Tofacitinib to prevent anti-drug antibody formation against LMB-100 immunotoxin in patients with advanced mesothelin-expressing cancers.

Background: LMB-100 is a mesothelin (MSLN)-targeting recombinant immunotoxin (iTox) carrying a Pseudomonas exotoxin A payload that has shown promise against solid tumors, however, efficacy is limited by the development of neutralizing anti-drug antibodies (ADAs). Tofacitinib is an oral Janus Kinase (JAK) inhibitor that prevented ADA formation against iTox in preclinical studies. Methods: A phase 1 trial testing LMB-100 and tofacitinib in patients with MSLN-expressing cancers (pancreatic adenocarcinoma, n=13; cholangiocarcinoma, n=1; appendiceal carcinoma, n=1; cystadenocarcinoma, n=1) was performed to assess safety and to determine if tofacitinib impacted ADA formation. Participants were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 µg/kg) while oral tofacitinib was administered for the first 10 days of the cycle (10 mg BID). Peripheral blood was collected for analysis of ADA levels, serum cytokines and circulating immune subsets. Results: The study was closed early due to occurrence of drug-induced pericarditis in 2 patients. Pericarditis with the combination was not reproducible in a transgenic murine model containing human MSLN. Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred. No radiologic decreases in tumor volume were observed. Discussion: Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings. Clinical trial registration: https://www.clinicaltrials.gov/study/NCT04034238.

Two rare cancers of the exocrine pancreas: to treat or not to treat like ductal adenocarcinoma?

Pancreatic cancer is an aggressive malignancy with increasing incidence. Pancreatic ductal adenocarcinoma (PDAC) accounts for > 90% of pancreatic cancer diagnoses, while other exocrine tumors are much rarer. In this review, we have focused on two rare cancers of the exocrine pancreas: adenosquamous carcinoma of the pancreas (ASCP) and pancreatic acinar cell carcinoma (PACC). The latest findings regarding their cellular and molecular pathology, clinical characteristics, prognosis, and clinical management are discussed. New genetic and transcriptomic data suggest that ASCP is related to or overlaps with the basal transcriptomic subtype of PDAC. These tumors are highly aggressive and driven by activated KRAS and MYC expression. Clinical outcomes remain poor and effective treatments are limited. PACC has no morphologic or genetic resemblance to PDAC and more favorable outcomes. Early stage PACC patients have improved survival with surgical resection and patients with advanced disease benefit most from platinum- or fluoropyrimidine-containing chemotherapy. Frequency of actionable genetic mutations is high in this disease and case reports suggest good outcomes when matched therapy is given. Dedicated clinical studies examining ASCP and PACC are limited and difficult to accrue. Further research is needed to define optimal clinical management for these rare diseases.

Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma.

Pancreatic cancer has a complex tumor microenvironment which engages in extensive crosstalk between cancer cells, cancer-associated fibroblasts, and immune cells. Many of these interactions contribute to tumor resistance to anti-cancer therapies. Here, new therapeutic strategies designed to modulate the cancer-associated fibroblast and immune compartments of pancreatic ductal adenocarcinomas are described and clinical trials of novel therapeutics are discussed. Continued advances in our understanding of the pancreatic cancer tumor microenvironment are generating stromal and immune-modulating therapeutics that may improve patient responses to anti-tumor treatment.

A phase II trial of the super-enhancer inhibitor Minnelide™ in advanced refractory adenosquamous carcinoma of the pancreas.

Adenosquamous carcinoma of the pancreas (ASCP) is a very rare and highly aggressive variant of pancreatic ductal adenocarcinoma, accounting for 0.5-4% of all pancreatic cancer cases in the USA. Current data indicate that epigenetic changes and MYC overexpression lead to squamous transdifferentiation of pancreatic tumor cells and development of ASCP. Minnelide™, an oral anti-super-enhancer drug that inhibits MYC expression in preclinical models of ASCP, has demonstrated safety in a phase I study. We describe the design for a phase II, open-label, single-arm trial of Minnelide in patients with advanced refractory ASCP.

Adenosquamous carcinoma of the pancreas (ASCP) is a rare and highly aggressive variant of pancreatic cancer, with limited treatment options. Changes in activation of DNA elements called super-enhancers drive the growth of ASCP. Minnelide™ is an oral drug that blocks the super-enhancer network and is safe to give to patients with advanced cancer. This trial is designed to determine whether Minnelide can shrink tumors in patients with ASCP who have already received at least one previous treatment for their cancer.  Clinical Trial Registration: NCT04896073 (ClinicalTrials.gov).

Low serum mesothelin in pancreatic cancer patients results from retention of shed mesothelin in the tumor microenvironment.

