Correspondence

Vaccination with HPV-18 E7–Pulsed Dendritic Cells in a Patient with Metastatic Cervical Cancer

N Engl J Med 2002; 346:1752-1753May 30, 2002

Article

To the Editor:

The management of disseminated carcinoma of the cervix that is no longer amenable to control with surgery or radiation therapy has not improved significantly with the advent of modern chemotherapy. The one-year survival rate remains between 10 percent and 15 percent.1 Studies have provided a rationale for using dendritic cells as natural adjuvants for human immunotherapy.2-4

We describe a 52-year-old woman with multiple lung metastases secondary to recurrent human papillomavirus type 18 (HPV-18)–associated adenocarcinoma of the uterine cervix. In 1997 she underwent external irradiation and intracavitary brachytherapy combined with weekly intravenous infusions of cisplatin and followed by an adjunctive hysterectomy for stage IB2, grade III, cervical cancer. The patient did well until January 2000, when a chest x-ray film and computed tomographic (CT) scans revealed metastatic lesions in both lungs and bilateral pleural effusions.

To inhibit tumor progression, we subcutaneously administered autologous mature, monocyte-derived dendritic cells pulsed with HPV-18 E7 oncoprotein. The first five injections were given at intervals of 10 to 14 days (3 million to 5 million dendritic cells per injection). To increase the number of T cells potentially responsive to disease, the first, second, and fourth vaccinations were followed 72 hours later by the adoptive transfer of autologous T cells (1.5×10⁷ cells) that had been stimulated in vitro with HPV-18 E7–pulsed dendritic cells. Low-dose interleukin-2 (1 million U per square meter of body-surface area per day for three days, infused over a six-hour period) was concomitantly administered. Vaccinations 6 to 14 were administered at intervals of 30 to 60 days.

The patient had minor side effects, including tender induration at the site of the injections and an influenza-like syndrome at the time of interleukin-2 infusion. After the third vaccination, we assessed whether delayed hypersensitivity had occurred by intradermally injecting the patient with HPV-18 E7 oncoprotein (Figure 1AFigure 1Immunologic and Histologic Findings in a Woman with Metastatic Cervical Cancer.) or lethally irradiated autologous tumor cells. There was swelling and induration, indicating a strong local reaction to the HPV antigen and tumor cells. A skin biopsy of both injection sites, used to assess whether delayed-type hypersensitivity had occurred, revealed marked CD4+ and CD8+ T-cell infiltration. Serial CT scans showed no evidence of tumor progression during 13 months of therapy. Cavities developed in the majority of lesions. In contrast to results obtained before vaccination (Figure 1B), after 10 months of treatment, CT-guided fine-needle biopsy revealed fibrosis and macrophage infiltration but no viable tumor cells (Figure 1C).

After the initiation of dendritic-cell immunotherapy, the patient resumed her normal activities. Twenty months later, she became short of breath. CT showed that her pulmonary masses had increased in size. Bronchoscopic biopsy confirmed that metastatic disease had recurred (Figure 1D). Delayed-hypersensitivity status against HPV-18 E7 oncoprotein was not reassessed at this time. The patient died 23 months after the beginning of the dendritic-cell immunotherapy. Although this approach did not result in permanent remission, it inhibited disease progression and markedly improved the patient's performance status for an extended period without clinically significant adverse effects.

Alessandro D. Santin, M.D.
Stefania Bellone, Ph.D.
Murat Gokden, M.D.
Martin J. Cannon, Ph.D.
Groesbeck P. Parham, M.D.
University of Arkansas for Medical Sciences, Little Rock, AR 72205
santinalessandrod@uams.edu

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