When combined with chemotherapy, a vaccine against the human papillomavirus type 16 (HPV16) elicited strong T-cell responsiveness and improved clinical outcomes in patients with advanced cervical cancer.
According to results from the phase 1/2 CervISA study, the response rate to the combined treatment was 69% among patients not previously treated for advanced disease. Long-term benefit was also greater in this subset of patients, with a median survival of 16.8 months compared with 7.9 months when the therapy was given in the second-line setting or beyond (P = .011).
“We found that this chemotherapy combination really potentiates T-cell responsiveness,” said Marij Welters, PhD, Leiden University Medical Center, Netherlands. “And induction of strong HPV16-specific T-cell responses was associated with improved clinical outcomes, including overall survival.”
As Dr Welters reported at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium, there is still an unmet medical need for treatment of advanced HPV-induced cancers. In patients with a high-grade premalignant lesion of the vulva associated with HPV16, Dr Welters and colleagues demonstrated that therapeutic vaccination with HPV16 synthetic long peptides caused successful clearance of the lesion in almost half of the patients. In addition, the vaccine (called ISA101) was correlated with the strong T-cell response. However, for the treatment of HPV16-induced cancers, timed combination of the ISA101 vaccine with standard-of-care chemotherapy is required, an approach that has proved successful in preclinical and early-phase clinical studies.
Phase 1/2 CervISA Study
For this study, metastatic and recurrent cervical cancer patients with an HPV+ tumor received 6 cycles of standard-of-care chemotherapy consisting of carboplatin/paclitaxel. In addition, 3 doses of ISA101 vaccine were given 2 weeks after the second, third, and fourth cycles. Four cohorts involving a total of 60 patients were vaccinated with various dose levels (20, 40, 100, and 300 µg per peptide), with or without pegylated interferon-alpha, which was predicted to enhance the immune response but failed to do so in the current study.
An assay used to quantify the number of T cells secreting a cytokine after stimulation via antigen showed a “very strong T-cell response” induced by vaccination, Dr Welters reported. More importantly, she added, when compared with historical controls, the vaccine-chemotherapy combination was associated with improved clinical outcomes, especially among previously untreated patients.
Responses were observed in 69% of patients receiving first-line chemotherapy, compared with 25% of previously untreated patients. In addition, stable disease plus response was seen in 94% of patients in the first-line setting. Furthermore, tumor shrinkage was “substantial” in a large proportion of patients, said Dr Welter, who noted that historical responses to first-line treatment have ranged from 36% to 63%.
In previously untreated patients, a long-term survival benefit was also suggested by the data. Median overall survival was 16.8 months among patients receiving first-line chemotherapy versus 7.9 months for those treated in the second-line setting and beyond. Patients in the first-line setting had a 55% reduced chance of dying, said Dr Welters, compared with their previously treated counterparts (P = .011).
“Here again, overall survival seems much better than that achieved with standard treatments, for which overall survival at 24 months has not exceeded 38%,” said Dr Welter, who noted that median overall survival has not yet been reached for patients treated with the 2 highest doses. “Maturing data for higher doses might further improve the median overall survival and overall survival tail.”
The investigators also observed a strong association between robust HPV-specific T-cell responses and overall survival. There was a 62.6% lower rate of death for patients whose HPV-specific T-cell responses were above the median. Furthermore, the ISA101 effect on overall survival was independent of general immune status.
“These results indicate that the survival advantage is specifically related to the strength of the vaccine-induced T-cell response and is not due to generally better immunocompetence,” Dr Welters explained.
“The CervISA data provide a strong rationale to conduct randomized phase 2 trials,” she added. “We think that additional combinations with checkpoint blockers is also an attractive strategy.”
Study discussant Heather L. McArthur, MD, MPH, Medical Director, Breast Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, called the findings “provocative” and said that data from the CervISA study suggest a role for therapeutic vaccination.
“This is the most impressive waterfall plot I’ve seen recently, if ever,” said Dr McArthur. “There are responses at every dose. And with response rates like this, I think we can expect to see future development and the vaccine being used in our clinics.”
