Immunotherapy is currently ineffective for nearly all pancreatic ductal adenocarcinomas (PDAC), largely due to its tumor microenvironment (TME) that lacks antigen-experienced T effector cells (Teff). ...Vaccine-based immunotherapies are known to activate antigen-specific Teffs in the peripheral blood. To evaluate the effect of vaccine therapy on the PDAC TME, we designed a neoadjuvant and adjuvant clinical trial of an irradiated, GM-CSF-secreting, allogeneic PDAC vaccine (GVAX).
Eighty-seven eligible patients with resectable PDAC were randomly assigned (1:1:1) to receive GVAX alone or in combination with two forms of low-dose cyclophosphamide. Resected tumors following neoadjuvant immunotherapy were assessed for the formation of tertiary lymphoid aggregates (TLA) in response to treatment. The clinical endpoints are disease-free survival (DFS) and overall survival (OS).
The neoadjuvant treatment with GVAX either alone or with two forms of low-dose cyclophosphamide is safe and feasible without adversely increasing the surgical complication rate. Patients in Arm A who received neoadjuvant and adjuvant GVAX alone had a trend toward longer median OS (35.0 months) than that (24.8 months) in the historical controls who received adjuvant GVAX alone. However, Arm C, who received low-dose oral cyclophosphamide in addition to GVAX, had a significantly shorter DFS than Arm A. When comparing patients with OS > 24 months to those with OS < 15 months, longer OS was found to be associated with higher density of intratumoral TLA.
It is safe and feasible to use a neoadjuvant immunotherapy approach for PDACs to evaluate early biologic responses. In-depth analysis of TLAs is warranted in future neoadjuvant immunotherapy clinical trials.
Abstract
Background and Aims
Kidney Supportive Care (KSC) is a standard of care for patients with advanced kidney failure where health systems are responding to the high burden of experienced ...physical and psychosocial symptoms. While symptom burden in those receiving haemodialysis (HD) has been previously studied, there is a paucity of studies examining the symptom experience of those on peritoneal dialysis (PD). The aim of this study was to describe symptom burden experienced by patients on PD and HD seen in a KSC clinic.
Method
This retrospective cohort study analysed data of patients attending a multisite KSC clinic in Brisbane, Australia between February 2016 and October 2022. Patient demographic characteristics, dialysis modality, Charlson Comorbidity Index (CCI) scores and Integrated Palliative Care Outcome Scale Renal (IPOS-Renal) scores were extracted from clinical records. Intra-person physical symptom burden at baseline, determined by IPOS-Renal physical scores, was compared to the scores at the subsequent clinic visit where applicable. Descriptive and group analyses were performed. P values < 0.05 were considered significant.
Results
Of the 232 participants, 31 were on PD and 201 were on HD. Median age was 68 years (IQR 25), 57.3% were male, and 55.2% were referred to KSC primarily for symptom management. There were no significant differences in demographic characteristics and referral reasons between groups. At baseline (entry to KSC clinic), median CCI was 9 (IQR 4) and mean total IPOS score was 16.59 $ \pm $ 8.87. The results were not significantly different between groups. The most prevalent symptoms were weakness (76%), poor mobility (74.2%), pain (60.9%), drowsiness (55.8%) and dyspnoea (54.9%), which was similar between groups. Those on PD had a significantly higher prevalence of severe and overwhelming rated diarrhoea (p = 0.01) and pruritis (p 0.03) compared to those on HD.
145 participants attended a second clinic appointment, of which 23 were on PD and 122 on HD, a median of 91 days later (IQR 106 days). Individual symptom burden was not significantly different at the second clinic appointment. However, there was a significant improvement in the subcategory of pruritis in the PD cohort by the second appointment (mean change 0.45 $ \pm \ $0.51, p = 0.02).
Conclusion
Our results show that patients on PD have a similar burden of comorbidities and symptoms to patients on HD, as well as unique symptoms to address. In addition to the five most prevalent symptoms, pruritis and diarrhoea were identified as experienced more severely by the PD cohort. Of these, pruritis was shown to improve between KSC appointments, which may suggest that the interventions commenced at the first appointment were effective. These findings also indicate the need for further bowel assessment and management for patients on PD by KSC clinicians in our health service. This KSC cohort had fewer patients on PD than HD. Further studies are needed to elicit if there is a selection bias or if there is an underappreciation for the symptom burden of this cohort, especially given PD is delivered outside of the hospital system.
A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients ...with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.
