Recent research by John Morris, MD, professor of medicine, director of the UC Cancer Institute’s Phase I/Experimental Therapeutics Program and UC Health oncologist, published in the academic journals BMC Cancer and JAMA Oncology, unveils clues at the basic science and clinical levels that could help in the fight against cancer—and in using the body’s own defense, the immune system, to do so.
Clues to Using the Immune System to Fight Lung Cancer in BMC Cancer
"It has been proposed that the development and recurrence of cancer may be connected to a unique population of tumor cells called cancer-initiating cells (CICs) that include characteristics of stem cell-like cells,” says Morris, who is the corresponding author on the study. "Studies have shown that such cells can be enriched by culturing tumor cells in serum-free suspension to form tumorspheres—solid, spherical formations developed from the increased multiplication of cancer stem or ‘starter’ cells under these conditions. CICs have been characterized for their stem cell-like qualities and their role in establishing tumors and maintaining tumor growth, but less is known about the interaction of CICs with the immune system.”
In this study, researchers created CIC-enriched tumorspheres using animal lung cancer cells (TC-1) that are modified to express human papillomavirus 16 (HPV-16) antigens to evaluate their susceptibility to antitumor immune responses. This study was evaluated both in animal models and in human tissue samples.
"The animal lung CICs showed reduced expression of surface major histocompatibility complex (MHC)-I molecules compared to non-CICs from the same cell line,” Morris says. "MHC is a set of proteins found on cell surfaces that are essential for the immune system to recognize foreign antigens, which allows the immune system to function properly in responding to viruses and tumors. We also found decreased MHC-I expression in five of six human lung cancer cell lines cultured under conditions supporting CICs.”
In animal models, Morris adds that the lung cancer cells with CICs were resistant to a HPV-16 peptide vaccine aimed at targeting cells expressing these antigens to cause cell death.
"We found that HPV-vaccinated animals with tumors derived from CIC-enriched tumorspheres had shorter survival times and showed significantly fewer tumor attacking T-cells when compared with tumors generated without CICs,” he says. "These results suggest that the reduced expression of MHC-I molecules in CICs may cause them to not be recognized by the immune system, decreasing successful immunotherapy strategies. More studies are needed to find out how to target CICs using the immune system.”
This study was funded by a National Institutes of Health T32 Ruth L. Kirschstein National Research Service Award (2T32CA117846-06A1), the Cyril Gilbert Testimonial Fund and the Gallipoli Medical Research Foundation, and the Lcs Foundation. Morris cites no conflict of interest.
Adding a Molecule to Combination Therapy for Head and Neck Cancer in JAMA Oncology
"Immunotherapy for recurrent and metastatic squamous cell carcinoma of the head and neck is promising, and activation of a class of immune receptors found in the body, called Toll-like receptors (TLR), stimulates immunity. An investigational agent called motolimod has been shown to activate one of these receptors (TLR-8),” says Morris, a co-investigator on the study who led the trial locally. "We wanted to determine whether motolimod improves outcome for head and neck cancer when combined with standard chemotherapy.”
The study, which was a multicenter, randomized, double-blind, placebo-controlled clinical trial, enrolled adult patients (ages 18 and older) with recurrent squamous cell carcinoma of the head and neck between October 2013 and August 2015. Follow-up ended September 2016, and analysis was conducted between June 2016 and December 2017.
Patients were given combination chemotherapy treatments with carboplatin or cisplatin plus fluorouracil and cetuximab, and either placebo or motolimod, administered every three weeks. Patients received a maximum of six chemotherapy cycles, after which patients received weekly cetuximab with either placebo or motolimod every four weeks.
"Of 195 patients enrolled in the study, 85 percent (166) were men and 82 percent (159) were white,” says Morris. "The average age was 58 years. The average overall survival was 13 versus 11 months for all patients treated with motolimod versus a placebo. Increased incidence of injection site reactions—chills, anemia and rash—were noticed with motolimod. Of 83 cases of oropharyngeal cancer, 52 (63 percent) were human papillomavirus (HPV) positive, a common cause of some types of head and neck cancer. "Patients developing injection site reactions had longer progression-free and overall survivals.”
Morris says the results of this analysis show that the addition of motolimod could be beneficial in certain head and neck cancer patients.
"We found that adding motolimod to chemotherapy was well tolerated, but did not improve the overall outcome of all patients; however, significant benefit was observed in HPV-positive patients and those who developed motolimod injection site reactions, suggesting that stimulating the Toll-like receptor-8 using this molecule may benefit a subset of biomarker-selected patients.”
This trial was supported by VentiRx Pharmaceuticals. Morris cites no conflict of interest.