Mesothelin (MSLN) is overexpressed by many cancers, including pancreatic ductal adenocarcinoma (PDAC) and has consequently become a target for anti-cancer therapeutics. Mature, membrane bound MSLN is cleaved by proteases, releasing a shed form that transits to the circulation. Many patients with mesothelioma and ovarian cancer have abnormally high serum MSLN concentration. However, serum MSLN concentration in PDAC patients rarely exceeds levels of healthy controls. Here, serum MSLN concentration in advanced PDAC patients was examined pre- and post-treatment. Serum MSLN did not correlate with tumor MSLN expression, nor with changes in tumor burden as assessed by PDAC serum tumor marker CA19-9. Subsequently, tumor-bearing mouse models were used to investigate the fate of shed MSLN in PDAC versus a control cervical cancer model. Efficiency of MSLN secretion into the serum was cell-line dependent. Tumors from some PDAC lines had poor MSLN secretion efficiency although these lines had similar or higher MSLN shedding rate, total and surface MSLN expression. Measurements of compartment-specific MSLN concentration taken at equilibrium suggested that tumors with poor MSLN secretion efficiency trapped shed MSLN in the tumor microenvironment (TME), a finding confirmed by dynamic experiments using a doxycycline-inducible MSLN expression system. Tumors with the poorest MSLN secretion efficiency had higher collagen density and increased abundance of MSLN binding partner MUC16. The tumor with the worst secretion efficiency could rebind shed MSLN to the cancer cell surface. Altogether, these data suggest that PDAC can trap shed MSLN within the TME. This finding has potential significance for design of MSLN-targeted therapeutics.

Trends in Grade 5 Toxicity and Response in Phase I Trials in Hematologic Malignancy: 20-Year Experience From the Cancer Therapy Evaluation Program at the National Cancer Institute.

PURPOSE: Cancer drug development has largely shifted from cytotoxic chemotherapy to targeted treatment in the past two decades. Although previous studies have highlighted improvement in response rates in recent phase I trials, disease-focused reporting is limited. METHODS: We integrated patient-level data for patients with hematologic malignancies who participated in phase I trials sponsored by the National Cancer Institute Cancer Therapy Evaluation Program between January 2000 and May 2019 and estimated the trend of grade 5 toxicity and response by disease subtype over time. RESULTS: We analyzed 161 trials involving 3,308 patients, all of whom were assessed for toxicity and 2,404 of whom were evaluable for response to therapy. The overall rate of grade 5 toxicities was 1.81% (95% CI, 1.36 to 2.27), with no significant change in the rate over time. Baseline characteristics associated with higher risk of grade 5 toxicity were age and performance status ≥ 2 at enrollment. Overall response rate (ORR) and complete response (CR) rate for all trials during the study period were 25.1% and 14.7%, respectively. A significant increase in both ORR and CR rate was observed over time (ORR, 18.5% in 2000-2005, 25.9% in 2006-2012, and 50.6% in 2013-2019, P < .001). ORR in phase I trials varied across disease subtypes: 20.2% in acute myeloid leukemia, 9.1% in myelodysplastic syndrome, 43.2% in lymphoma, 42.9% in chronic lymphocytic leukemia, 15.1% in acute lymphoblastic leukemia, and 16.5% in myeloma. CONCLUSION: Over time, the ORR and CR rates in phase I trials for hematologic malignancy have improved meaningfully, whereas the rate of toxicity-related death remains stable. This study provides broad experience that physicians can use when discussing the potential outcomes for patients with hematologic malignancy considering participation in phase I trials.

Patterns of bevacizumab use in patients with glioblastoma: an online survey among experts in neuro-oncology.

BACKGROUND: Bevacizumab (BEV) received accelerated FDA approval in 2009 for the treatment of recurrent glioblastoma (rGBM). Unfortunately, prospective randomized controlled phase 3 studies (AVAglio and Radiation Therapy Oncology Group 0825 in newly diagnosed, European Organisation for Research and Treatment of Cancer 26101 in rGBM) failed to show an overall survival benefit with BEV added to standard therapy. In light of these data, we aimed to capture current utilization patterns and perceived value of BEV in the treatment of GBM among experts in the field. METHODS: An online questionnaire comprising 14 multiple choice questions was sent out in spring 2017 to 207 oncologists/neuro-oncologists treating patients with GBM at all National Cancer Institute-designated cancer centers in the United States. RESULTS: Sixty-two of 207 (30%) invitees responded (by training, 70% neuro-oncologists, 20% medical oncologists, 10% pediatric oncologists/neuro-oncologists). Participants reported use of BEV most frequently in rGBM for control of edema (85% of respondents) and/or when no other treatment options were available (68%). BEV is rarely used in newly diagnosed GBM (<5% of cases by 78% respondents and in 5% to 10% cases by 15% respondents). Sixty-six percent of participants indicated that they thought BEV improved symptoms, 30% that it improved symptoms and survival, 3% that it had no benefit in GBM patients. CONCLUSION: In this cross-sectional online survey we found that among neuro-oncology experts in the United States in 2017, BEV is predominantly utilized in select patients with rGBM, and is only rarely used in a small subgroup of patients with newly diagnosed GBM for control of edema. The low response rate may have introduced a nonresponse bias.

