By Will Boggs MD
NEW YORK (Reuters Health) - 15/2/2019
Neoadjuvant immunotherapy with anti-PD-1 agents may improve outcomes in patients with resectable or recurrent glioblastoma, researchers report.
"The findings strongly suggest that the timing of immunotherapy can influence the magnitude and efficacy of the induced antitumor immune response," Dr. Timothy F. Cloughesy and Dr. Robert M. Prins from David Geffen School of Medicine, University of California, Los Angeles, told Reuters Health in a joint email. "Neoadjuvant immunotherapy may actually serve as a primer to enhance the antitumor immune response."
PD-1 blockade with pembrolizumab, nivolumab and other anti-PD-1 monoclonal antibodies leads to cytotoxic T cell-mediated tumor elimination. Though promising in early studies of metastatic breast cancer, resectable lung cancer and melanoma, PD-1 blockade has shown limited efficacy in patients with glioblastoma.
In one of three studies reported online February 11 in Nature Medicine, Dr. Cloughesy, Dr. Prins, and colleagues investigated whether neoadjuvant PD-1 blockade with pembrolizumab (with ongoing adjuvant therapy after surgery) would alter the functional immune landscape and extend survival in 35 patients with recurrent, surgically resectable glioblastoma, compared with adjuvant pembrolizumab alone.
Patients randomly assigned to the neoadjuvant group had a median overall survival of 417 days, compared with only 228 days among patients randomly assigned to the adjuvant-only group (P=0.04). Median progression-free survival was also significantly longer in the neoadjuvant group (99.5 days) than in the adjuvant-only group (72.5 days).
Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-gamma-related gene expression and downregulation of cell-cycle-related gene expression within the tumor, changes not seen with adjuvant therapy alone.
Patients in the neoadjuvant group were also more likely than patients in the adjuvant only group to show focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells, and a decreasing monocytic population.
"These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor," the researchers conclude. "Given the noted improvement in survival, we intend to expand the current study and pursue further clinical trials with neoadjuvant combination immunotherapeutics."
"There are two kinds of cancer patients that tend to respond to PD-1 blockade: 1) one group of cancers that have a high number of somatic mutations (e.g., melanoma and lung cancer); and 2) another group of cancers that may not have a high tumor mutational load, but can upregulate a robust interferon gene expression signature," Dr. Prins and Dr. Cloughesy said. "The second group can be glioblastoma patients, and enhanced if the immunotherapy is given prior to and after surgical resection."
"Many other immune therapies might benefit from the neoadjuvant approach, both by better understanding the mechanism of effect, and providing an opportunity for a clinical benefit," they said.
In the second study, Dr. Ignacio Melero from Clinica Universidad de Navarra, in Pamplona, Spain, and colleagues explored the feasibility, safety and immunobiological effects of nivolumab given before and after surgery to 30 patients with primary or recurrent glioblastoma.
Median progression-free survival in these patients was 4.1 months, and median overall survival was 7.3 months. There was no obvious clinical benefit following salvage therapy, but two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.
Compared with historical controls with glioblastoma who had not received immunotherapy, these patients treated with nivolumab showed enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented clonal diversity among tumor-infiltrating T lymphocytes.
Dr. Melero told Reuters Health by email, "We observe that treatment presurgery with nivolumab reaches intratumor lymphocytes and changes the tumor immune microenvironment. However, efficacy is limited if compared to neoadjuvant PD-1-blockade immunotherapy of other malignancies."
"A clinical trial testing neoadjuvant nivolumab or pembrolizumab in primary resectable glioblastoma should be undertaken in a sufficiently statistically powered manner to be conclusive (or not) of clinical benefit," he said.
In the third study, Dr. Adam M. Sonabend from Northwestern University Feinberg School of Medicine, in Chicago, and colleagues explored immune and genomic correlates of response to anti-PD-1 immunotherapy (with nivolumab or pembrolizumab) in 66 patients with glioblastoma, including 17 long-term responders.
Tumors from immunotherapy responders showed enrichment of BRAF/PTPN11 mutations, which participate in the MAPK pathway, as well as differences in T cell clonal diversity and tumor microenvironment profiles, compared with tumors from nonresponders.
"PD-1 inhibitors are effective for a subset of glioblastoma patients," Dr. Sonabend told Reuters Health by email. "The identity of these patients was elusive, and our results provide an insight into how to identify them."
"Our results suggest that PD-1 inhibitors could be used and be effective for patients with glioblastomas bearing alterations in the MAPK pathway, which are associated with specific features in the microenvironment," he said. "Glioblastomas with PTEN mutations have immunosuppressive features that influence the microenvironment and are associated with lack of response to PD-1 inhibitor immunotherapy."
Co-author Dr. Raul Rabadan from Columbia University, in New York City, told Reuters Health by email, "Understanding genetic markers of response can help stratify patients - select patients that we suspect could be more responsive to the therapy. In addition, these markers provide information about the specific mechanism of resistance that could lead to modify or alternative therapies."
Dr. Fabio M. Iwamato, also a co-author, from Columbia University Irving Medical Center added in an email to Reuters Health, "The identifbitors, such as those with PTEN mutation, will allow us to design trials that enrich for patients who are more likely to respond to these therapies."
Dr. Michael Lim from Johns Hopkins University School of Medicine, Baltimore, Maryland, who recently explored the efficacy of combination immune checkpoint inhibitor therapy in a mouse model of glioblastoma, said, "I found the improved survival in patients given anti-PD-1 in a neoadjuvant setting to be very interesting. The findings suggest that surgery may help 'break-up' the immunosuppressive environment of glioblastoma to kindle a robust antitumor immune response. This falls into paradigms where some treatments focus on focal therapies to ignite a systemic immune response."
"We still have a lot to learn about the immune microenvironment of glioblastoma, and there are likely subsets of glioblastoma that can respond to immunotherapy," Dr. Lim, who was not involved in the new research, told Reuters Health by email.
Nat Med 2019