Levels and in vitro functional effects of circulating anti-hinge antibodies in melanoma patients receiving the immune checkpoint inhibitor pembrolizumab.

The efficacy of PD-1 monoclonals such as pembrolizumab can be modulated by the signals delivered via their Fc region. Tumour/inflammation associated proteases can generate F(ab')2 fragments of therapeutic monoclonals, and subsequent recognition of F(ab')2 epitopes by circulating anti-hinge antibodies (AHA) can then, potentially, link F(ab')2 binding to the target antigen with novel Fc signalling. Although elevated in inflammatory diseases, AHA levels in cancer patients have not been investigated and functional studies utilising the full repertoire of AHA present in sera have been limited. AHA levels in pembrolizumab treated melanoma patients (n = 23) were therefore compared to those of normal donors and adalimumab treated patients. A subset of melanoma patients and the majority of adalimumab patients had elevated levels of AHA reactive with F(ab')2 fragments of IgG4 anti-PD-1 monoclonals (nivolumab, pembrolizumab) and IgG1 therapeutic monoclonals (rituximab, adalimumab). Survival analysis was restricted by the small patient numbers but those melanoma patients with the highest levels (>75% percentile, n = 5) of pembrolizumab-F(ab')2 reactive AHA had significantly better overall survival post pembrolizumab treatment (p = 0.039). In vitro functional studies demonstrated that the presence of AHA+ sera restored the neutrophil activating capacity of pembrolizumab to its F(ab')2 fragment. Neither pembrolizumab nor its F(ab')2 fragments can induce NK cell or complement dependent cytotoxicity (CDC). However, AHA+ sera in combination with pembrolizumab-F(ab')2 provided Fc regions that could activate NK cells. The ability of AHA+ sera to restore CDC activity was more restricted and observed using only one pembrolizumab and one adalimumab patient serum in combination with rituximab- F(ab')2. This study reports the presence of elevated AHA levels in pembrolizumab treated melanoma patients and highlight the potential for AHA to provide additional Fc signaling. The issue of whether tumour associated proteolysis of PD-1 mAbs and subsequent AHA recognition impacts on treatment efficacy requires further study.

Intralesional SD-101 in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naïve Head and Neck Squamous Cell Carcinoma: Results from a Multicenter, Phase II Trial.

PURPOSE: To determine whether SD-101, a Toll-like receptor 9 agonist, potentiates the antitumor activity of anti-PD-1 antibodies in patients with anti-PD-1/PD-L1 naïve, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Patients with PD-1 Ab-naïve HNSCC received either 2 mg SD-101 injected in one to four lesions or 8 mg SD-101 injected into a single lesion weekly × 4 doses then every 3 weeks × 7 doses. Pembrolizumab was administered at 200 mg every 3 weeks. RESULTS: A total of 28 patients received 2 mg and 23 received 8 mg per injection, respectively. A total of 76% of patients had received prior systemic therapy. Combined positive score was ≥1 to < 20 in 35 patients (70%) and ≥ 20 in 15 patients (30%) of 50 patients with available data. There were 12 patients with grade ≥3 treatment-related adverse events (24%), and no treatment-related deaths. The objective response rate was 24% including 2 complete and 10 partial responses. The median duration of response was 7.0 [95% confidence interval (CI): 2.1-11.1] months. The response rate was higher in human papillomavirus-positive (HPV+) patients (44%, N = 16). Responses were not associated with PD-L1 expression levels or IFNγ-related gene expression at baseline. Responses were observed both in injected (32%) and in noninjected lesions (29%). Progression-free and overall survival at 9 months were 19.0% (95% CI: 9.1-31.7) and 64.7% (95% CI: 45.3-78.7), respectively. CONCLUSIONS: SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity.

Testing for dihydropyrimidine dehydrogenase deficiency in New Zealand to improve the safe use of 5-fluorouracil and capecitabine in cancer patients.

