Cancer immunotherapies, which empower patients’ immune systems to eliminate tumors, are revolutionizing cancer treatment. Many patients respond well to these treatments, sometimes experiencing long-lasting remissions.
But some cancers remain difficult to treat with immunotherapy, and expanding the impact of the approach is a high priority.
In the October 30 issue of the Proceedings of the National Academy of Sciences, a team led by Cold Spring Harbor Laboratory scientists Tobias Janowitz and Douglas Fearon together with Duncan Jodrell at the Cancer Research UK Cambridge Institute and Centre, University of Cambridge reports on a clinical trial of a drug that induces an integrated immune response in the tumors of patients with cancer types that do not usually respond to immunotherapy.
The researchers hope the potential treatment might make such tumors more responsive to the class of drugs known as immune checkpoint inhibitors.
Checkpoint inhibitors release natural brakes on the immune system, freeing it to find and destroy cancer cells. But they generally have not been effective against cancer cells with low levels of genetic mutation. Janowitz said:
“Those tumors often do not seem to be visible to the immune system and do not seem to be unmasked by these therapies that are currently available. And we have reasons to believe that that is because they can engage an immune suppressive pathway that keeps most of the immune cells out of the cancer cell nest.”
In this clinical trial, the research team interrupted that immunosuppressive pathway with a drug called plerixafor. The drug was administered continuously by I.V. for one week to 24 patients with either pancreatic cancer or colorectal cancer with a low tumor mutational burden.
All patients had advanced disease, and biopsies were collected from metastatic tumors before and after treatment.
When the team analyzed those patient samples, they found that critical immune cells had infiltrated the tumors during the time patients received plerixafor, including a cell type known to summon and organize key players in the anti-cancer response.
The finding was encouraging because the team detected changes that have also been observed in patients whose cancers responded well to checkpoint inhibitors.
Jodrell, who led the planning and patient recruitment for the clinical study, said, “I am delighted that the work of this multi-disciplinary team has translated important laboratory findings into patients, with the potential to make a difference in these hard-to-treat cancers.”
A clinical trial based on this study is about to start recruitment and will test the effects of combining plerixafor with an approved checkpoint inhibitor.
Plerixafor (Mozobil®, Sanofi, Cambridge, MA, USA) is an antagonist of the 7 transmembrane G protein coupled chemokine (C-X-C motif) receptor 4 (CXCR4) that works by disrupting the interaction of CXCR4 with stromal cell-derived factor-1, resulting in the release of CD34+ stem cells into the circulation [1–4].
In the United States, plerixafor is licensed for use in combination with granulocyte colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSCs) into peripheral blood (PB) for collection and subsequent autologous HSC transplantation (HSCT) in adult patients with non-Hodgkin lymphoma or multiple myeloma (MM).
In the European Union, plerixafor is indicated for use in combination with G-CSF to enhance mobilization of HSCs into PB and subsequent autologous HSCT in adults with lymphoma and MM, who are proven to be poor mobilizers.
While the efficacy and safety of plerixafor is well established in adults, limited data for its use in children are available. This study investigated the appropriate dosing, safety, and efficacy of plerixafor when given in combination with G-CSF, in pediatric patients with different types of cancer.
Discussion
This study is the first to address the dose and timing of plerixafor in pediatric patients with cancer and allowed for efficacy and safety to be assessed in this patient population.
Stage 1 of this study was conducted to establish the PK of plerixafor in the pediatric population. No apparent dose-dependent effect of plerixafor on CD34+ cumulative cell yield or fold increases were observed observed and efficacy and safety of plerixafor in this study was similar to that observed in adults at all three doses explored.
Therefore the recommended adult dose of 240 µg/kg, administered 8–12 h prior to apheresis, was recommended in pediatric patients.
The primary endpoint, defined as at least a doubling of PB CD34+ cell count in the 24 h prior to first apheresis (i.e., prior to first administration of plerixafor in the experimental arm), was significantly higher in the plerixafor arm than in the standard arm (p = 0.0019).
The primary endpoint allowed for the measure of the role of plerixafor in addition to standard mobilization with G-CSF alone or in combination with chemotherapy in order to not modify the standard mobilization regimens currently used. Of note, on the day prior to the first planned apheresis, CD34+ cell counts were more than twofold higher in patients randomized to the standard arm than in the plerixafor arm.
The added value of plerixafor treatment can be seen in the increase in CD34+ cell counts on day 1 of apheresis from the day prior to apheresis, with patients in the plerixafor arm experiencing a greater median fold change (3.2-fold vs. 1.39-fold) in CD34+ cell counts than those in the standard arm.
