We have now completed a chemoimmunotherapy study in a larger number of patients with late-stage HPV16-positive cervical cancer, and we have shown that in these patients, the combination is worthwhile.— Marij Welters, PhD
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When combined with chemotherapy, a vaccine against the human papillomavirus (HPV) type 16 potentiated T-cell responsiveness and improved clinical outcomes in patients with advanced cervical cancer enrolled in the phase I/II CervISA study.1 The findings were reported at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium by Marij Welters, PhD, of Leiden University Medical Center in The Netherlands.
As background, Dr. Welters noted that in the setting of premalignant high-grade lesions of the vulva induced by HPV type 16, therapeutic vaccination with HPV type 16 synthetic long peptides, covering the oncoproteins E6 and E7 results in robust vaccine-induced T-cell responses and regression of lesions. For the treatment of HPV16-induced cancers, however, timed combination of the vaccine with chemotherapy is required—an approach that has proven successful in an early-phase clinical study.
“In this pilot study, we noted that a single dose of the vaccine 2 weeks after the second cycle of chemotherapy was optimal, because at this time, the abnormal high numbers of myeloid cells, including the immunosuppressive myeloid cells were normalized,” she said. “We have now completed a chemoimmunotherapy study in a larger number of patients with late-stage HPV16-positive cervical cancer, and we have shown that in these patients, the combination is worthwhile.”
Study Details
The ISA101 vaccine comprises 13 overlapping HPV16 synthetic long peptides, together covering 2 oncogenic protein: E6 and E7. Three doses of ISA101 were given 2 weeks after the second, third, and fourth cycles of standard-of-care chemotherapy consisting of paclitaxel and carboplatin. Eight cohorts involving a total of 60 patients were vaccinated with various dose levels (20, 40, 100, and 300 µg/peptide), with or without pegylated interferon-alpha, which was predicted to enhance the immune response but failed to do so in the current study.
Vaccine and Chemotherapy for Cervical Cancer
- The ISA101 vaccine against HPV type 16, administered with chemotherapy to patients with advanced cervical cancer, elicited strong responses against the virus and was associated with impressive long-term clinical outcomes.
- The response rate to the combined treatment was best for patients not previously treated with chemotherapy for their advanced disease. Long-term benefit was also greater for patients not previously treated.
- In both previously treated and previously untreated patients, overall survival was better than that observed with standard therapies.
- A strong association was observed between the magnitude of HPV-specific T-cell response and overall survival.
“We found that this chemotherapy combination potentiates T-cell responsiveness,” reported Dr. Welters. “Induction of strong HPV16-specific T-cell responses was associated with improved clinical outcomes, including overall survival.”
The objective response rate was “strong,” compared with historical controls, she noted. This was especially true for patients who received first-line chemotherapy, compared with those treated in the second line and beyond. Tumor shrinkage was “substantial” in a large proportion of patients, she added.
Potential Long-Term Benefit
Preliminary overall survival data point to the potential for long-term benefit, especially for previously untreated patients. Here again, she added, overall survival seems much better than that achieved with standard treatments.
The data are weighted toward patients receiving the lowest vaccine doses, as they have been followed longer. Median overall survival has not yet been reached for patients treated with the two highest doses. “Maturing data for higher doses might further improve the median overall survival and overall survival tail,” Dr. Welters predicted.
A strong association emerged between robust HPV-specific T-cell responses as measured by enzyme-linked immunospot [ELISpot] assay and overall survival.
The ISA101 effect on overall survival was independent of general immune status as measured by response against common recall (microbial) antigens. These results indicate that the survival advantage is specifically related to the strength of the vaccine-induced T-cell response and not due to generally better immunocompetence, she explained.
“The CervISA data provide a strong rationale to conduct randomized phase II trials. We think that additional combinations with checkpoint blockers are also an attractive strategy,” Dr. Welters said. ■
Disclosure: Dr. Welters reported no potential conflicts of interest.
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