Dihydropyrimidine dehydrogenase deficiency is a rare inherited disorder. Approximately 3% of people of European ancestry are likely to have a partial deficiency in this enzyme. These individuals are typically asymptomatic until exposed to 5-fluorouracil (5-FU) or capecitabine (which forms 5-FU) for treatment of gastrointestinal or breast cancer. These individuals are then at considerably increased risk of severe to life-threatening adverse events. There are four well established risk variants within the DPYD gene that encodes dihydropyrimidine dehydrogenase. Although consensus guidelines for genotype-guided dosing of 5-FU and capecitabine have existed for a number of years, the implementation of this type of personalised medicine has not been widely adopted. This viewpoint covers the current state of knowledge about both genotype and phenotype testing, as well as the reported cost-savings and clinical effectiveness of pre-screening patients followed by dose-adjustment. Recent recommendations by agencies and professional societies, both in Europe and the USA, highlight the need for New Zealand oncologists to begin an informed discussion about whether it is now an appropriate time to advocate for routine access to testing for this enzyme deficiency in New Zealand cancer patients.

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.

BACKGROUND: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I-V and of grade III-V immune-related adverse events (irAEs) was 37% and 7%, respectively. METHODS: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes. RESULTS: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over ('crossover'). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 ('rechallenge'). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7-15.2) and the 3-year PFS rate was 32% (95% CI 25-40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48-83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6-NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I-IV irAE and 11 (6%) had a grade III-IV irAE. CONCLUSIONS: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged.

Influence of serum inflammatory cytokines on cytochrome P450 drug metabolising activity during breast cancer chemotherapy: a patient feasibility study.

Individual response to chemotherapy in patients with breast cancer is variable. Obesity and exercise are associated with better and worse outcomes, respectively, and it is known that both impact the systemic cytokine milieu. Cytochrome P450 (CYP) enzymes are responsible for the metabolism of many chemotherapy agents, and CYP enzyme activity has been shown to be modified by inflammatory cytokines in vitro and in vivo. Cytokine-associated changes in CYP metabolism may alter chemotherapy exposure, potentially affecting treatment response and patient survival. Therefore, better understanding of these biological relationships is required. This exploratory single arm open label trial investigated changes in in vivo CYP activity in twelve women treated for stage II or III breast cancer, and demonstrated for the first time the feasibility and safety of utilising the Inje phenotyping cocktail to measure CYP activity in cancer patients receiving chemotherapy. Relative CYP activity varied between participants, particularly for CYP2C9 and CYP2D6, and changes in serum concentrations of the inflammatory cytokine monocyte chemoattractant protein 1 inversely correlated to CYP3A4 activity during chemotherapy. Future use of phenotyping cocktails in a clinical oncology setting may help guide drug dosing and improve chemotherapy outcomes.Clinical Trial Registration: Trial was retrospectively registered to the Australia New Zealand Clinical Trial Registry (ANZCTR). ACTRN12620000832976, 21 Aug 2020, https://www.anzctr.org.au/ACTRN12620000832976.aspx .

Functional effects of immune complexes formed between pembrolizumab and patient-generated anti-drug antibodies.