In adults, plerixafor has been observed to be advantageous in patients considered to be poor mobilizers using the current consensus threshold for poor mobilization in adults (<20 CD34+ cells/µL) [5–7]. However, the adult “consensus” threshold for poor mobilization may not be appropriate in the pediatric setting [8].
Few studies have been published exploring poor mobilization in pediatric patients and therefore there is no current consensus threshold for poor mobilization in this patient group. In a single retrospective study of pediatric patients, who received a mobilization regime consisting of G-CSF for 4 days, prior to collection of CD34+ cells, [8] no differences were observed in the numbers of patients reaching the target cell dose (2 × 106 cells/µL) for autologous PB progenitor cell transplantation in patients with baseline PB CD34+ cells counts of >20 cells/µL compared with those with baseline CD34+ cells counts of 11–20 cells/µL [8].
Of 26 pediatric patients with a PB CD34+ cell count of ≤10 cell/µL, 18 underwent hematopoietic progenitor cell collection, two reached the target CD34+ cell dose after one apheresis, and 16 failed to reach the target [8].
Data for use of plerixafor for mobilization of HSC in pediatric patients are sparse. Studies, with limited numbers of pediatric patients who had failed earlier mobilization with chemotherapy and G-CSF, or G-CSF alone, have demonstrated that plerixafor combined with G-CSF can result in successful mobilization [9–12].
In a more comprehensive study of 33 pediatric patients who had previously failed to mobilize using G-CSF mobilization regimes, 31 patients successfully mobilized CD34+ cells after treatment with plerixafor, with 27 patients meeting the target of 2 × 106 cell/kg after one apheresis procedure and 24 patients proceeded to transplant [13].
In the current study, more patients in the plerixafor arm than in the standard arm successfully mobilized cells it is important to note that both arms had high levels of successful mobilization, suggesting plerixafor may have a specific role in the population of patients who are poor mobilizers [14].
Again, it was noted that the plerixafor arm had a higher proportion of potential poor mobilizers (as defined using the current consensus threshold for poor mobilization in adults, <20 CD34+ cells/µL), than in the standard arm. The higher number of poor mobilizers in the plerixafor group may have contributed to a trend in slower platelet engraftment observed in the plerixafor group, median time to engraftment 28 days in the plerixafor arm compared with 23 days in the standard arm.
However, in another study in children with malignant tumors, the median time to platelet engraftment with plerixafor was 16 days (range 9–30 days) [13], which is similar to the median time of 18–21 days for platelet engraftment observed for both plerixafor plus G-CSF and the G-CSF alone arms in adult patients with non-Hodgkin’s lymphoma and MM [15, 16].
It is known that there are differences in the cellular composition of apheresis products recovered from healthy adults who received either plerixafor plus G-CSF or G-CSF alone [17]. Nevertheless, there is no evidence from studies in adult lymphoma or MM patients that potential differences in apheresis product affects platelet engraftment [15, 16].
The results of the previous pediatric published literature, in which high levels of successful mobilization were observed in patients that had previously failed to mobilize on alternative mobilization regimes, provide further support for the use of plerixafor in HSC mobilization [9–13].
Adverse events reported as related to study treatment in the current study were mild and consistent with the known safety profile of plerixafor. In addition, few AEs have been reported in other studies investigating the use of plerixafor in pediatric patients [9, 11, 12].
Maschan et al. [13] noted mild toxicity in 8 out of 33 patients including World Health Organization grade 1/2 diarrhea (n = 5), grade 2 nausea (n = 2), grade 1 bone pain (n = 1), and urticaria (n = 1). Hong et al. reported that two patients with medulloblastoma developed pneumomediastinum, with pathogenic findings consistent with diffuse alveolar damage [10].
In summary, this study has established the dose and timing of plerixafor in pediatric patients as 240 µg/kg to be administered between 6 and 11 h before apheresis.
More patients in the plerixafor arm, than in the standard arm, met the primary endpoint of successful mobilization supporting the role of plerixafor on increasing the number of mobilized CD34+ cells in PB, especially in poor mobilizers. Adverse events reported as related to study treatment were mild, and no new safety concerns were identified in this study.
Overall, plerixafor was generally well tolerated and efficacious when used to mobilize CD34+ cells in pediatric patients with a variety of different cancers.
reference link : https://europepmc.org/articles/pmc7452813/bin/41409_2020_836_moesm1_esm.pdf
More information: Biasci, D., et al., “CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response”, PNAS, October 30, 2020. DOI: 10.1073/pnas.2013644117
