Immunotherapy and Checkpoint Inhibitor Research Showing Huge Potential
Immunotherapy in general and checkpoint inhibitors in particular have created a path for the treatment of lung cancer that has the potential to lead to long-term survival, even for patients at the most advanced stages. Investigators at NewYork-Presbyterian/Columbia University Irving Medical Center are among the leaders in this research and are driving efforts to expand the reach of immunotherapy.
The head of the effort at NewYork-Presbyterian/Columbia is Naiyer A. Rizvi, MD, Director of Immunotherapeutics for the Division of Hematology and Oncology. Active in this field for almost 10 years, Dr. Rizvi was principal investigator or co-investigator for several important trials that led to FDA approvals of the checkpoint inhibitors nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck), both of which are now licensed for advanced non-small cell lung cancer (NSCLC). He is now active in initiatives to extend durable responses through combinations using conventional cytotoxic drugs or other types of immunotherapy.
"Some lung cancer patients achieve extended disease control on checkpoint inhibitors, but others do not," Dr. Rizvi said. "There has been progress in understanding why. We know, for example, that tumors with high levels of PD-L1 expression and those with more mutations—genetic damage—correlate with response. This 'foot in the door' to harness the immune system has led us to understand the immune system interaction with the tumor better and develop more effective immunotherapy approaches."
Checkpoints are proteins expressed by tumors that deactivate an immune response and appear to explain why the immune system fails to recognize and attack cancer cells. Checkpoint inhibitors such as nivolumab, pembrolizumab, and a proliferating number of additional agents that are being tested for a broad array of malignancies, block this signal.
In second-line therapy for advanced cancer, checkpoint inhibitors have become an important option, but there are many reasons to expect that efficacy will be further improved when these are used with other therapies.
"As we begin to understand the activity of these drugs in the context of a patient's specific mutational profile, we, like others, are exploring a variety of strategies to improve response," Dr. Rizvi explained. "There are studies ongoing or planned with checkpoint inhibitors combined with chemotherapy, targeted tyrosine kinase inhibitors (TKIs), and a second checkpoint inhibitor."
One recent, early-phase study led by Dr. Rizvi demonstrated that nivolumab plus platinum-based doublet chemotherapy had an acceptable safety profile with highly encouraging overall survival in first-line treatment of advanced NSCLC (Rizvi et al. J Clin Oncol 2016 June 27. [Epub ahead of print]). Dr. Rizvi also is the study chair of a phase 3 trial called MYSTIC that is comparing a combination of 2 checkpoint inhibitors to platinum-based chemotherapy in first-line treatment of stage IV NSCLC (ClinicalTrials.gov Identifier: NCT02453282).
The work in immunotherapies at NewYork-Presbyterian/Columbia is not confined to checkpoint inhibitors, however. Dr. Rizvi reported that he is involved in a very active research program to create personalized vaccines to stimulate the immune response to "target" the most important mutations within a tumor.
While checkpoint inhibitors remove an important barrier to an immune response, it appears that activating the immune system to attack the specific antigens associated with the cancer's molecular signature may enable more patients to achieve the durable response now observed in a small percentage of patients.
"We are looking to create a vaccine in real time based on the patient's own genetic code," Dr. Rizvi said. "We have done a great deal of work in whole-exome sequencing of NSCLC that supports the concept that the specific genomic landscape of an individual's lung cancer determines response to checkpoint inhibitors, and this same information is relevant to work in developing vaccines."
Nivolumab and pembrolizumab both block the PD-1 checkpoint to activate T cells, but a growing array of immune modulators is being developed as either agonists that can put the foot on the accelerator of T cells or antagonists that can release the brake on T cells.
Another area of exploration is to employ immunotherapies earlier, such as before surgery or during earlier stages of lung cancer (ClinicalTrials.gov Identifier: NCT02716038).
"This is an exciting area that is continuing to unfold," Dr. Rizvi said. Regarding the unprecedented durable responses now seen in a subset of lung cancer patients treated with immunotherapy, he added, "This is only the beginning; by understanding who does and doesn't respond, we hope to be able to tailor immunotherapy based on each patient's immune and genetic profile."
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