Immunotherapy is an exciting new option for aggressive head and neck cancers and, in combination with radiation, may even help patients who resist immune checkpoint blockade, said panelists at a symposium October 8, 2018, at the AAO–HNS Annual Meeting in Atlanta. The Korean Society of Otorhinolaryngology-Head and Neck Surgery and the Korean American Otolaryngology Society co-sponsored the symposium.
Cancer Treatment’s New Frontier
“Immunotherapy is based on the idea that when cancer cells develop, they undergo mutations, which then change the expression of the surface antigens of tumor cells sufficiently enough so the immune system can now recognize the tumor cells as foreign entities, and can mount an immune reaction to them,” said Seungwon Kim, MD, associate professor in the department of otolaryngology at the University of Pittsburgh Medical Center (UPMC).
The programmed-death ligand (PD-1/PD-L1) pathway is essential in immunotherapy. The immune system mounts an inflammatory response to infection or what it perceives as foreign invaders. Cells present antigens via the major histocompatibility complex (MHC), which then bind to receptors on T cells.
“This results in T-cell activation, which propagates an inflammatory reaction. But, just like any other process in the body, once this process starts, at some point it needs to stop; otherwise, the process will continue unchecked, leading to autoimmune disorders,” said Dr. Kim. T-regulatory (T-reg) cells express PDL-1, which binds to a PD-1 receptor on the T cell, inhibiting the T cell and stopping the inflammatory response. Tumors tend to “kidnap” the body’s normal mechanisms, however. The immune system recognizes a tumor cell as foreign, and sends lymphocytes to infiltrate it and mount a cytotoxic reaction. Tumor cells respond by producing PD-1 to bind to the receptor on the T cells and turn them off.
“The argument for immunotherapy is that if you can break this reaction, by utilizing either an antibody against the ligand or the receptor of the PD1/PD-L1 pathway, it will reactivate those T cells, leading to the T cells mounting a cytotoxic reaction against the tumor cells,” he said.
Two immunotherapies are currently approved for use as second-line agents in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) who have failed the standard EXTREME regimen of cetuximab, cisplatin or carboplatin, and 5-FU: nivolumab (Opdivo) and pembrolizumab (Keytruda).
Relevant clinical trials, such as the KEYNOTE-012 Phase I-b trial of pembrolizumab and CheckMate-141 of nivolumab, have shown that these drugs have similar efficacy and adverse events, most frequently hypothyroidism (J Clin Oncol. 2016;34:3838–3845; Oral Oncol. 2018;81:45–51). Both are both superior second-line agents compared to the standard of care approach in these patients, he said.
Patients in KEYNOTE-012 had an overall response rate of 18%, with 3% achieving a complete response, 15% achieving a partial response, and 20% achieving stable disease. There was also a correlation between PD-1 expression in tumor cells and improved survival. A subsequent Phase III trial of pembrolizumab, KEYNOTE-040, did not meet its primary endpoint of a 20% decrease in death compared to patients receiving chemotherapy, but median survival for the pembrolizumab patients was 8.4 months, compared to 7.1 months for those receiving chemotherapy, a significant response nonetheless, said Dr. Kim. In 2018, an updated presentation on KEYNOTE-040 showed that the drug did meet its overall survival goal.
In a 2017 Phase III trial of nivolumab, CheckMate-141, the immunotherapy agent had a better survival rate than the investigators’ chemotherapy of choice: methotrexate, docetaxel, or cetuximab. The study and a later follow-up showed that patients on nivolumab had a 30% decrease in risk of death, and patients with a higher expression of PD-L1 had a better response. Also, patients with P16-positive disease had a much better response to nivolumab than those with P16-negative disease. One reason may be that “because P16 tumors are induced by HPV, a foreign virus, the expression of the viral particles on the surface of the tumor cells may make them more antigenic, allowing the nivolumab to be more effective,” said Dr. Kim.
Mechanisms of Resistance
The tumor microenvironment can help physicians understand the resistance mechanisms of immune checkpoint blockade, said Yoon Woo Koh, MD, a professor of otolaryngology at Yonsei Head and Neck Cancer Center in Seoul, South Korea.