The PD-1-targeting IgG4 antibody pembrolizumab has significant anti-tumor activity in a proportion of stage IV melanoma patients. A subset of patients develop anti-drug antibodies (ADA) which can form immune complexes (IC) with pembrolizumab. Although IC can induce powerful, Fc-mediated, immune-regulatory effects, their functional impact during pembrolizumab treatment is unclear. The functional effects of IC generated in vitro using pembrolizumab and patient-derived ADA was, therefore, investigated. Screening identified a patient whose trough serum samples from three treatment cycles contained both ADA with neutralizing activity and low levels of pembrolizumab. This patient responded well to therapy over 2 years and had ongoing, infusion-related, hypersensitivity reactions despite the later absence of detectable ADA. The components of IC were mimicked by forming a complex of pembrolizumab by absorption onto a solid phase with or without subsequent exposure to the ADA+ patient sera. Complexes comprised of pembrolizumab alone significantly inhibited TLR4 (LPS)-driven IL-10 production by PBMC and stimulated the generation of reactive oxygen species by granulocytes. In contrast, soluble and solid-phase F(ab´)2 fragments of pembrolizumab had no effect demonstrating the requirement for cross-linked Fc regions. IC containing pembrolizumab and ADA could additionally induce complement and NK activation. The results of this study demonstrate that, when oligomerized, the Fc region of pembrolizumab alone can provide immuno-regulatory signals. Furthermore, IC containing both pembrolizumab and patient-generated ADA can induce additional signals. These Fc-mediated signals may modulate both hypersensitivity reactions and anti-tumor responses associated with pembrolizumab therapy.

The effectiveness of pancreatic enzyme replacement therapy for malabsorption in advanced pancreatic cancer, a pilot study.

Advanced adenocarcinoma of the pancreas has a globally poor prognosis. One of the characteristic features of pancreatic cancer (PC) is pancreatic exocrine insufficiency (PEI). This leads to a malabsorption syndrome and subsequent digestive symptoms. Given the high prevalence of PEI and malabsorption in PC, empiric use of pancreatic enzyme replacement therapy (PERT) is recommended. The aim of this pilot study was to determine the potential efficacy of PERT in improving symptoms and quality of life in those with metastatic PC. The study recruited patients with advanced PC referred to a specialist palliative care service. Following an initial assessment, patients were commenced on pancrealipase 25,000IU (Creon) and reassessed after 1 week and 3 weeks post-initiation of supplementation. These assessments included demographics, malabsorption symptom checklist, and completion of two validated quality-of-life questionnaires, the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-PAN26. PERT was associated with statistically significant improvement of symptoms in both the general (QLQ-C30) and pancreatic cancer specific tool (PAN26). Within 1 week of PERT initiation, there was a reduction in diarrhoea scores (26 vs. 8, p<0.005), pancreatic and hepatic pain (47 vs. 33 and 24 vs. 11, respectively, p<0.05). After 3 weeks, there were significant improvements in pancreatic pain and bloating/gas symptoms (47 vs. 26 and 46 vs. 26, respectively, p< 0.005). PERT appears to have the potential to improve symptoms of malabsorption in patients with metastatic PC.

Randomized Phase IIA Trial of Gemcitabine Compared With Bleomycin Plus Vincristine for Treatment of Kaposi's Sarcoma in Patients on Combination Antiretroviral Therapy in Western Kenya.

PURPOSE: Kaposi's sarcoma (KS) is a spindle cell tumor resulting from growth dysregulation in the setting of infection with human herpes virus-8 (also called KS herpes virus). Advanced KS is characterized by poor responses to antiretroviral therapy and some of the chemotherapy readily accessible to patients in low-resource areas. Gemcitabine induced partial and complete regression of AIDS-associated KS (AIDS-KS) in 11 of 24 patients in a pilot study. The current study compares the antimetabolite gemcitabine with the standard care bleomycin and vincristine (BV) in the treatment of chemotherapy-naïve patients with AIDS-KS in a resource-limited setting. PATIENTS AND METHODS: Patients with persistent or progressive KS despite treatment with combined antiretroviral therapy were randomly assigned to receive gemcitabine 1,000 mg/m2 or bleomycin 15 IU/ m2 and vincristine 1.4 mg/m2 given twice weekly. The main end point was objective response by bidirectional measurement, adverse events, and quality of life after three cycles of chemotherapy. RESULTS: Of 70 participants enrolled, 36 received gemcitabine and 34 received BV. Complete response was achieved in 12 patients (33.3%) in the gemcitabine arm and six (17.6%) in the BV arm ( P = .175). The partial response rate was 52.8% (n = 19) in the gemcitabine arm and 58.8% (n = 20) in the BV arm. Both study arms reported similar neurologic and hematologic adverse events; there was statistically significant baseline to post-treatment improvement in health-related quality-of-life scores. CONCLUSION: The results of this randomized, phase IIA trial demonstrate gemcitabine activity in chemotherapy-naïve patients with AIDS-KS, on the basis of response rates, adverse events, and health-related quality-of-life scores.

