CHICAGO – A small study with just nine patients is sparking enormous hope after demonstrating for the first time that immunotherapy using adoptive T-cell therapy can induce complete remission in metastatic cervical cancer.
A single infusion of human papillomavirus (HPV)-targeted T-cell therapy induced complete responses in two women. A third woman had a partial response, with tumor shrinkage of 39% lasting 3 months.
Follow-up performed during the last week of the two women with complete responses showed no sign of disease 15 and 22 months after treatment.
"This study provides proof of principle that an immunotherapy can induce regression of cervical cancer, and that adoptive T-cell therapy can mediate regression of an epithelial cancer," said lead study author Dr. Christian S. Hinrichs, an investigator with the National Cancer Institute.
Patrice Wendling/Frontline Medical News
Dr. Christian Hinrichs
Cervical cancer harbors attractive targets for immunotherapy in the HPV E6 and E7 oncoproteins, but clinical trials of immunotherapy in this disease have thus far been disappointing.
The goal with vaccines against HPV is to reduce the future incidence of cervical cancer. But new therapies for advanced-stage disease are desperately needed because chemotherapy is not curative and rarely provides durable palliation, he said during a press briefing at the annual meeting of the American Society of Clinical Oncology.
He noted that one of the patients with a complete response had been previously treated with three different combination cytotoxic chemotherapy regimens for her HPV-16–positive squamous cell carcinoma, while the other had aggressive HPV-18–positive adenocarcinoma that had spread to the pelvis and distant sites despite chemoradiation. Both women were only 36 years old.
The best treatment we have commits women to chemotherapy and/or a biologic for the rest of their lives, which is no more than 2 years for most of the young women being treated, commented Dr. Don S. Dizon, director of the Oncology Sexual Health Clinic at the Massachusetts General Hospital Cancer Center, Boston.
"If all the academic centers can standardize this approach and identify the patients most likely to benefit, we could really reduce the deaths from this disease," he said.
Method
Research using adoptive T-cell therapy (ACT) in epithelial cancers, however, has been limited. ACT has been shown to induce dramatic, complete durable regression of melanoma and certain B-cell malignancies through use of T cells genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CARS).
"The difference here is that these are not genetically engineered cells," Dr. Hinrichs said in an interview. "These are naturally occurring T cells that are present in the tumors, grown out, and selected out for their reactivity against tumor antigens [HPV-E6 and -E7]."
The HPV-targeted tumor-infiltrating lymphocytes (TILs) are grown in the laboratory until they number in the billions and then are infused back into the patient. The women are pretreated with a lymphocyte-depleting conditioning regimen of cyclophosphamide and fludarabine (Fludara), and given aldesleukin (Proleukin), dosed to tolerance, after cell infusion.
All patients had HPV-positive cervical cancer and received a median of 81 x 10-9 T cells (range 33-159 x 10-9), Dr. Hinrichs reported.
The two women with complete responses by RECIST criteria demonstrated prolonged repopulation with the HPV-reactive T cells, detectable after 13 months in one and 6 months in the other. Two patients showed no repopulation of T cells and did not respond to treatment.
The most common severe adverse events seen with the therapy were the hematologic toxicities of the conditioning regimen, which occurred in all nine patients, Dr. Hinrichs said in an interview. Five patients had febrile neutropenia and six had infections, primarily positive blood cultures that were treated with antibiotics. All toxicities were completely reversible, and since it’s a one-time therapy, they were better tolerated than if they were repeated in cycles like traditional chemotherapy infusions, he observed.
Though encouraging, Dr. Hinrichs and others urged caution in interpreting these early data. Dr. Steven O’Day, with the University of Southern California, Los Angeles, said it’s costly and labor intensive to gather and manipulate cells and that questions remain about how to make the process more efficient, the therapy less toxic, and to determine whether cells could possibly be manipulated in vivo.
"There’re many questions, but the science is exciting, and it’s giving us an opportunity to direct the immune system against a cancer that traditionally isn’t seen by the immune system very well at all," he said. "So there are lots more to come."
Dr. Hinrichs said they plan to expand the study to 35 women to better define the response rate and that HPV-TIL is also being tested in a separate cohort of patients with noncervical HPV-positive cancers like oropharyngeal, anal, vulvar, and vaginal cancer. Physicians interested in enrolling patients should contact the National Institutes of Health. Patient referrals should be directed to June Kryk (jkryk@mail.nih.gov, 301-451-1929) or Linda Williams (lwilliams@cc.nih.gov, 301-402-4124).