Adoptive T-cell therapy is a promising salvage approach for advanced or recurrent metastatic cervical cancer.

Abstract

Cervical cancer is one of the leading causes of cancer-related death in women worldwide. Although the disease is frequently curable in early stages with surgery alone or surgery and adjuvant chemoradiotherapy, there are no effective therapies for advanced or recurrent metastatic cervical cancers. Recently, antiangiogenic therapy using bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, has demonstrated clinical efficacy in combination with paclitaxel and cisplatin, leading to its regulatory approval for advanced and recurrent cervical cancer. Although this represents some progress in the treatment of patients with cervical cancer, the addition of bevacizumab is unlikely to translate into durable cure for the majority of these patients. Thus, there is an enormous clinical need to develop novel effective strategies, such as immunotherapy, for this patient population. Persistent infection with specific high-risk human papillomavirus (HR-HPV; eg, HPV-16, HPV-18, HPV-31, HPV-33, and HPV45) has been identified as an essential factor in the pathogenesis of the majority of cervical cancers, with detectable HR-HPV in up to 99.7% of carcinoma specimens. Similar to nononcogenic viruses, such as influenza and cytomegalovirus, HPV is highly immunogenic and elicits immune responses in humans. Although prophylactic HPV vaccines targeting L1 and L2 virion structural proteins have demonstrated efficacy in preventing HPV-related cancers, therapeutic vaccines targeting E6 and E7 oncoproteins have not produced significant clinical responses. The barrier to establishing an effective therapeutic HPV vaccine against cervical cancer has been a lack of clinical response to any of the existing regimens. This is probably because of the relatively low magnitude of vaccine-induced immune responses, and tumormediated immune suppression. In the article that accompanies this editorial, Stevanovic et al present a promising adoptive T-cell therapy (ACT) approach by which patients with recurrent, chemotherapyresistant metastatic cervical cancer were treated with a single infusion of ex vivo–expanded tumor-infiltrating T cells. In contrast with tumor vaccination strategies, ACT allows for more rigorous control over the magnitude of the targeted response by appropriate in vitro manipulation and selection of the T cells used for therapy. Tumor-reactive effector cells of a desired specificity and phenotype can be identified in vitro, exposed to cytokines and immunomodulators that influence differentiation during priming, expanded to large numbers, and produce frequencies of antigen-specific T cells in the peripheral blood that are more than 10-fold greater than those possible by current vaccine regimens alone. Initial results that demonstrated the potential of T-cell immunotherapy to eradicate solid tumors came from the National Cancer Institute in studies of adoptive transfer of in vitro–selected tumor-infiltrating lymphocytes (TILs). In a pioneering clinical trial in 13 patients with melanoma, adoptive transfer of ex vivo–amplified autologous tumor-infiltrating T cells induced objective clinical responses in six patients and mixed responses in four additional patients. However, results in solid tumors and epithelial malignancies are still limited, mainly because of the technical challenges in obtaining enough tumor specimens and isolating and expanding tumor-reactive T cells. In the protocol used by Stevanovic et al, the T cells were obtained from tumor specimens that required a surgical excision of 1 cm tumor in each patient, expanded with interleukin-2 (IL-2), and used for ACT. T-cell products were tested for reactivity against HPV-16 or HPV-18 E6 and E7 oncoproteins. T-cell infusion was preceded by lymphodepleting chemotherapy and was followed by the administration of multiple doses of aldesleukin. In the study, nine patients were treated using this protocol, and three patients showed objective tumor response. Of these, two patients (both young, age 36 years, who were experiencing progression during receipt of palliative treatment) had a durable complete clinical response that lasted more than a year. Although the numbers are small, these results are impressive and suggest that this highly personalized therapeutic modality warrants further investigation. Importantly, the treatment was safe and well tolerated, but, as expected, the major toxicity resulted from the preconditioning lymphodepleting chemotherapy before the infusion. It is currently well recognized that the preconditioning step is critical for achieving a high level of T-cell engraftment because it creates space for the adoptively transferred T cells to populate in the absence of host-cell competition. Although the number of patients was too small to draw a general conclusion, the results clearly showed a correlation between HPV reactivity of the infused T-cell products and objective clinical responses. First, only when the infusion product had reactivity against the HPV E6 and E7 peptides did the patient show objective clinical response. Second, in patients with objective responses, HPV-specific T JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 14 MAY 1