A very promising immunotherapy approach to the treatment of lung cancer is the use of immune checkpoint inhibitors. These treatments work by “taking the brakes off” the immune system, allowing it to mount a stronger and more effective attack against cancer. Several different types of checkpoint inhibitors, targeting different checkpoints or "brakes" on immune cells, are currently in use:
PD-1/PD-L1 checkpoint inhibitors
One important braking molecule targeted by checkpoint inhibitors is called PD-1, found on certain immune cells. In March 2015, the FDA approved the PD-1 checkpoint inhibitor nivolumab (Opdivo®), made by Bristol-Myers Squibb (BMS), for the treatment of advanced squamous NSCLC that has stopped responding to chemotherapy. This approval was based on results of a phase III trial in which patients receiving nivolumab lived, on average, 3.2 months longer than patients receiving standard chemotherapy. This translates into a 40% reduced risk of death compared to standard chemotherapy. In October 2015, the FDA expanded its approval of nivolumab to include non-squamous NSCLC. This approval was based on the results of a phase III trial that showed that patients who received nivolumab lived an average of 12.2 months compared to 9.4 months for those receiving standard chemotherapy. Atezolizumab (TECENTRIQ®), an anti-PD-L1 checkpoint inhibitor manufactured by Genentech, is also approved for advanced NSCLC patients.
In addition, pembrolizumab (Keytruda®), a PD-1 checkpoint inhibitor made by Merck, has been approved as a first-line option for patients with advanced NSCLC (both squamous and non-squamous). (PD-L1 is a protein that binds to the PD-1 checkpoint on immune cells; cancers often make PD-L1 as a way to ward off an immune attack.) In a phase I clinical trial, about 22% of NSCLC tumors tested had PD-L1 expression at a level of at least 50%. This subset of NSCLC had a response rate of 41%.
Other checkpoint inhibitors are also in late-stage clinical testing, and are listed below along with a sampling of relevant clinical trials.
Durvalumab (MEDI4736), a PD-L1 antibody, made by AstraZeneca/MedImmune, is being tested in a variety of trials for patients with lung cancer. Open phase III trials include:
- A phase III study of MEDI4736 for patients with completely resected NSCLC (NCT02273375)
CTLA-4 checkpoint inhibitors
Ipilimumab (Yervoy®), made by BMS, is a checkpoint inhibitor that targets the CTLA-4 checkpoint on immune cells. Developed by James P. Allison, Ph.D., director of CRI’s Scientific Advisory Council, and manufactured by BMS, ipilimumab was the first treatment ever shown to extend survival in patients with metastatic melanoma, and was approved for that indication in 2011. It is now being tested in clinical trials for lung cancer. Tremelimumab, made by AstraZeneca/MedImmune, is another CTLA-4-targeting antibody in development. Although there is limited clinical development of CLTA4-targeting drugs in NSCLC as single agents, combination approaches with PD-1 and PD-L1 antibodies have demonstrated encouraging data (discussed below).
Combination checkpoint inhibitor approaches
For patients with other types of cancer (i.e., melanoma), clinical trials have shown the superiority of approaches that combine two different immune checkpoint inhibitors. Combination immunotherapy approaches are also now being explored for patients with lung cancer. Two separate combinations (nivolumab + ipilimumab and durvalumab + tremelimumab) are being tested in phase III trials versus standard-of-care chemotherapy as first-line treatment for both PD-L1-positive and PD-L1-negative NSCLC:
- A phase III trial of nivolumab versus nivolumab plus ipilimumab versus chemotherapy in patients with stage IV NSCLC (CheckMate 227, NCT02477826)
- A phase III trial of durvalumab (MEDI4736) plus tremelimumab versus standard-of-care chemotherapy for patients with NSCLC (NEPTUNE, NCT02542293; not yet open)
Monoclonal antibodies (mAbs) are molecules, generated in the lab, that target specific markers, called antigens, found on tumors. Many mAbs are currently used in cancer treatment, and some appear to generate an immune response. Several mAbs are FDA approved to treat lung cancer, including bevacizumab (Avastin®) and Ramucirumab (Cyramza®). Other mAbs, including some that are conjugated to anti-cancer drug molecules, are currently being tested in clinical trials for patients with lung cancer, including:
- IMMU-132, an antibody-drug conjugate (ADC), is being tested in a phase I/II study for patients with epithelial cancers, including NSCLC and SCLC (NCT01631552)
Therapeutic cancer vaccines are immunotherapies designed to elicit an immune response against shared or tumor-specific antigens. These antigens include MAGE-3, which is found in 42% of lung cancers; NY-ESO-1, found in 30% of lung cancers; p53, which is mutated in approximately 50% of lung cancers; survivin and MUC1.
CRI/Ludwig investigators have shown promising results in lung cancer patients with vaccines targeting the NY-ESO-1 antigen. In a phase I clinical trial in Japan of a NY-ESO-1 vaccine completed in 2011, the treatment achieved integrated immune responses in nine of the ten patients treated, and two patients with lung cancer and one patient with esophageal cancer showed stable disease .
The slide at left shows expression of NY-ESO-1 in lung cancer, highlighted by antibody staining. Benign stromal cells and tumor infiltrating lymphocytes in between the clusters of tumor cells do not express NY-ESO-1. (Image courtesy of Yao-Tseng Chen.)
Therapeutic cancer vaccines in clinical trials for lung cancer include:
- DRibbles (DPV-001), a vaccine made from nine cancer antigens plus TLR adjuvants, is being tested in a phase II trial for patients with stage III NSCLC (NCT01909752)
A fourth major avenue of immunotherapy for lung cancer is adoptive cell therapy. In this approach, immune cells called T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response. Several clinical trials of adoptive cell therapy techniques are currently under way:
- A phase II trial of T cells genetically engineered to recognize NY-ESO-1, given along with dendritic cells pulsed with NY-ESO-1 antigen as a vaccine, for patients with advanced or refractory malignancies, including lung cancer (NCT01697527)
- A phase II trial of tumor-infiltrating lymphocytes (TIL) in people with NSCLC following chemotherapy (NCT02133196)
- A phase II trial of T cells engineered to target NY-ESO-1 antigen in patients with cancers that express NY-ESO-1, including lung cancer (NCT01967823)
- A phase I/II trial of T cells engineered to target MAGE-A3 in patients with metastatic cancer that expresses MAGE-A3, including lung cancer (NCT02111850)
- A phase I/II trial of T cells genetically engineered to recognize mesothelin, for patients with mesothelin-expressing metastatic cancer or mesothelioma (NCT01583686)
- A phase I study of T cells genetically engineered to target NY-ESO-1 in combination with the checkpoint inhibitor ipilimumab (NCT02070406)
- A phase I trial of T cells genetically engineered to target mesothelin for patients with malignant pleural disease (NCT02414269)
- A phase I/II study genetically engineered T cells in patients with WT1-expressing NSCLC and mesothelioma (NCT02408016)
Go to our Clinical Trial Finder to find clinical trials of immunotherapies for lung cancer that are currently enrolling patients.