Advaxis recently presented new data demonstrating the clinical benefit of Axal, its lead immunotherapy candidate, both as a single therapy and in combination with other immunotherapies, for patients with HPV-associated cervical cancer.
The presentations took place at the Society for Immunotherapy of Cancer (SITC) Annual Meeting & Associated Programs in National Harbor, Maryland.
Axal (axalimogene filolisbac) is a new vaccine approach that uses the live attenuated bacteria Listeria monocytogenes genetically altered to present the human papillomavirus (HPV)-16 protein at the surface. The protein is then recognized by T-cells, which will become specific to HPV-positive cancer cells.
Advaxis presented preliminary Phase 1 results from a Phase 1/2 clinical trial (NCT02291055) evaluating Axal combined with durvalumab (an investigational monoclonal antibody targeting the PD-L1 protein) in 66 patients with advanced, recurrent or refractory HPV-associated cervical cancer and HPV-associated head and neck cancer (HNSC).
The Phase 1 Part A study was designed to determine the safety and tolerability of the combination treatment and to identify the recommended Phase 2 dose. Patients were treated with Axal at a dose of 1×109 colony-forming units (CFU) every four weeks and durvalumab at a dose of 3 mg per kg body weight, or 10 mg/kg administrated every two weeks.
Preliminary results showed no treatment-related dose limiting toxicities. The Phase 2 dose was established as 10 mg/kg for durvalumab and 1×109 CFU for Axal. One cervical cancer patient achieved a complete response, which remains ongoing after 12 months. A partial response to treatment was seen in one patient, but the disease subsequently progressed. Two patients achieved stable disease. Treatment-related adverse events were reported in 91 percent of patients and included chills, fever, nausea, and hypotension.
In the Phase 2 part of the trial, patients will be randomized to receive either durvalumab alone or Axal in combination with durvalumab.
“When treating or evaluating investigational therapies for these kinds of metastatic, recurrent tumors, it is rare for an immunotherapy to result in a complete response,” Brian Slomovitz, MD, principal investigator and director of the Division of Gynecologic Oncology in the Department of Obstetrics and Gynecology at the University of Miami Miller School of Medicine, said in a press release.
“These early data show encouraging anti-tumor activity of the combination of Axal and durvalumab and the regimen was generally well tolerated, which supports continued study of this combination regimen,” he said.
Advaxis also presented data from a preclinical study conducted in a HPV-positive tumor model that evaluated Axal’s ability to control tumor growth, prolong survival, and reprogram the tumor microenvironment in combination with other immunotherapies. Those included either antibodies that stimulated T-cell co-stimulatory receptors or immune checkpoint inhibitors.
Anti-CD137 and anti-CTLA-4 antibodies, two of the monoclonal antibodies (mAbs) tested, were found to be most effective when used in combination with Axal in eradicating HPV-positive tumors and in providing long-term survival of eight weeks or more.
There was a complete regression of the HPV-positive tumors in 28% of the mice treated with Axal and anti-CD137 mAb, and a 33% complete tumor regression in mice treated with Axal and anti-CTLA-4 mAb.
Advaxis reported that both treatment combinations showed antitumor immunity. The results of this preclinical study also demonstrated that compared to treatment with compounds alone, both combination treatments were able to increase the percentages of tumor antigen-specific T-cells and mature dendritic cells, and to decrease the percentages of regulatory T-cells and immunosuppressive macrophages.
At the meeting, Advaxis also outlined its AIM2CERV study. This Phase 3 muticenter clinical trial (NCT02853604) is designed to compare the disease-free survival of Axal to a placebo administered following concurrent chemotherapy and radiotherapy (CCRT), as adjuvant treatment for high-risk locally advanced cervical cancer with curative intent.
Participants are being recruited for the clinical trial, in which 450 patients will be assigned randomly to receive either Axal or a placebo every three weeks for the first three months. Then patients will be treated with Axal every eight weeks with up to five doses or until disease recurrence.
In July, the U.S. Food and Drug Administration (FDA) granted Advaxis a Special Protocol Assessment for the AIM2CERV trial. Axal was also granted FDA Fast Track Designation to treat high-risk locally advanced cervical cancer following surgery to remove the tumor, and was granted orphan drug status to treat invasive cervical cancer.