“What are the key characteristics of the immune system? One is memory,” said Dr. Koh. T cells and immune cells mount a stronger, faster response to secondary challenges. Other characteristics are balance and regulation. “Overactivation of the immune system will incur autoimmune diseases or, sometimes, allergy or asthma. Oversuppression will sometimes result in cancer or infection.” Both innate and adaptive immunity play strong roles in how immunotherapy works, as well as potential resistance to it, he said.
“We have to understand the cancer-immunity cycle,” including its aspects as both a regulator and a diverse stimulator, and develop it as a cancer immunotherapy. Diverse mechanisms are involved in this cycle, said Dr. Koh. Two important mechanisms are positive and negative co-stimulation. Molecules like CD28 are constitutively expressed on naïve T cells and augment TCR [T cell antigen receptor]-mediated activating signals. CD28 is a stimulatory molecule. CTLA-4, expressed in the T cells, is an inhibitory molecule that attenuates TCR-mediated activating signals. Anti-CTLA-4 therapies include ipilimumab (Yervoy).
In principle, anti-PD-1 and anti-PD-L1 work differently than anti-CTLA-4 blockers due to different ligand-receptor interactions, he said. However, in practice, they show similar efficacy and toxicity. Anti-CTLA-4 promotes T cell priming by antigen-presenting cells in the lymph nodes. Anti-PD-1 or anti-PD-L1 promote the affector functions of T cells in tumors. “T-reg cells play a somewhat tricky role—they are a subset of T cells that suppress the immune response. In humans, the role of anti-CTLA-4 and T-regs are still controversial,” he said.
Anti-PD-L1 is a negative co-stimulator, said Dr. Koh. PD-L1 expression is in response to IFN-γ expressed by T cells. This is an example of adaptive resistance: Tumor cells express PD-L1 to protect them from the T cells’ attack, and anti-PD-1 or anti-PD-L1 therapies rescue the T cells from this adaptive resistance.
Researchers must explore the extrinsic control of PD-L1 expression and the intrinsic control of the PD-L1 pathway, said Dr. Koh. Various carcinogenesis-related pathways also trigger PD-L1 expression, and its expression in tumors does not always guarantee the efficacy of anti-PD-1 or anti-PD-L1 therapies. “We have to know the biomarkers to overcome the resistance to checkpoint blockade. We have to know: What is the issue with PD-L1 as a biomarker?” he said.
In general, checkpoint blockade works better for high-frequency, somatic mutation tumors, said Dr. Koh. Due to diverse mechanisms of innate or adaptive resistance, some patients may not respond well to immunotherapy. Researchers must learn more about the role of IFN-γ on cancer cell growth, and the phenomenon of T-cell exhaustion, he said.
“Despite unprecedented efficacy, many patients fail to respond, or they may acquire resistance to the drugs over time,” said Dr. Koh. “There is an urgent need to identify the mechanisms of resistance to predict outcomes and identify targets for combination therapy.”
Combination with Radiation
Would combining immunotherapy and radiation overcome resistance? Recent research is optimistic, said John B. Sunwoo, MD, Edward C. and Amy H. Sewall Professor of Medicine and director of head and neck cancer research at Stanford University.
Immunotherapy includes initiators (ipilimumab) and amplifiers (pembrolizumab or nivolumab) of the immune response. “What are the effects of radiation on the immune response? Radiation is also an initiator,” he said. A 2017 murine study by researchers at the University of Colorado Denver showed that radiation can make the tumor more sensitive to PD-L1 therapy, leading to enhanced tumor control and improved survival (Oncoimmunology. 2017;6(10):e1356153). Several ongoing trials are exploring combination therapy with checkpoint inhibitors and radiation.
Combination therapy may work due to the “abscopal effect,” where a patient experiences regression of metastatic cancer distant from the site of local radiation, possibly a systemic response, said Dr. Sunwoo. He shared a case of a female patient with melanoma who had a growing paraspinal mass and high levels of pain. She started ipilimumab therapy, but her cancer slowly progressed. Once she started a combination therapy of radiation and ipilimumab, her cancer responded, and she progressed to stable disease.
This led to a new trial at Stanford of ipilimumab and radiation in Stage IV melanoma. So far there have been three complete and three partial responders, and five stable patients, he said. Mass cytometry revealed potentially predictive markers for positive response: Responders had higher central-memory T cells that express IL-2. Research in this area may point the way to more effective treatment of patients with aggressive head and neck cancers, the panel concluded.
Susan Bernstein is a freelance medical writer based in Georgia.