Quantification and clinical application of carboplatin in plasma ultrafiltrate.

Carboplatin is a chemotherapy drug used in a variety of cancers with the primary toxicity being exposure-dependant myelosuppression. We present the development and validation of a simple, robust inductively coupled plasma mass spectrometry (ICP-MS) method to measure carboplatin in plasma ultrafiltrate. Plasma ultrafiltrates samples were prepared using Amicon Ultra 30,000da cut-off filters and then diluted with ammonia EDTA before ICP-MS analysis. The assay was validated in the range 0.19-47.5mg/L carboplatin in ultrafiltrate. The assay was linear (r2>0.9999), accurate (<6% bias, 12% bias at LLOQ) and precise (intra- and inter-day precision of <3% coefficient of variation). No matrix effects were observed between plasma ultrafiltrate and aqueous platinum calibrators and recovery was complete. The assay was applied to 10 clinical samples from patients receiving carboplatin. Incurred sample reanalysis showed reproducible values over 3 analysis days (<6% CV). As plasma stability prior to ultrafiltration has been a major concern in previous clinical studies this was studied extensively at room temperature (22°C) over 24h. Carboplatin was found to be stable in both spiked plasma (n=3) and real patient samples (n=10) at room temperature for up to 8h before ultrafiltration. This makes routine measurement of carboplatin concentrations in clinical settings feasible.

Body mass index (BMI): association with clinicopathological factors and outcome of women with newly diagnosed breast cancer in New Zealand.

AIMS: To identify associations of obesity with breast cancer and its outcome in a New Zealand population, including those treated with adjuvant chemotherapy. METHODS: Data was collated from four regional Breast Cancer Registers, Auckland, Waikato, Wellington and Christchurch, for all women with newly diagnosed breast cancer, with weight and height recorded. Associations of body mass index (BMI) with patient and tumour characteristics, and all-cause mortality were determined. RESULTS: BMI was available for 5,458 new breast cancers, 27% of all registered. BMI was normal (18.5-24.9kg/m2) for 32.7%, overweight (25-29.9kg/m2) 31.1%, obese (>30kg/m2) 34.9% and 1.3% underweight (<18.5kg/m2). Median age was 55 years. Higher BMI was associated with non-European ethnicity, post-menopausal status, screen-detection, older age and tumours with higher grade, greater size and positive progesterone receptors. Mean survival for women younger than 56 years was 18.0 years for normal BMI and 14.8 years for BMI >35 (p=0.055, Log-rank). Women younger than 56 years treated with adjuvant chemotherapy had lower survival if obese compared with normal BMI (p=0.055, Log-rank). CONCLUSIONS: High BMI was associated with larger tumours, of higher grade, progesterone receptor positive and post-menopausal status. Obese pre-menopausal women treated with adjuvant chemotherapy had a trend to poorer outcome.

Mind the gap: An analysis of foregone health gains from unfunded cancer medicines in New Zealand.