Pneumocystis jirovecii prophylaxis in patients treated for high-grade gliomas: a survey among neuro-oncologists.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is a known complication in patients with high-grade gliomas (HGGs) who are treated with radiation and chemotherapy. PJP prophylaxis is commonly recommended, but there are currently no clear guidelines regarding duration of treatment and choice of drugs. This study aimed to assess current practice patterns of PJP prophylaxis among neuro-oncologists. METHODS: An online survey of 14 multiple choice questions was sent to 207 neuro-oncologists and medical oncologists treating brain cancers at all National Cancer Institute-designated cancer centers in the United States. Recipients were identified via a search of the cancer centers' websites. RESULTS: Sixty-one invited experts completed the survey (response rate 29%; of these, 72% were neuro-oncologists, 18% were medical oncologists, and 10% were pediatric neuro- or medical oncologists). Seventy percent of respondents stated that they routinely prescribe PJP prophylaxis, while 7% do not provide prophylaxis. Eighty-one percent of respondents use absolute lymphocyte count (ALC) to assess lymphopenia and 13% also monitor CD4 lymphocyte counts during prophylaxis. The most commonly used first-line agent is trimethoprim-sulfamethoxazole (88% of respondents), followed by pentamidine (6%). Discontinuation of PJP prophylaxis is determined by the following: count recovery (33% by ALC; 18% by CD4 lymphocyte counts), radiation completion (23%), and chemotherapy completion (7%). Glucose-6-phosphate dehydrogenase levels were routinely checked by only 13% of respondents. CONCLUSIONS: PJP prophylaxis is commonly used in HGG patients, but there are large variations in practice patterns, including the duration of prophylaxis. As consideration for PJP prophylaxis affects all patients with HGG, standardization of prophylaxis should be formally addressed.

Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas.

PURPOSE: H3 K27 mutations, most commonly in H3F3A, are common in diffuse midline glioma. The exact frequency of these mutations in adults with gliomas in the midline location is unknown. This study was conducted to define the incidence of H3 K27M mutations in this location and to compare clinicopathological features with those of patients who do not harbor this mutation. METHODS: Consecutive glioma cases from 2007 to 2017 were screened for gliomas in the midline location. Immunohistochemistry was performed on all available tissue for mutations of H3 K27M, IDH1, and ARTX. RESULTS: Of 850 gliomas screened, 163 cases had midline glioma on MRI. Sufficient FFPE tissue was available for 123 cases (75%). H3 K27M mutation was identified in 18 of 123 cases (15%). All except one H3 K27M-mutant tumors were WHO grade III or IV on histology, while non-mutant tumors encompassed all four grades. The most common midline locations for H3 K27M-mutated tumors were midbrain (2/3; 67%), pons (4/11; 36%), and cerebellum (6/24; 25%). As compared to H3 K27M-wildtype tumors, there were no differences in age at diagnosis, sex, tumor grade, contrast enhancement on MRI, extent of resection, or treatment received. In this cohort, median survival was longer for patients with H3 K27M-mutated tumors (n = 18; 17.6 months) compared with high-grade wildtype tumors (n = 74; 7.7 months, p = 0.03). CONCLUSIONS: H3 K27M mutations are common in midline gliomas in adults and can present in all midline locations. Survival comparison between H3 K27M-mutant and wildtype midline gliomas suggests that survival may be similar or possibly improved if the mutation is present.

Pharmacological analysis of the rat femoral artery response to bradykinin.

Bradykinin (BK) plays an important role in different physiological processes including the general preservation and modulation of vascular systems. The present study was designed in order to examine the effect of BK on isolated rat femoral artery rings and to investigate the participation of intact endothelium, cyclooxygenase products, Ca(2+) channels, Na(+)/K(+)-ATPase, and B2 kinin receptors in BK-induced action. Circular artery segments were placed in organ baths. The endothelium was mechanically removed from some arteries. Concentration-contraction curves for BK were obtained in the rings previously equilibrated at the basal tone. BK produced a concentration-dependent contraction, which was reduced by endothelial denudation. The BK-induced effect was almost completely inhibited by indomethacin (cyclooxygenase inhibitor) or OKY-046 (thromboxane A2-synthase inhibitor). Nifedipine (Ca(2+) channel blocker), ouabain (Na(+)/K(+)-ATPase inhibitor), or HOE-140 (selective B2 kinin receptor antagonist) significantly reduced the BK-evoked effect. In conclusion, it can be proposed that BK produces concentration- and endothelium-dependent contractions of the isolated rat femoral artery, which is for the most part a consequence of B2 kinin receptor activation. Cyclooxygenase contractile products, especially thromboxane A2, play a significant role in this course of action. The transduction mechanism involved in the process of BK-induced femoral artery contraction include the activation of voltage-gated Ca(2+) channels, and in a smaller extent Na(+)/K(+)-ATPase as well.