Several lines of evidence support immunotherapy in hepatocellular carcinoma (HCC). We have shown that intratumoral injections of the immune primer ilixadencel (pro-inflammatory allogeneic dendritic ...cells) are safe in renal-cell carcinoma. Here, we assessed ilixadencel as a single agent and combined with sorafenib in advanced HCC. Of 17 HCC patients enrolled, 12 patients received ilixadencel at the dose of 10 × 10
cells (six as monotherapy and six in combination with sorafenib), and five received ilixadencel at the dose of 20 × 10
cells as monotherapy. The primary objective was to evaluate tolerability. All patients had at least one adverse event, with 30% of such events considered as treatment-related, with one single treatment-related grade three event. The most common toxicity was grade 1 and 2 fever and chills. Eleven of 15 evaluable patients (73%) showed increased frequency of tumor-specific CD8
T cells in peripheral blood. Overall one patient had a partial response (with ilixadencel as monotherapy), and five had stable disease as overall best response per mRECIST. The median time to progression was 5.5 months, and overall survival ranged from 1.6 to 21.4 months. Our study confirms the safety of ilixadencel as single agent or in combination with sorafenib and indicates tumor-specific immunological responses in advanced HCC.
www.ClinicalTrials.gov, identifier: NCT01974661.
Gut - brain communications disorders in irritable bowel syndrome (IBS) are associated with intestinal microbiota composition, increased gut permeability, and psychosocial disturbances. Symptoms of ...IBS are difficult to medicate, and hence much research is being made into alternative approaches. This study assesses the potential of a treatment with pasteurized Akkermansia muciniphila for alleviating IBS-like symptoms in two mouse models of IBS with different etiologies. Two clinically relevant animal models were used to mimic IBS-like symptoms in C57BL6/J mice: the neonatal maternal separation (NMS) paradigm and the Citrobacter rodentium infection model. In both models, gut permeability, colonic sensitivity, fecal microbiota composition and colonic IL-22 expression were evaluated. The cognitive performance and emotional state of the animals were also assessed by several tests in the C. rodentium infection model. The neuromodulation ability of pasteurized A. muciniphila was assessed on primary neuronal cells from mice dorsal root ganglia using a ratiometric calcium imaging approach. The administration of pasteurized A. muciniphila significantly reduced colonic hypersensitivity in both IBS mouse models, accompanied by a reinforcement of the intestinal barrier function. Beneficial effects of pasteurized A. muciniphila treatment have also been observed on anxiety-like behavior and memory defects in the C. rodentium infection model. Finally, a neuroinhibitory effect exerted by pasteurized A. muciniphila was observed on neuronal cells stimulated with two algogenic substances such as capsaicin and inflammatory soup. Our findings demonstrate novel anti-hyperalgesic and neuroinhibitory properties of pasteurized A. muciniphila, which therefore may have beneficial effects in relieving pain and anxiety in subjects with IBS.
A primary defect of the tight junctions and, hence, increased intestinal epithelial permeability has been proposed as a basic pathogenic event in Crohn's disease. Challenge of the mucosal immune ...system by the commensal gut flora would then result in chronic inflammation. Alternatively, increased permeability could be the result of inflammation. Our aim was to study intestinal permeability in refractory Crohn's disease before and after treatment with monoclonal chimeric antibodies directed against tumor necrosis factor (TNF) to investigate whether the abnormal permeability persists after control of inflammation.
Twenty-three patients with active Crohn's disease were evaluated before and 4 wk after a single infusion of 5 mg/kg infliximab. Intestinal permeability was studied by measurement of urinary excretion of 51Cr-EDTA after oral intake.
The increased permeation of 51Cr-EDTA through the small intestine (1.63% interquartile range IQR 1.06-2.07) and the overall permeation (3.27% IQR 2.40-4.38) before therapy decreased significantly after infliximab infusion to values (1.04% IQR 0.74-1.54 and 2.42% IQR 2.03-2.80, respectively) in the range of those found in normal volunteers (1.12% IQR 0.85-1.58 and 2.28% IQR 1.88-2.86, respectively).
