A randomized, open-label study is currently under way to test the safety and efficacy of the novel immunoadjuvant, Multikine, in patients with head and neck cancer.
A randomized, open-label study is currently under way to test the safety and efficacy of the novel immunoadjuvant, Multikine, in patients with head and neck cancer. To date, this is the only phase III trial to administer an anticancer immunotherapy as a first line of defense before standard treatment.
Earlier this month, the University of Minnesota’s Masonic Cancer Center became the seventh US member of CEL-SCI’s multisite international trial.1
This will be “the world’s largest phase III trial in head and neck cancer,” said the Virginia-based biotechnology company’s chief executive, Geert Kersten, “on schedule to complete global enrollment with approximately 880 patients by the end of 2015.”2
Worldwide, head and neck cancer is considered the sixth leading form of cancer, caused largely by tobacco and alcohol use, as well as oral infection with human papillomavirus. Head and neck squamous cell carcinoma (HNSCC) accounts for over 90% of cases, with over 350,000 related deaths per year.
The current standard of care (SOC) involves surgery supplemented by either radiation alone or radiochemotherapy. Toxicity and radiochemotherapy-resistance lead to a high relapse rate and a 3-year survival of only 50%.
HNSCC is an immunosuppressive disease that interferes with the patient’s natural immune response, preventing tumor cell recognition and immune-mediated clearance. Malignancy is characterized by the induction of tumor-permissive cytokines, defective cellular immune responses, functional anergy, and insufficient antigen presentation.
As a result, therapeutics designed to target HNSCC must have the ability to overcome its immunosuppressive nature, promoting proper surveillance, recognition, and destruction of tumor cells.
Immunotherapies designed to improve immunity toward tumor cells have gained attention in recent years. The most commonly studied approach focuses on the use of monoclonal antibodies (mAb) to manipulate the patient’s antitumor response.
mAbs have been created to target a variety of immune processes, with the goal of either blocking immunosuppressive cytokines and coinhibitory receptors, or augmenting tumor antigen (TA) presentation and costimulatory molecule expression.
In HNSCC, tumors have been shown to poorly present TA on the cell surface, making recognition and destruction of these cells by immune effectors more difficult. As such, mAbs facilitating better TA presentation are one avenue for therapeutics.
Dr. Barbara Burtness on Immune Checkpoint Inhibitors for Head and Neck Cancers
Burtness is the Clinical Research Program Leader for the Head and Neck Cancers Program at Yale Cancer Center
In 2006, cetuximab (Bristol-Myers Squibb, Eli Lilly), a mAb blocking the extracellular domain of theEGFR,was approved for HNSCC combination therapy by the United States Food and Drug Administration (FDA).
Recent studies have shown that cetuximab also enhances both innate and adaptive immunity against HNSCC tumors by enhancing TA presentation through natural killer cell (NK)-dendritic cell (DC) cross-priming.
Other mAb-based immunotherapies aim to promote TA presentation by acting as agonists for costimulatory receptors or blocking coinhibitory receptors. Monoclonals activating the tumor necrosis factor receptor (TNFR)-family of costimulatory molecules are currently in preclinical development. Ipilimumab (Bristol-Myers Squibb), which blocks the coinhibitory receptor, CTLA-4, is also being pursued in a phase I trial.
HNSCC tumors also demonstrate an imbalance in signal transducer and activator of transcription (STAT) signaling, with poor immunostimulatory STAT1 and heightened immunosuppressive STAT3. This imbalance leads to the production of largely inhibitory cytokines, such as vascular endothelial growth factor (VEGF).
As the presence of immunosuppressive cytokines in patients with HNSCC correlates with a poor treatment response and high rates of relapse, some mAb immunotherapies have focused on blocking these targets. Bevacizumab (Genentech), for instance, aims at neutralizing VEGF.
Unfortunately, response rates to mAb therapies are often limited by heterogeneity among TAs and the possibility of mutation as a result of chemotherapy and radiation.
Additionally, mAb immunotherapy is typically administered as a combination or supplement to standard radiation or chemoradiation therapy, a process that already weakens the patient’s immune system. Over time, the potential for immune tolerance also increases.
As an alternative to traditional mAb approaches, CEL-SCI is currently testing the use of an immunostimulatory cytokine mixture for safety and efficacy in the treatment of head and neck cancer.
“This [trial] is taking…a different direction and trying to see if we can harness the strength of our immune system to fight cancer,” said Gautam Jha, MD, lead principal investigator of the CEL-SCI study site at the University of Minnesota.1
CEL-SCI’s Multikine (leukocyte interleukin injection) uses naturally-derived, nonrecombinant cytokines and chemokines to augment cellular immunity against the tumor. The mixture demonstrated safety and immunomodulatory activity in phase I and phase II clinical trials, where no serious adverse events were reported.
In the current phase III study, Multikine is being tested as a primary therapy before conventional treatment for those newly diagnosed with squamous cell carcinoma of the oral cavity and soft palate.3The study is expected to include roughly 100 centers in 20 countries across North America, Europe, and Asia.
"There has never been a cancer drug that workswiththe body; ours, workswiththe body,” commented Kersten. “We believe we will have a drug that will have minimal to no toxicities. That doesn't exist today.”4
In the trial, patients will receive SOC therapy either with or without the addition of Multikine. By administering Multikine first, before the patient’s immune system is weakened by radiotherapy and/or chemotherapy, the investigators hope to see a more robust therapeutic response.
The primary outcome of the study will investigate overall survival in patients receiving Multikine therapy followed by SOC versus SOC alone. Secondary outcomes of progression-free survival, local-regional control, tumor histopathology, and quality of life will also be tested.
Early-phase clinical data showed that approximately 2 out of 3 patients with head and neck cancer would be candidates for this combined therapy, were it to be approved by the FDA. Independent monitoring of the trial thus far has raised no concerns regarding safety.
"This is the first cancer drug being developed as a true first-line therapy,” Kersten stated, “meaning before you get surgery, radiation, or chemotherapy, we would boost your immune system.”4
“If it were to be approved for use following completion of our clinical development program,” the company noted, “Multikine would be a different kind of therapy in the fight against cancer.”5