Figure provided by Dr. Laura Chow.
Head and Neck cancer (or SCCHN for squamous cell carcinoma of the head and neck) represents 3% of all cancers in the United States according to the National Cancer Institute. The disease can affect different area of the head or neck such as nasal or oral cavity, larynx, pharynx or salivary glands. In spite of considerable progress in diagnosis and treatments, many patients are still diagnosed at advanced stages, hampering treatment efficiency. Various treatment options are available such as surgery, radiation therapy, chemotherapy or targeted therapy. However, at an advanced stage of the disease the 5-year survival rate is estimated at 50% or less, highlighting the need to develop new improved therapies for these patients. In antibody-mediated immunotherapy, therapeutic antibodies are directed against one specific protein, the antigen, selected based on its dominant expression at the surface of cancer cells. By binding to this protein, the antibody activates and directs the immune response against the antibody-bound tumor cells thus identifying cells for elimination. In the case of SCCHN, the Epidermal Growth Factor Receptor (EGFR) protein is overexpressed by more than 90% of tumors and as such represents an ideal target antigen. The FDA-approved therapeutic antibody cetuximab, targets EGFR, with only moderate activity alone in late stages of the disease.
Dr. Laura Chow (Clinical Research Division), in collaboration with Dr. Mary Nora Disis, Dr. Renato Martins and colleagues from Fred Hutchinson Cancer Research Center and University of Washington, recently published the results of an investigator-initiated phase I clinical trial conducted at the Seattle Cancer Care Alliance, assessing cetuximab efficiency in combination with the toll-like receptor agonist and novel immunotherapeutic, Motolimod (VTX-2337), in the journal of Clinical Cancer Research. VTX-2337 is a small molecule drug that stimulates natural killer cells recruited by antibodies to target and kill the antibody-bound tumor cells. This phenomenon is called Antibody-Dependent Cellular Cytotoxicity (ADCC) and is one of the mechanisms involved in antibody-mediated immunotherapy. Since the EGFR-targeting antibody cetuximab antibody administered as a single agent has shown moderately low efficiency in recurrent and metastatic head and neck cancer, its association with a drug known that potentially can improve the ADCC response appeared scientifically ideal. VTX-2337 in combination with cetuximab has been successfully demonstrated in vitro, further supporting investigation in human patients.
A phase Ib clinical trial was initiated to determine whether this combination is well tolerated and biologically active. Thirteen patients with metastatic or recurrent SCCHN were enrolled. The cetuximab antibody was administered as standard of care dosing with a loading dose followed by fixing weekly dosing with a 4 week lead-in period to monitor single-agent toxicity, before combining with VTX-2337 in patient cohorts of three escalating doses.
Preliminary efficacy was observed: disease control was achieved in 54% of patients, with two patients showing partial responses and five demonstrating disease stabilization. As Dr. Chow explained, “a few patients that had been previously treated with cetuximab and had progressed, did have response or prolonged stability when treated to the combination with cetuximab and VTX-2337 possibly hinting that there could be some enhancement of the effects of cetuximab when administered in combination with VTX-2337”. One patient in particular showed stable disease for 19 months. Importantly, the combination did not show any synergistic toxicity and the therapy was tolerable.
Blood analyses also revealed a significant boost in natural killer cells frequency, and activity as well as an increase in the presence of cytokines (immune mediators), as early as 8 hours following treatment administration. Higher amounts of VTX-2337 did not correlate with an increased immune response. These data demonstrate the positive impact of treatment administration on immune response stimulation.
Overall the patients responded positively to the treatment. “The combination was active with some early efficacy and no substantial increased toxicity. The interesting future applications include further combining or sequencing this combination with other immunotherapeutics or chemotherapies to enhance the response. In particular, the recent approval of anti-PD1 antibodies which are very active in platinum (chemotherapeutic drugs)-treated recurrent/metastatic SCCHN has been a therapeutic break-through. Some patients treated on this trial had tremendous responses to subsequent clinical trials with anti-PD-1 therapy. In fact, one patient had a complete response and another had disease stability for several years. The combination of VTX-2337 and cetuximab and with anti-PD-1 therapy, other immunologic agents or chemotherapy would be of interest and potentially high activity in future development” added Dr. Chow.
This study was funded by the FHCRC/UW Cancer Consortium Cancer Center Support Grant of the National Institutes of Health, Life Sciences Discovery Fund and VentiRx Pharmaceuticals.
Chow LQ,Morishima C,Eaton KD,Baik CS,Goulart BH,Anderson LN,Manjarrez KL,Dietsch GN,Bryan JK,Hershberg RM,Disis ML,Martins RG. 2016. Phase 1b Trial of the Toll-Like Receptor 8 Agonist, Motolimod (VTX-2337), Combined with Cetuximab in Patients with Recurrent or Metastatic SCCHN. Clinical Cancer Research [Epub ahead of print].