Inhibiting the proinflammatory cytokine tumor necrosis factor dramatically reduces gut inflammation and largely restores the gut barrier in Crohn's disease. Our data confirm the central role of TNF in gut barrier modulation in inflammatory conditions in vivo.
Intratumoral injection of ilixadencel, consisting of proinflammatory allogeneic dendritic cells, before nephrectomy, followed by sunitinib treatment after nephrectomy showed a trend for improved ...tumor response rate and overall survival, compared with sunitinib monotherapy.
The prognosis of patients with synchronous metastatic renal cell carcinoma (mRCC) is poor. Whereas single-agent tyrosine kinase inhibition (TKI) is clearly insufficient, the effects can be enhanced by combinations with immune checkpoint inhibitors. Innovative treatment options combining TKI and other immune-stimulating agents could prove beneficial.
To evaluate the clinical effects on metastatic disease when two doses of allogeneic monocyte-derived dendritic cells (ilixadencel) are administrated intratumorally followed by nephrectomy and treatment with sunitinib compared with nephrectomy and sunitinib monotherapy, in patients with synchronous mRCC.
A randomized (2:1) phase 2 multicenter trial enrolled 88 patients with newly diagnosed mRCC to treatment with the combination ilixadencel/sunitinib (ILIXA/SUN; 58 patients) or sunitinib alone (SUN; 30 patients).
The primary endpoints were 18-mo survival rate and overall survival (OS). A secondary endpoint was objective response rate (ORR) assessed up to 18 mo after enrollment. Statistic evaluations included Kaplan-Meier estimates, log-rank tests, Cox regression, and stratified Cochran-Mantel-Haenszel tests.
The median OS was 35.6 mo in the ILIXA/SUN arm versus 25.3 mo in the SUN arm (hazard ratio 0.73, 95% confidence interval 0.42–1.27; p = 0.25), while the 18-mo OS rates were 63% and 66% in the ILIXA/SUN and SUN arms, respectively. The confirmed ORR in the ILIXA/SUN arm were 42.2% (19/45), including three patients with complete response, versus 24.0% (six/25) in the SUN arm (p = 0.13) without complete responses. The study was not adequately powered to detect modest differences in survival.
The study failed to meet its primary endpoints. However, ilixadencel in combination with sunitinib was associated with a numerically higher, nonsignificant, confirmed response rate, including complete responses, compared with sunitinib monotherapy.
We studied the effects of intratumoral vaccination with ilixadencel followed by sunitinib versus sunitinib only in a randomized phase 2 study. The combination treatment showed numerically higher numbers of confirmed responses, suggesting an immunologic effect.
Intratumoral administration of an immune primer is a therapeutic vaccine strategy aimed to trigger dendritic cell (DC)-mediated cross-presentation of cell-associated tumor antigens to cytotoxic CD8
+
...T cells without the need for tumor antigen characterization. The prevailing view is that these cross-presenting DCs have to be directly activated by pathogen-associated molecular patterns (PAMPS), including Toll-like receptor ligands or live microbial agents like oncolytic viruses. Emerging data are however challenging this view, indicating that the cross-presenting machinery in DCs is suboptimally activated by direct PAMP recognition, and that endogenous inflammatory factors are the main drivers of DC-mediated cross-presentation within the tumor. Here we present preclinical mode of action data, CMC and regulatory data, as well as initial clinical data on ilixadencel. This cell-based drug product is an off-the-shelf immune primer, consisting of pro-inflammatory allogeneic DCs secreting high amounts of pro-inflammatory chemokines and cytokines at the time of intratumoral administration. The mechanism of action of ilixadencel is to induce recruitment and activation of endogenous immune cells, including NK cells that subsequently promotes cross-presentation of cell-associated tumor antigens by co-recruited DCs.
Background
The majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic ...inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma.
Methods
The trial was a single arm phase I trial assessing safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Three patients were progressing while on sunitinib (second line), one on regorafenib (third line), and two on pazopanib (fourth line). TKI treatment was maintained throughout, while two intratumoral injections of ilixadencel (10 × 10
6
viable and HLA-DR expressing cells per dose) were administered.
