Novel Combination Immunotherapy Developed at Hollings Cancer Center to be Offered in Lung-MAP Trial

A bench-to-bedside-pioneered lung cancer immunotherapy developed at MUSC Hollings Cancer Center is to be included in one of the largest lung cancer clinical trials being offered by the National Cancer Institute.

Hollings researcher and MUSC Health oncologist John Wrangle, MD, is bringing a novel combination immunotherapy treatment – pembrolizumab + N-803 – to NCI’s Lung-MAP clinical trial. Lung-MAP, or the Lung Cancer Master Protocol, is open at more than 700 sites across the United States. The combination immunotherapy developed by Wrangle and colleague Mark Rubenstein, Ph.D., will be offered as a treatment in the unmatched arm, which comprises patients with tumors that do not have mutations targetable with a drug, as opposed to a treatment arm. The team anticipates that the unmatched arm will have hundreds of patients enrolled in it.

“There is a great need for treatment options in the unmatched arm, since most tumors do not have mutations that are targetable with a drug,” said Wrangle. The Lung-MAP trial is an umbrella precision medicine clinical trial. This means that the efficacy of many drugs will be tested in this one trial, in the patients that they are most likely to benefit.

Launched in 2014, the Lung-MAP trial is designed specifically for patients with advanced non-small cell lung cancer (NSCLC) that has continued to grow after initial treatment. NSCLC accounts for approximately 85% of all lung cancer diagnoses. There are very few successful treatment options for these patients once the cancer spreads beyond the lungs.

When a patient is enrolled in the trial, his or her tumor genetics are screened. If that tumor has targetable genetics, then the patient is assigned to a treatment arm. However, 90% of patients are anticipated to be in the unmatched arm. Beneficially, umbrella trials allow new treatment groups to be added over time as new drugs emerge. The unmatched arm provides patients with a treatment option that is not usually available without actionable tumor mutations, said Wrangle.

“Cooperative group trials, such as this umbrella trial, are harder for industry to do. But they are really important because they can open multiple concepts at one time for patients. The whole process becomes more streamlined,” said Wrangle. “MUSC’s involvement in this trial is a huge deal. Every time any patient across the country receives the combination immunotherapy in the unmatched arm, they will hear about MUSC.”

The pembrolizumab + N-803 combination immunotherapy performed well in the phase one safety trial. These results, along with evidence of its effectiveness in NSCLC were published in Lancet Oncology in 2018. This immunotherapy combines the power of the PD-1 checkpoint inhibitor pembrolizumab with the new and powerful immune stimulation drug N-803. This combination is designed to drive the immune system into “attack mode” against the tumor.

The use of this combination immunotherapy will address the basic question of whether this combination is better than the current standard of care for lung cancer patients with advanced NSCLC. This question is broad, since a cancer drug must either be effective for a biomarker population or must be better for overall survival than the current standard of care therapy in order to get Food and Drug Administration (FDA) approval.

“Moving from a lab-based Hollings Cancer Center ‘homebrew’ in 2015 to a national concept in 2021 is lightning fast,” said Wrangle. “Moving a therapy from an investigator-initiated trial (IIT) to an NCI-sponsored trial to potential FDA approval is a very unique development path versus the usual longer industry-sponsored path.”

“By leveraging atypical mechanisms, combined with the unique IIT support that Hollings provides, we have been able to move this therapy along in the most cost- and time-efficient manner. This is a real bench-to-bedside transition. This is the way science is supposed to work.”

The combination immunotherapy will be available in the Lung-MAP trial in a couple of months and is expected to remain available for 18 months. The unmatched arm is expected to accrue 400 to 800 patients through the numerous nationwide clinical trial locations. “Since many community cancer centers are trial sites, not just NCI-designated cancer centers, we will get more real-world data of how this combination immunotherapy works in a broader population,” said Wrangle.

The hope is that this new combination immunotherapy will create additional options for patients so they can avoid the poorly tolerated and lower-efficacy single chemotherapies. A more in-depth understanding of the choreography between tumors and immune cells is necessary as oncologists work to move toward prescribing cancer treatments that are specific to a patient’s tumor, he said.

The more mutations that are in a tumor, the more likely that the immune system will recognize and be on guard for killing the tumor. However, it is also important that the patient’s immune system has high diversity. T-cells recognize foreign invaders (cancer cells, bacteria, viruses) based on their T-cell receptor (TCR). TCR sequencing allows researchers to determine a patient’s immune system diversity; the more diverse the better.

Biospecimens will be collected from each patient who receives the combination immunotherapy. White blood cells (immune cells), circulating tumor DNA and circulating tumor RNA will be collected from the patient’s blood and preserved for analysis. This will allow Wrangle’s team to look at the TCR repertoire to ask the question of how prepared the patient’s body is to recognize foreign cells. This information, combined with the patient’s response to the combination immunotherapy, will allow the researchers to find out who will benefit from the combination immunotherapy, even if there is not a difference in overall survival rates in the unmatched arm.

“Getting a drug used outside of the research environment is a major accomplishment. This is the dream of a cancer researcher – moving a promising therapy from an investigator-initiated trial to the higher phase clinical trials in order to help more patients,” said Wrangle.