Publicly funded cancer medicines listed on the New Zealand Pharmaceutical Schedule were compared with those listed on the Australian Pharmaceutical Benefits Scheme. To quantify the health gains offered by the cancer medicines funded in Australia but not in New Zealand, clinical trial data reporting median progression-free survival (PFS) and overall survival (OS) were sought. The differences in the median PFS and OS for the unfunded medicines, relative to the comparator medicine funded in NZ, were then assessed against the American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC) recommended targets for clinically meaningful health gains. Our analysis confirms that, whilst New Zealand funds fewer cancer medicines than Australia, most of the additional medicines funded in Australia do not deliver clinically meaningful health gains as defined by the ASCO-CRC guidance. This suggests that New Zealand is not missing substantive opportunities for improvements to New Zealand's cancer survival rates through additional medicines funding. A policy of funding more new cancer medicines in order to achieve numerical parity with Australia or other countries would not result in substantive health improvement and would cost significantly more, and investing the millions of dollars needed to achieve funding parity with other countries would not represent good value for money in terms of delivering the best health outcomes for all New Zealanders, rather selective funding of new medicines that demonstrate clear clinical benefit and that are cost-effective and affordable is the sensible approach.

Successes and challenges of establishing a cervical cancer screening and treatment program in western Kenya.

OBJECTIVE: To describe the challenges and successes of integrating a public-sector cervical screening program into a large HIV care system in western Kenya. METHODS: The present study was a programmatic description and a retrospective chart review of data collected from a cervical screening program based on visual inspection with acetic acid (VIA) between June 2009 and October 2011. RESULTS: In total, 6787 women were screened: 1331 (19.6%) were VIA-positive, of whom 949 (71.3%) had HIV. Overall, 206 women underwent cryotherapy, 754 colposcopy, 143 loop electrical excision procedure (LEEP), and 27 hysterectomy. Among the colposcopy-guided biopsies, 27.9% had severe dysplasia and 10.9% had invasive cancer. There were 68 cases of cancer, equating to approximately 414 per 100000 women per year. Despite aggressive strategies, the overall loss to follow-up was 31.5%: 27.9% were lost after a positive VIA screen, 49.3% between biopsy and LEEP, and 59.6% between biopsy and hysterectomy/chemotherapy. CONCLUSION: The established infrastructure of an HIV treatment program was successfully used to build capacity for cervical screening in a low-resource setting. By using task-shifting and evidence-based, low-cost approaches, population-based cervical screening in a rural African clinical network was found to feasible; however, loss to follow-up and poor pathology infrastructure remain important obstacles.

Epidemiology of diagnosed childhood cancer in Western Kenya.

SETTING: Basic epidemiological information on childhood cancer in Western Kenya is lacking. This deficit obstructs efforts to improve the care and survival rates of children in this part of the world. OBJECTIVE: Our study provides an overview of childhood cancer patients presenting for treatment in Western Kenya. DESIGN: A retrospective analysis of childhood cancer patients presenting for treatment in Western Kenya was carried out using information from three separate databases at the Moi Teaching and Referral Hospital in Eldoret. All patients aged 0-19 years first presenting between January 2006 and January 2010 with a newly diagnosed malignancy were included. RESULTS: A total of 436 children with cancer were registered during the period. There were 256 (59%) boys and 180 (41%) girls with a male/female ratio of 1.4:1. The group aged 6-10 years contained most children (29%). Median age at admission was 8 years. Non-Hodgkin's lymphoma was the most common type of cancer (34%), followed by acute lymphoblastic leukaemia (15%), Hodgkin's lymphoma (8%), nephroblastoma (8%), rhabdomyosarcoma (7%), retinoblastoma (5%) and Kaposi's sarcoma (5%). Only four (1%) children with brain tumours were documented. Ewing's sarcoma was not diagnosed. CONCLUSIONS: Our study provides an overview of childhood cancer patients presenting for treatment in Western Kenya. The distribution of malignancies is similar to findings from other equatorial African countries but differs markedly from studies in high-income countries. The new comprehensive cancer registration system will be continued and extended to serve as the basis for an evidence-based oncology program. Eventually this may lead to improved clinical outcomes.

Protocol development for ovarian cancer treatment in Kenya: a brief report.

