting Lung Tumor Response to Immunotherapy - NYU Langone Health