Combining Drugs and Biologics to Treat Nasopharyngeal Cancer

An optimal cancer therapeutic would secure effective disease control with only minimal adverse effects so that tumor destruction is not achieved at the cost of the patient's quality of life. Chemotherapy with small-molecule drugs remains the standard treatment for most cancers, but, despite their ready availability and rapid action of onset, most of these agents also cause both short- and long-term toxicity. Conversely, immunotherapy using tumor-directed T cells has shown promise in some malignancies without long-term toxicity, but broader application has been limited by the time taken to manufacture the T-cell products and the complexity of the process.^1,2,3,4 In the long term, the optimal approach might be to combine emerging immunotherapy approaches with targeted small molecules, exploiting the lack of cross-resistance and the potential for synergy. In this issue of Molecular Therapy, Chia et al. take the first steps toward evaluating such combination approaches.⁵

Nasopharyngeal cancer (NPC), one of the most common malignancies in many parts of Southeast Asia and southern China, is almost always associated with the presence of Epstein–Barr virus (EBV) antigens in the tumor cells. Although localized primary disease is often successfully treated by a combination of drugs and radiation therapy, advanced or recurrent malignancy is rarely cured, and toxicity from the therapy is often severe and prolonged. Chia et al. now report the results of a phase II trial in which patients with advanced EBV⁺ NPC underwent a regimen that combined standard chemotherapy with T-cell immunotherapy using a schedule of four cycles of gemcitabine and carboplatin followed by up to six doses of EBV-specific T cells.⁵ This combination therapy resulted in an encouraging response rate of 71.4% with 3 complete and 22 partial responses. Moreover, the median overall survival of 29.9 months and the 2- and 3-year overall survival rates at 62.9 and 37.1%, respectively, were significantly higher than those observed in historical controls receiving chemotherapy alone (11–22 months). This article suggests that the combination of chemotherapy with immunotherapy may improve response rates in patients with advanced NPC and sets the stage for a randomized trial.

Many head and neck cancers are associated with viruses, and more than 95% of cases of NPC express a limited array of EBV antigens, including EBNA1, BARF1, LMP1, and LMP2 (refs. 6,7), making immunotherapy approaches targeting EBV an attractive therapeutic option. Several groups have shown that administration of EBV-specific T cells to patients with NPC is safe and has antitumor activity. Comoli et al. treated 10 patients with progressive NPC after conventional therapy, using autologous EBV-specific T cells generated using EBV-infected lymphoblastoid cell lines (LCLs) as antigen-presenting cells to stimulate a polyclonal response to latent EBV antigens. The investigators observed partial responses in two patients and stable disease in four.⁸ Our group has given LCL-activated EBV-specific T cells to patients with NPC and observed 10 responses in 15 patients treated with active disease (5 complete responses, 2 partial responses, and 3 with stable disease).^9,10 An additional 8 patients were treated in their second or subsequent remission, and 5 remain free of disease with follow-up of 6 years. Both groups have attempted to improve these results by pretreating patients with lymphodepletion using either chemotherapy with cyclophosphamide and fludarabine¹¹ or CD45-depleting antibodies,¹² but neither approach improved the response rate.

In the studies by both our group and Comoli et al., the LCL-induced EBV-specific T cells contain T-cell clones that target all nine latent-cycle antigens of EBV as well as some of the virus's lytic antigens. The majority of the T cells, however, are responding to the most immunogenic antigens, including EBNA3 and the lytic-cycle antigens such as BZLF1, which are not expressed by EBV-infected NPC cells. Instead, the tumor cells express antigens associated with the type II latency pattern, including LMP1, LMP2, EBNA1, and BARF, which are less immunogenic and are present at a lower frequency in polyclonal LCL-induced EBV-specific T cells. It is therefore notable that both groups have identified an association between measurable benefit of EBV-specific T cells and the presence in the product of LMP2-reactive clones that expand in the patient after infusion.^8,9 This intriguing observation was confirmed by Chia et al., who showed a strong association of benefit with specificity for EBV-LMP2 in the infused line (P = 0.04).⁵

There have been no detailed studies of the association of response with the presence of other EBV antigens expressed in type II latency infections (and hence by NPC), but we have reported one patient who attained a complete response after receiving a line that contained a large T-cell population specific for an EBNA1-derived, HLA class I–restricted epitope.¹⁰ Current studies are therefore enriching lines for cells that recognize the EBV antigens expressed in NPC and other type II latency tumors, using either overlapping peptide pools pulsed on dendritic cells¹³ or an adenoviral construct termed AdE1-LMPpoly that encodes EBNA1 fused to CD8⁺ T-cell epitopes from LMP1 and LMP2 to stimulate T cells.¹⁴ The latter approach has been tested in 16 patients with recurrent and metastatic NPC who received EBV-specific T cells generated by stimulation with AdE1-LMPpoly. After adoptive transfer, there was a transient increase in the frequency of T cells responding to LMP1, LMP2, and EBNA1. The median overall survival of these patients was 523 days, compared with 220 days in patients who did not receive T cells.¹⁴

The study reported by Chia et al. is apparently the first in which the design included a chemotherapy regimen followed by a planned cell-therapy regimen as frontline therapy. One of their important findings is the feasibility of manufacturing cells in a timely manner so that they were available for administration once chemotherapy had been completed. As a consequence, the study also had a high overall completion rate, with 35 of the 38 enrolled patients receiving the planned consolidation with EBV-specific T cells. Moreover, the study reports an excellent survival outcome for patients with advanced NPC as compared with historical results with chemotherapy alone.⁵ In the intention-to-treat analysis of all 38 patients, the median overall survival in the combination study was 26.6 months, with a 2-year survival of 57.9% compared with the two previous prospective first-line chemotherapy regimen studies conducted at the authors' center (17.7 months and 29.5%; 21.4 months and 42.0%). A randomized study is now needed to confirm the potential benefit of adding EBV-directed cell therapy to chemotherapy for NPC. The chemotherapy regimen used by Chia et al. is a standard, nonspecific one that has significant toxicity. In the future it should be possible to combine immunotherapy with more targeted drug therapies to achieve better antitumor activity with fewer long-term sequelae. Such possibilities include combining BRAF inhibitors, T-cell checkpoint inhibitors, and tumor-infiltrating lymphocytes in melanoma,¹⁵ or inhibitors of Bruton's tyrosine kinase with T cells transduced with chimeric antigen receptors targeting B-cell antigens in chronic lymphocytic leukemia.¹⁶