Results
No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. One patient (on third line regorafenib) had stable disease for 9 months and another patient (on second line sunitinib) had stable disease at end of study (12 months) as per RECIST 1.1. These two patients developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. The median progression-free survival (PFS) was 4.0 months.
Conclusion
Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation.
Clinical trial registration
www.clinicaltrials.gov
; NCT: 02432846; registration date: February 22, 2016.
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Background: Ilixadencel is a cell-based, off-the-shelf product based on allogeneic monocyte-derived inflammatory cells aimed to prime an anti-cancer immune response when injected ...intratumorally. The present single arm Phase I trial (ClinicalTrials.gov Identifier: NCT02686944) assessed the safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Methods: Three GIST patients were progressing while on sunitinib (second-line), one on regorafenib (third-line), and two on pazopanib (fifth-line). Treatment consisted of two intratumoral injections of ilixadencel two weeks apart. If further tumor progression was observed at the 3-month follow up, the TKI was withdrawn and the subject performed an end of study visit. If stable disease or objective response was observed, the subject continued with the TKI until progression of disease. Results: No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. Two patients had stable disease as best response; one of these patients (on third-line regorafenib) progressed at 12 months and the other (a patient on second-line sunitinib) showed continued stable disease at end of study (12 months) as per RECIST 1.1. These two patients also developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. No serious adverse events were found to be possibly or probably related to ilixadencel administrtion. Conclusions: Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial information: 02686944.
The third multistakeholder Paediatric Strategy Forum organised by ACCELERATE and the European Medicines Agency focused on immune checkpoint inhibitors for use in combination therapy in children and ...adolescents. As immune checkpoint inhibitors, both as monotherapy and in combinations have shown impressive success in some adult malignancies and early phase trials in children of single agent checkpoint inhibitors have now been completed, it seemed an appropriate time to consider opportunities for paediatric studies of checkpoint inhibitors used in combination.
Among paediatric patients, early clinical studies of checkpoint inhibitors used as monotherapy have demonstrated a high rate of activity, including complete responses, in Hodgkin lymphoma and hypermutant paediatric tumours. Activity has been very limited, however, in more common malignancies of childhood and adolescence. Furthermore, apart from tumour mutational burden, no other predictive biomarker for monotherapy activity in paediatric tumours has been identified. Based on these observations, there is collective agreement that there is no scientific rationale for children to be enrolled in new monotherapy trials of additional checkpoint inhibitors with the same mechanism of action of agents already studied (e.g. anti-PD1, anti-PDL1 anti-CTLA-4) unless additional scientific knowledge supporting a different approach becomes available. This shared perspective, based on scientific evidence and supported by paediatric oncology cooperative groups, should inform companies on whether a paediatric development plan is justified. This could then be proposed to regulators through the available regulatory tools. Generally, an academic-industry consensus on the scientific merits of a proposal before submission of a paediatric investigational plan would be of great benefit to determine which studies have the highest probability of generating new insights.
There is already a rationale for the evaluation of combinations of checkpoint inhibitors with other agents in paediatric Hodgkin lymphoma and hypermutated tumours in view of the activity shown as single agents. In paediatric tumours where no single agent activity has been observed in multiple clinical trials of anti-PD1, anti-PDL1 and anti-CTLA-4 agents as monotherapy, combinations of checkpoint inhibitors with other treatment modalities should be explored when a scientific rationale indicates that they could be efficacious in paediatric cancers and not because these combinations are being evaluated in adults.
Immunotherapy in the form of engineered proteins (e.g. monoclonal antibodies and T cell engaging agents) and cellular products (e.g. CAR T cells) has great therapeutic potential for benefit in paediatric cancer. The major challenge for developing checkpoint inhibitors for paediatric cancers is the lack of neoantigens (based on mutations) and corresponding antigen-specific T cells. Progress critically depends on understanding the immune macroenvironment and microenvironment and the ability of the adaptive immune system to recognise paediatric cancers in the absence of high neoantigen burden. Future clinical studies of checkpoint inhibitors in children need to build upon strong biological hypotheses that take into account the distinctive immunobiology of childhood cancers in comparison to that of checkpoint inhibitor responsive adult cancers.