INTRODUCTION: Ovarian cancer is a leading cause of cancer death for Kenyan women. Most women are diagnosed with an advanced stage of disease. The current North American standard of care includes surgery followed by carboplatin and paclitaxel. Neither drug is available for Kenyan women. We performed a literature search investigating chemotherapy in low resource countries with the aim to write an evidence-based chemotherapy protocol for women diagnosed with ovarian cancer in Eldoret, Kenya, at the Moi Teaching and Referral Hospital. METHODS: We systematically searched PubMed and EMBASE for articles describing chemotherapy treatment outcomes of ovarian epithelial cancer in low-resource settings. After data analysis, a secondary review was undertaken on randomized controlled trials(RCTs) aligning with chemotherapy availability in Kenya. RESULTS: We identified 1184 articles. Fourteen met our criteria: ovarian epithelial cancer,low resource, chemotherapy use, and survival or response data. No publications were RCTs or had a cohort larger than 100 patients. There was no consistency in drug choice between studies. After this search, we reviewed commonly quoted and relevant RCTs and meta-analyses conducted on ovarian cancer since the 1980s. Although RCTs in the developed world suggest carboplatin and taxol provide optimal survival benefit, these drugs are unavailable in Kenya. Cyclophosphamide and cisplatin provide the next most optimal survival benefit, with acceptable and manageable toxicity. Because these drugs are more available and affordable in Kenya, we have developed a protocol recommending their use, which has been accepted by the Moi Teaching and Referral Hospital. CONCLUSIONS: Currently, there is a paucity of published RCTs that may guide treatment in low-resource settings. One considerable barrier to establishing and evaluating chemotherapy protocols in low-resource settings may be the cost of chemotherapy drugs. There needs to be an international movement to make cancer chemotherapeutics available at lower prices in low-resource settings.

Independent influence of dietary protein on markers of kidney function and disease in obesity.

Obesity is associated with glomerular hyperfiltration and increased urinary protein excretion, as well as structural and functional changes that lead to kidney disease and failure. Dietary protein mimics obesity's effects on the glomerular filtration rate (GFR) and proteinuria and, in certain circumstances, may have the potential to adversely affect kidney function. Here we tested the hypothesis that dietary protein independently explains elevations in the GFR and proteinuria found in obese persons with a normal serum creatinine. Seventeen patients were randomized in a double-blind, crossover fashion for 1-week periods to high (140 g/day) and low (50 g/day) protein diets with a 1-week washout interval separating these periods. High protein consumption was associated with a very modest but significant increase in the GFR of 5 ± 6 ml/min. Hence, while dietary protein does modulate kidney parameters, it is unlikely to fully account for the elevations in GFR and proteinuria found in obesity.

Measuring the glomerular filtration rate in obese individuals without overt kidney disease.

BACKGROUND: Identifying methods to accurately measure the glomerular filtration rate (GFR) in obese individuals without kidney overt kidney disease is necessary to understanding the pathophysiology and natural history of obesity-related kidney disease. METHODS: Using a cross-sectional design, iohexol clearance and disposition was measured, an optimal sampling schedule was identified, and the reliability of GFR-estimating methods was described in 29 obese individuals with normal serum creatinine levels. Iohexol disposition was measured using population pharmacokinetics. The agreement with GFR-estimating equations was assessed by intraclass coefficients. RESULTS: Mean age was 44 ± 10 years, body mass index 45 ± 10, creatinine 0.7 ± 0.2 mg/dl (62 ± 18 µmol/l) , and cystatin C 0.83 ± 0.18 mg/dl (8.3 ± 1.8 mg/l). Iohexol disposition fit a two-compartment model and 5 sampling windows were identified over a 4-hour period to optimize model accuracy and minimize blood draws. Precision was not compromised with this sampling design. Neither creatinine nor cystatin C were linearly correlated with the measured GFR though cystatin C was independent of body composition. Agreement was fair to poor between the measured GFR and GFR-estimating equations. CONCLUSION: This study offers a rigorous method to study obesity-related kidney disease and improve upon suboptimal GFR-estimating methods.