Immunotherapy Targeting HPV Demonstrates Activity in Cervical Cancer

Christian S. Hinrichs, MD

Two patients with metastatic cervical cancer achieved durable complete responses that have so far lasted from 15 to 22 months through an adoptive T-cell therapy (ACT) targeting the human papillomavirus (HPV) in a study that researchers say supports the concept that the experimental immunotherapy approach may be beneficial in a variety of tumor types.

Scientists at the National Cancer Institute (NCI) initiated the study to determine whether ACT would be a viable strategy to deploy against epithelial cancers, according to Christian S. Hinrichs, MD, an assistant clinical investigator at the NCI in Bethesda, Maryland, who discussed the research during a press briefing on June 2 at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

“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 Hinrichs, an immunologist and medical oncologist.

He said the results suggest that ACT can be used in a broader range of tumor types than metastatic melanoma and certain B-cell malignancies, where it has been studied more extensively than in cervical carcinoma. Hinrichs said ACT targeted to HPV T cells is under study not only in cervical cancer, where the virus is a major cause of the disease, but also in other HPV-positive cancers including oropharyngeal, anal, vulvar, vaginal and penile cancers.

Meanwhile, the results of the small cervical cancer study are so promising that the research team is seeking to recruit 35 patients for an expanded study, said Hinrichs.

The ASCO experts agreed that new treatments are needed for patients with cervical cancer, which causes more than 4000 deaths a year in the United States. Hinrichs noted that chemotherapy “is not curative and rarely provides durable palliation” for these patients.

HPV Targeted

For the cervical cancer study, the researchers zeroed in on HPV E6 and E7 oncoproteins, which Hinrichs said were “attractive therapeutic targets for immunotherapy” that the tumor harbors.

A customized treatment was created for each patient by culturing T cells harvested from the patient’s tumor, testing the cells for reactivity against the HPV E6 and E7 antigens, and preferentially extracting and then expanding the reactive cultures. The patient then receives a single infusion of tumor-infiltrating lymphocytes (TILs), followed with aldesleukin dosed to tolerance.

In all, 9 patients ranging in age from 30 to 59 years who were diagnosed with metastatic cervical cancer participated in the study. Two patients experienced a complete response and 1 patient had a partial response of 3 months’ duration, while the remaining 6 participants had progressive disease.

One of the complete responders is a 36-year-old woman with HPV16-positive metastatic squamous cell carcinoma of the uterine cervix who had multiple tumor sites and had undergone three different cytotoxic chemotherapy combinations, said Hinrichs. He said her response has now lasted 22 months.

Hinrichs described the second complete responder as a woman with “a very aggressive primary tumor refractory to chemoradiation” whose disease had spread to her pelvis and distant sites. This patient, also 36 years of age, had HPV18-positive adenocarcinoma cervical cancer. She had complete regression at all sites, a response that has now lasted 15 months.

The most common severe adverse events associated with the therapy are hematologic effects that result from the conditioning regimen, which consists of lymphocyte-depleting chemotherapy regimen of cyclophosphamide and fludarabine, said Hinrichs. He said all patients have suppressed blood counts and bone marrow counts, and that approximately half of the patients have febrile neutropenia. “The cells themselves do not seem to cause any autoimmunity,” said Hinrichs.

He also noted that all the toxicities are reversible and that, since the therapy is administered in a single infusion, “It’s a little bit more tolerable to handle intense toxicities for just one treatment.”

In response to a question during the briefing, Hinrichs said the HPV-TIL form of ATC explored in this study does not pose the danger of generating a “cytokine storm,” in which T cells infused into the patient expand and release cytokines that cause fever, hypotension, nausea, and other symptoms that can be severe. Such reactions have been seen in chimeric antigen receptor (CAR) T-cell therapy, another form of ACT that is attracting intense interest in B-cell malignancies.

Hinrichs said a key difference in the approaches is that the HPV-TIL therapy that his group studied is generated from naturally occurring T cells in the tumor, whereas CARs are composed of genetically engineered T cells.

Immunotherapy Hopes High

Leaders in the field of gynecologic cancer treatment are looking to immunotherapy for new answers for patients whose prognosis often is bleak, said Don S. Dizon, MD, the director of the Oncology Sexual Health Clinic at Massachusetts General Hospital in Boston, who participated in the briefing as an ASCO expert in gynecologic cancers.

“This is one of the areas that we do believe is going to be one of the most promising for this field, but we will need international help to prove this concept,” said Dizon, noting that he wanted to encourage patients who might be candidates for immunotherapy to check out clinical trials.

“It’s a very exciting approach to a cancer that really has not been immunologically targeted,” commented Stephen J. O’Day, MD, a clinical associate professor of Medicine at the University of Southern California’s Keck School of Medicine who served as moderator for the briefing. “This obviously has implications for other solid tumors. There’s a whole new area here.”

Hinrichs CS, Stevanović S, Draper L, et al. HPV-targeted tumor-infiltrating lymphocytes for cervical cancer. Presented at: 2014 ASCO Annual Meeting Press Briefing; June 2, 2014; Chicago, IL. Abstract LBA3008.

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