Blog by Arthur N. Brodsky, PhD, published on Cancerresearch.org on 27 March 2020. Click here to access the original article.
Just weeks after International Human Papilloma Virus (HPV) Awareness
Day, new results
from two long-time Cancer Research Institute (CRI) scientists highlighted the
promise of immunotherapy against HPV-associated cervical cancer.
In a phase 1/2 study, women with advanced, recurrent, or
metastatic cervical cancer were treated with the combination of an
HPV-targeting vaccine and standard-of-care chemotherapy. Of 72 evaluable
patients, 43 percent had their tumors shrink.
Led by Cornelis J.
M. Melief, M.D, Ph.D., and Sjoerd H. van der Burg, Ph.D.,
this clinical breakthrough was the latest fruit borne by the duo, both of
whom have been supported by CRI during their time at Leiden University
Medical Center in the Netherlands. In addition to being a member of
the CRI Scientific Advisory Council, Melief was the recipient of the 2019 AACR-CRI
Lloyd J. Old Award in Cancer Immunology and is currently the
chief scientific officer at ISA Pharmaceuticals. Van der Burg, who earned
his doctorate in Melief’s lab in 1998, is also affiliated with ISA as a member
of their Scientific Advisory Board, as well as the Oncode Institute.
In 2002, CRI-funded preclinical
work by Melief and van der Burg provided an early proof of principle that therapeutic
HPV vaccines could eliminate HPV-associated cancers. To do so, they used
synthetic long peptide (SLP) vaccines to target the E6/E7 oncoproteins produced
by the HPV16 strain.
Next, they demonstrated that
HPV-targeting vaccines could clear pre-malignant lesions. However, vaccination
wasn’t effective against advanced cancers because of the presence of immunosuppressive
myeloid cells. By adding chemotherapy to the treatment regimen, the current study
sought to decrease the number of myeloid cells and thereby enable more potent
anti-tumor immune responses after vaccination, especially by the immune
system’s “killer” T cells.
In many patients, the combination appears to have done just
Two weeks after chemotherapy, when patients’ myeloid cells
were at their lowest point, varying doses of the ISA-101 vaccine were
administered. Half of them also received a molecule called pegylated type 1 interferon
that may help boost adaptive immune responses. Overall, about one-third of patients
analyzed had low levels of HPV-targeting T cells after chemotherapy alone and
prior to vaccination. Post-vaccination, HPV-specific T cell responses were
detected at all dose levels, and “the patients with higher than median strength
responses survived the best,” Melief told CRI.
“These results, provided they are validated in larger
trials, could lead to significantly improved care for patients with cervical
In another ongoing study, this vaccine paired well with checkpoint
blockade immunotherapy in patients with advanced head and neck cancer—another
cancer linked to HPV infection. A similar trial will soon be testing that approach
in cervical cancer, according to Melief, who believes we might benefit from going
even further with vaccine combinations.
“Last year, we demonstrated the
synergy between vaccination and anti-PD-1 checkpoint immunotherapy in patients
with recurrent or metastatic HPV+ head and neck cancer. It is therefore
tempting to combine all three therapeutic measures—anti-PD-1, vaccination, and
chemotherapy—for additional synergy because chemotherapy and anti-PD-1 act by
non-overlapping mechanisms. This chemotherapy combination also pinches in
nicely with other types of immunotherapy because many types of late-stage
cancer induce this kind of myeloid cell-mediated immunosuppression in patients.”