One alternative to targeting specific tumor-associated proteins is to entice the patient’s immune system to attack the tumor directly.
The immune system can also be spurred into action by vaccines, and several immunization regimens are being tested in non-small cell lung cancer.
Lung cancers with gene mutations that drive the disease, including EGFR and ALK, can be treated with targeted drugs that are often more effective and less toxic than chemotherapy. “But the majority of lung cancer patients do not have a mutation that points to a specific, highly active therapy,” says oncologist Jeffrey Engelman of Massachusettes General Hospital in Boston.
One alternative to targeting specific tumor-associated proteins is to entice the patient’s immune system to attack the tumor directly, an approach that could offer a more universal treatment for patients, regardless of tumor histology or genetics. Immune cells called T cells have a natural ability to recognize and attack abnormal cells in the body, including infected cells and tumor cells. But T cell activity must be carefully controlled to avoid collateral damage to the body’s normal tissues. T cell self-control is mediated in part by inhibitory “checkpoint” proteins that are expressed on the cell surface, including PD-1 and cytotoxic-lymphocytic antigen 4 (CTLA-4).
Recent studies have found that at least half of lung tumors express high levels of PD-L1, a protein that binds to and activates PD-1 on T cells and dampens their function; high PD-L1 expression is associated with poor prognosis. New strategies are focused on blocking these pathways and thus invigorating T cells to attack the tumor. “These pathways are the brakes on the immune system, and we’re letting up on the brakes,” explains Julie Brahmer, an oncologist who specializes in lung cancer and mesothelioma at Sidney Kimmel Comprehensive Cancer Center in Baltimore.
An investigational drug that blocks PD-1, nivolumab, is now in clinical trials, either by itself or in combination with other therapies, after showing a survival benefit in patients with previously treated non-small cell lung cancer. PD-L1 blockers (BMS-936559, MPDL- 3280A) are also in early-phase clinical trials and appear to also have good response rates.
CTLA-4 is blocked by the drug Yervoy (ipilimumab), which, in early trials, extended progression-free survival in combination with carboplatin and paclitaxel, compared with chemotherapy alone. However, this combination only worked when Yervoy was delayed until after the second cycle of chemotherapy, and the benefit was mainly seen in patients with squamous cell disease (a phase 3 trial is currently underway to confirm this finding). Because Yervoy is a biologic agent, it is generally safer and better tolerated than other therapies, but it can’t be used in patients who have a history of autoimmune disease.
The immune system can also be spurred into action by vaccines, and several immunization regimens are being tested in non-small cell lung cancer. One strategy is to immunize patients with an antigen called MUC-1 that is highly expressed in many non-small cell lung tumors, an approach that has improved the survival rate by about four months in patients with advanced disease in an early trial. In a phase 3 trial, this approach increased median survival by 10 months when given to a subgroup of participants with locally advanced disease following a combination of chemotherapy and radiation.
Another investigational vaccine, Lucanix (belagenpumatucel-L), uses whole tumor cells engineered to suppress an immunedampening protein. Lucanix improved survival in participants with non-adenocarcinoma, and the effectiveness depended on the timing after initial chemotherapy.