CHICAGO—Vaccines and immune-modulating technology appear to be making headway in using the body's immune system to battle various cancers, researchers reported here at the ASCO Annual Meeting.
In some cases, researchers are working to develop cancer-specific vaccines to attack tumors or prevent them from growing. In other scenarios, pharmaceutical agents are being employed in an attempt to rev up immune system components to seek and destroy tumor cells.
“There has been a significant advance in our understanding of the cellular and molecular mechanisms of the immune system,” said Joshua Ellenhorn, MD, Chief and Associate Professor of General Oncologic Surgery at City of Hope National Medical Center.
For example, researchers said they have been able to develop a vaccine derived from a patient's own glioblastoma tumor cells that appears safe, and gives hints of efficacy in treating the deadly brain cancer.
“We observed a median overall survival of 47.6 weeks among the patients enrolled in this study of a heat shock protein-derived vaccine against glioblastoma multiforme,” said Andrew Parsa, MD, PhD, Associate Professor of Neurological Surgery at the University of California, San Francisco.
Progression-free survival time among the 33 patients treated in the trial was about 17 weeks. He said that both the overall and progression-free survival among these patients who received only the immunomodulatory injection compares well with outcomes observed in other trials in which various cytotoxic or targeted agents have been employed to control the disease.
The study participants were patients who had experienced recurrence of the brain tumor, and had undergone treatment with radiation and temozolomide. The patients with confirmed diagnoses of glioblastoma multiforme underwent surgery to remove as much of the malignancy as possible—greater than 90% of the cancer had to be removed.
To make the vaccine—Prophage Series G-200 vaccine (HSPPC-96; vitespen)—Dr. Parsa explained, the excised cancerous tissue is shipped frozen to a laboratory at Agenus, Inc., in Lexington, Massachusetts, where using a proprietary, standardized, quality-controlled procedure, scientists prepared heat shock protein peptide complex-96 (HSPPC-96), which is isolated from the tumor in about eight to 10 hours.
The peptide complex contains glycoprotein-96 polypeptide associated with cancer-specific antigenic peptides. The product is sterile-filtered, packaged in vials, and shipped frozen back to the hospital pharmacy or clinician for use when the patient has recovered from surgery, usually within five weeks after resection.
Patients received one intradermal injection of the vaccine every week for the first month, and then the patients were injected every other week for up to 52 weeks or until the vaccine was depleted.
Dr. Parsa explained that the research team wanted to explore whether the vaccine could induce the patient's own immune system to activate a tumor-specific CD8-positive T-cell response. In addition, it was hoped that use of the vaccine would kindle innate immune responses including increases in circulating natural killer cells that target the tumor.
Adverse events considered related to the vaccine were Grade 1 or 2 in nature and mainly associated with the injection, including skin reactions and stinging at the site of injection. Of the 33 patients in the study, 17 reported some adverse event, including 14 reports of injection site reactions. No related Grade 3 or 4 adverse events were reported.
The researchers detailed outcomes involving 30 of the evaluable patients. These per-protocol patients, who had a median age of 53, received at least four doses of the vaccine.
“The robust immune response coupled with survival benefit relative to historical controls makes the data from this trial especially encouraging,” Dr. Parsa said. “The safety profile of HSPPC-96 offers a great opportunity for its use in combination with other approved treatments for glioblastoma multiforme.”
He added that he considered that the results support advancement of the vaccine into later-stage randomized trials, and another Phase II trial among patients with newly diagnosed glioblastoma is now recruiting patients.
The trial was supported through funding from the American Brain Tumor Association, Accelerated Brain Cancer Cure, the National Brain Tumor Society, and the NCI Special Programs of Research Excellence.
Talactoferrin Alfa for NSCLC
Another approach utilizes the properties of the novel immunomodulatory agent talactoferrin alfa. In another encouraging study, patients with non-small-cell lung cancer were treated with the agent.
“Not only did patients treated with talactoferrin have long overall survival, but the safety profile of this drug was excellent,” said Purvish Parikh, MD, President of the non-governmental organization Indian Cooperative Oncology Network, based in Mumbai.
Among the 100 patients treated with talactoferrin, overall survival was improved when compared with placebo. In the main trial, patients whose disease had progressed on at least two previous lines of treatment achieved a survival time of 6.1 months compared with 3.7 months on placebo. All patients were treated with what their clinicians considered the best supportive care, and then were assigned to receive, in addition to that treatment, either talactoferrin or placebo.
In a number of substudies, the researchers found that however the population was stratified, those treated with talactoferrin achieved longer survival. When patients were stratified by age, those 65 or younger had a 6.1 month overall survival on talactoferrin compared with 3.3 months for those on placebo. For patients older than 65 years, survival was 5.8 months on talactoferrin and 4.7 months on placebo.
Men survived 6.1 months on talactoferrin compared with 3.3 months on placebo; women survived 6.3 months on talactoferrin compared with 5.1 months on placebo.
If their tumor was squamous cell histology, patients on talactoferrin survived 7.9 months compared with 4.2 months on placebo. For non-squamous cell histology, survival was 5.8 months for patients on talactoferrin compared with 3.5 months for patients on placebo.
Dr. Parikh noted that the Grade 3/4 adverse events were almost non-existent in the talactoferrin patients, with the main events—cough, dyspnea, and pleural effusion—all related to the disease. All these events occurred less often among the talactoferrin patients than the placebo patients.
The results with talactoferrin in this Phase II study have prompted the developer, Agennix, Inc., headquartered in Heidelberg, Germany, to proceed with a Phase III study of 700 patients, with results expected to be reported next year, Dr. Parikh said.
Talactoferrin “is a very interesting agent,” Dr. Ellenhorn said. “It doesn't directly attack cancer cells but it activates special immune cells, and it does appear to provide some modest benefit in patients who otherwise have very few options.”
Talactoferrin, a recombinant human lactoferrin member of the transferrin family of iron-binding glycoproteins, acts through dendritic cell recruitment and activation in the gut-associated lymphoid tissue, Dr. Parikh explained. Lactoferrins have multiple known biological activities, including cancer protection, cellular growth and differentiation and antimicrobial and anti-inflammatory properties.
Another agent that purportedly works by positively modulating the immune system is the autologous cellular immunotherapy known as sipuleucel-T (Provenge), approved by the FDA for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer.
Although the exact mechanism of action remains controversial, the agent is believed to stimulate the immune system to target and attack prostate cancer, Dr. Ellenhorn noted.
“It does appear to provide a modest survival extension, although many of us are not sure that long-term study of this treatment will show continued benefit.”
Other similar approaches with sipuleucel-T “drug cousins” are also being studied, he added, noting, though, that the renewed interest in vaccines and immunomodulatory therapies for cancer probably probably does more to improve knowledge overall about how the immune system works, rather than enhancing the success of sipuleucel-T specifically.
Also continuing to be studied are interleukin-2 and other immune system modulators, Dr. Ellenhorn said. “I think the use of these vaccines in combination with agents such as ipilimumab is going to increase the potential of these immunomodulating agents to attack some of the more difficult cancers.”
“It is very infrequent that one drug or one treatment provides a single modality that can defeat caner,” Dr. Ellenhorn said. “We have learned that combining cytotoxic drugs and chemotherapy and radiation often gives us better results in treating cancer. I think that combining vaccines—such as the heat shock protein complex or talactoferrin—with other immunomodulatory agents such as ipilimumab will prove to be the better treatment.”