BackgroundData analysis of specimens from prior clinical trials identified the immune co-simulatory molecule CD137 within the tumor microenvironment(TME) of pancreatic ductal adenocarcinoma(PDAC) ...that remain to be activated following vaccine induced T cell and PD-1 inhibitory treatments. The requirement of CD137 was subsequently supported by preclinical studies. Therefore, we conducted a clinical trial of combining anti-CD137 agonist antibody urelumab, anti-PD-1 antagonist antibody nivolumab and a GM-CSF-secreting allogeneic tumor cell vaccine(GVAX) as neoadjuvant and adjuvant therapy for resectable PDAC.MethodsPatients of >=18 years old with radiographic evidence of resectable PDACs were eligible for Arm C of this trial(NCT02451982) with an accrual goal of 10 evaluable subjects. The primary objective was to evaluate changes in numbers of tumor infiltrating CD137+CD8+ T cells. Secondary objectives were safety, overall survival, disease free survival, and other immune parameters. Patients who underwent R0/R1 resection were considered evaluable. All subjects received 480mg nivolumab and 8 mg urelumab both intravenously one day prior to receiving GVAX intradermally and two weeks before surgical resection (figure 1). After surgery, eligible patients continued to receive 5 combination immunotherapy cycles in addition to standard of care chemotherapy. Treatment-related toxicity and perioperative complications are monitored.ResultsBetween February 2019 and August 2020, we completed planned enrollment and treated 10 evaluable patients, who underwent R0 surgical resection of their PDACs. Nausea is the most common adverse event attributed to urelumab (table 1). Other adverse events and perioperative complication were observed in a type, frequency and degree similar to other treatment arms. After repeated dosing, 1 patient demonstrated grade 1 arthritis; 1 patient demonstrated self-limited, transient grade 2 elevated LFTs; 1 patient developed grade 3 rashes, which responded quickly to oral steroid and did not recur after re-dosing. Interestingly, two out of 10 resected patients demonstrated CAP grade 2 pathologic responses in the resected PDACs after a single neoadjuvant treatment; this was not observed with other treatment cohorts(GVAX alone or GVAX+nivolumab) in this neoadjuvant platform trial. Nine out of 10 resected patients remain disease free after a median follow up of 12 months. Immunology endpoints are being analyzed by multiplex immunohistochemistry, DNA sequencing for neoantigen loads, and RNA/TCR sequencing.Abstract 812 Figure 1Study SchemaAbstract 812 Table 1Adverse EventsConclusionsPrevious observations of liver toxicity with urelumab or other T cells agonists and severe immune-related adverse events were not observed in this trial, suggesting urelumab(8 mg) is safe as neoadjuvant/adjuvant therapy in this resectable PDAC patient population. Immune and clinical efficacy of anti-CD137 agonist-based combinations warrant further investigation.AcknowledgementsThis is an investigator initiated clinical trial and supported by the funding from the Rare Disease Program at Bristol-Myers Squibb.Trial RegistrationNCT02451982Ethics ApprovalThe study was approved by the Johns Hopkins Medical Institution Institutional Review Board, approved number IRB00050517
Treatment of advanced pancreatic cancer with a single therapeutic at a maximal dose has been largely ineffective at increasing survival. Combination therapies are commonly studied but often limited ...by toxicity. We previously showed that low-dose multiagent therapy with gemcitabine, docetaxel (taxotere), capecitabine (xeloda), and cisplatin (GTX-C) was safe, well tolerated, and effective (NCT01459614). Here, we hypothesize that adding irinotecan to GTX-C may improve survival with minimal toxicity.
Patients with treatment-naïve metastatic pancreatic adenocarcinoma were treated with gemcitabine, docetaxel (taxotere), capecitabine (xeloda), cisplatin, and irinotecan (GTX-CI). Treatment consisted of capecitabine 500 mg twice daily on days 1-14 and gemcitabine 300 to 500 mg/m
, docetaxel 20 mg/m
, cisplatin 15 to 20 mg/m
, and irinotecan 20 to 60 mg/m
on days 4 and 11 of a 21-day cycle. The primary objective was 9-month overall survival (OS). Secondary objectives included response rate (RR), disease control rate (DCR), progression-free survival (PFS), and OS.
The regimen was well tolerated. The recommended phase II dose was gemcitabine 500 mg/m
, docetaxel 20 mg/m
, capecitabine 500 mg po bid, cisplatin 20 mg/m
, and irinotecan 20 mg/m
. Median follow-up in phase II was 11.02 months (2.37-45.17). Nine-month OS rate was 57% 95% confidence interval (CI): (41-77). RR was 57% 95% CI: (37-75) 50% PR and 7% CR. DCR was 87% 95% CI: (69-96). Median OS and PFS were 11.02 95% CI: (8.54-21.09) and 8.34 95% CI: (6.34-NA) months, respectively.
The addition of irinotecan to GTX-C was safe and well tolerated. While the study did not meet its primary objective, the responses were clinically meaningful using a well-tolerated regimen.
We aimed to optimize the previously reported efficacious regimen of low-dose multiagent therapy with GTX-C for the treatment of metastatic pancreatic ductal adenocarcinoma by adding irinotecan. The primary objective was not met, but GTX-CI was well tolerated. The RR of 57%, median PFS of 8.3 months, median OS of 11 months, and 36-month OS rate of 19% suggest clinical benefit. Further optimization of this regimen is warranted.
Actively involving service users, patients and carers in the creation and development of health research in the UK has recently come under pressure to articulate why involvement is a good use of ...resources. This has led to a growing interest in creating ways to measure the impact of involving patients, service users and carers in research. However, there is a concern that fundamentally important issues about why we should meaningfully involve service users, patients and carers are missing from the current measurement discourses and activities undertaken in relation to measurement. This paper argues three distinct points, and is based on the experience of the authors working with Folk.us as well as other fields of involvement. Firstly, there should be an open and honest debate about what is meant by the need to measure and assess the effects of involving people in research, addressing issues such as who benefits from the measurement and assessment and why the involvement is being done. Secondly, if at the conclusion of the debate it is deemed necessary to measure and assess, there must be a full and frank discussion about what criteria are appropriate for the proper reporting of involvement activities. This discussion would need to include the less obvious activities that are crucial to active involvement, such as administrative tasks, and where such activities would sit within these criteria. Thirdly, we will consider when such criteria should be applied, at the beginning or end of projects and, indeed, whether one can categorize the ‘beginning’ or ‘end’ of involvement.
SUMMARY
Transition onto haemodialysis is a time of increased psychosocial difficulty, yet, many renal patients exhibit personal resilience in continuing to lead productive lives. Using a positive ...psychological methodology, this qualitative study aims to identify factors identified by patients as helpful in the transition onto haemodialysis. Semi‐structured interviews were undertaken with 10 patients within six months of starting haemodialysis. Interpretive content analysis identified three main themes (each with subthemes) in patients’ accounts—preparation, cognitive style and social support. Limited differences arose between patients who underwent a gradual versus acute transition onto haemodialysis. Themes are discussed with reference to implications for practice development.
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