•Paediatric Strategy Forums facilitate dialogue between all stakeholders.•Checkpoint inhibitors are active in Hodgkin lymphoma and hypermutant tumours.•Very limited activity as single agents in other paediatric tumours.•No rationale for other checkpoint inhibitors with the same mechanism of action.•Synthetic immunotherapy may be an effective combination with checkpoint inhibitors.
ABSTRACTGut -brain communications disorders in irritable bowel syndrome (IBS) are associated with intestinal microbiota composition, increased gut permeability, and psychosocial disturbances. ...Symptoms of IBS are difficult to medicate, and hence much research is being made into alternative approaches. This study assesses the potential of a treatment with pasteurized Akkermansia muciniphila for alleviating IBS-like symptoms in two mouse models of IBS with different etiologies. Two clinically relevant animal models were used to mimic IBS-like symptoms in C57BL6/J mice: the neonatal maternal separation (NMS) paradigm and the Citrobacter rodentium infection model. In both models, gut permeability, colonic sensitivity, fecal microbiota composition and colonic IL-22 expression were evaluated. The cognitive performance and emotional state of the animals were also assessed by several tests in the C. rodentium infection model. The neuromodulation ability of pasteurized A. muciniphila was assessed on primary neuronal cells from mice dorsal root ganglia using a ratiometric calcium imaging approach. The administration of pasteurized A. muciniphila significantly reduced colonic hypersensitivity in both IBS mouse models, accompanied by a reinforcement of the intestinal barrier function. Beneficial effects of pasteurized A. muciniphila treatment have also been observed on anxietylike behavior and memory defects in the C. rodentium infection model. Finally, a neuroinhibitory effect exerted by pasteurized A. muciniphila was observed on neuronal cells stimulated with two algogenic substances such as capsaicin and inflammatory soup. Our findings demonstrate novel anti-hyperalgesic and neuroinhibitory properties of pasteurized A. muciniphila, which therefore may have beneficial effects in relieving pain and anxiety in subjects with IBS.
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Background: Ilixadencel is a cell-based allogeneic off-the-shelf product aimed to prime anti-cancer immune response when injected intratumorally. The present randomized Phase II ...multicenter trial (MERECA; NCT02432846) evaluated intratumoral ilixadencel administration (2 doses 2 weeks apart) pre-nephrectomy followed by sunitinib post-nephrectomy compared with sunitinib monotherapy post-nephrectomy as first-line systemic therapy in patients with newly diagnosed synchronous metastatic renal cell carcinoma (mRCC). Methods: Patients were randomly assigned at two-to-one ratio to the combination (COMBO) or sunitinib (SUN) arm. Overall survival (OS) was assessed from enrollment while progression free survival (PFS) and tumor response was assessed per RECIST 1.1 (independent blinded central review) from start of sunitinib. Results: From April 2014 to January 2017, 88 patients (58 COMBO, 30 SUN) were randomized. In the COMBO arm, 2 patients did not receive ilixadencel, 10 did not receive sunitinib, and 1 did not have any follow up CT-scan. Five patients in the SUN arm never received sunitinib. Five patients (11%) in the COMBO arm had a complete response as best response versus one patient (4%) in the SUN arm. Confirmed ORR was 42.2 % (19/45) versus 24.0% (6/25). Median Duration of Response was 7.1 months versus 2.9 months. Median PFS was 11.8 months versus 11.0 months. Median OS has still not been reached in either group. As of July 2019, 57% and 43% were alive in the COMBO and SUN arms, respectively. Treatment with ilixadencel did not add any treatment-related Grade 3-4 Adverse Events. Conclusions: Compared to sunitinib monotherapy, combined treatment with ilixadencel followed by sunitinib demonstrated higher confirmed ORR, including several complete responses and longer duration of response, in patients with newly diagnosed synchronous mRCC. Clinical trial information: 02432846.
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