Background: CD73 upregulation in tumors leads to local immunosuppression. This phase I, first-in-human study evaluated oleclumab (MEDI9447), an anti-CD73 human IgG1λ monoclonal antibody, alone or with durvalumab in patients with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC). Methods: Patients received oleclumab 5–40 mg/kg (dose-escalation) or 40 mg/kg (dose-expansion) intravenously every 2 weeks (Q2W), alone (escalation only) or with durvalumab 10 mg/kg intravenously Q2W. Results: 192 patients were enrolled, 66 during escalation and 126 (42 CRC, 42 PDAC, 42 NSCLC) during expansion. No dose-limiting toxicities occurred during escalation. In the monotherapy and combination therapy escalation cohorts, treatment-related adverse events (TRAEs) occurred in 55 and 54%, respectively, the most common being fatigue (17 and 25%). In the CRC, PDAC, and NSCLC expansion cohorts, 60, 57, and 45% of patients had TRAEs, respectively; the most common were fatigue (15%), diarrhea (9%), and rash (7%). Free soluble CD73 and CD73 expression on peripheral T cells and tumor cells showed sustained decreases, accompanied by reduced CD73 enzymatic activity in tumor cells. Objective response rate during escalation was 0%. Response rates in the CRC, PDAC, and NSCLC expansion cohorts were 2.4% (1 complete response [CR]), 4.8% (1 CR, 1 partial response [PR]), and 9.5% (4 PRs), respectively; 6-month progression-free survival rates were 5.4, 13.2, and 16.0%. Conclusions: Oleclumab ± durvalumab had a manageable safety profile, with pharmacodynamic activity reflecting oleclumab’s mechanism of action. Evidence of antitumor activity was observed in tumor types that are generally immunotherapy resistant. Clinical trial registration: Clinicaltrials.gov, NCT02503774; date of registration, July 17, 2015.

The incidence and mortality of squamous cell carcinoma of the anus has been gradually increasing globally over the last few decades. The evolution of different modalities, including immunotherapies, has changed the treatment paradigm of metastatic anal cancers. Chemotherapy, radiation therapy, and immune-modulating therapies form the backbone of treatment of anal cancer in various stages. Most anal cancers are linked to high-risk human papilloma virus (HPV) infections. HPV oncoproteins E6 and E7 are responsible for an anti-tumor immune response triggering the recruitment of tumor-infiltrating lymphocytes. This has led to the development and utilization of immunotherapy in anal cancers. Current research in anal cancer is moving forward to discover ways to incorporate immunotherapy in the treatment sequencing in various stages of anal cancers. Immune checkpoint inhibitors alone or in combination, adoptive cell therapy, and vaccines are the areas of active investigations in anal cancer in both locally advanced and metastatic settings. Immunomodulating properties of non-immunotherapies are incorporated to enhance immune checkpoint inhibitors’ effectiveness in some of the clinical trials. The aim of this review is to summarize the potential role of immunotherapy in anal squamous cell cancers and future directions.

Purpose: Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models. Patients and Methods: We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2). The primary endpoint was safety, and secondary endpoints included overall response rate, progression-free survival (PFS), and overall survival (OS). Correlative objectives aimed to identify molecular predictors of response and alterations in the tumor stroma. Results: Twenty patients (10 each in DL1 and DL2) enrolled between March 2019 and May 2021. No grade 3/4 adverse events related to paricalcitol were observed. The most common toxicities were nausea, diarrhea and fatigue, which were similar in both cohorts. Three patients discontinued study after one cycle and were not radiographically evaluable. Of the remaining 17 evaluable patients, 2 had partial response and 12 had stable disease. The median PFS for response-evaluable patients in DL1 was 4.14 months, for DL2 was 4.83 months. Intent-to-treat median OS was 6.15 and 6.66 months for DL1 and DL2, respectively. Correlative studies showed increased tumor vascularity in posttreatment samples in patients receiving the higher dose of paricalcitol (DL2). Conclusions: Paricalcitol at 7 mcg/kg/week in combination with Nal-iri/ 5-FU/LV is safely tolerated, may increase tumor vascularity and warrants further investigation.

Background: Myocardial uptake on ⁶⁸Ga-DOTATATE PET/CT is often observed and its clinical relevance is poorly understood. Purpose: To detect any correlation between myocardial uptake of ⁶⁸Ga-DOTATATE and presence of cardiac disease or risk factors. Material and Methods: In this institutional review board-approved retrospective study, we reviewed ⁶⁸Ga-DOTATATE PET/CT scans in our institution between 1 May 2018 and 30 September 2018. A semi-quantitative score (MUS) for myocardial uptake of ⁶⁸Ga-DOTATATE was developed by measuring mean standardized uptake value (SUV) in five myocardial regions, corrected by blood pool activity, and MUS was validated between two readers. We investigated the relationship between MUS and presence of cardiac disease or risk factors, including Framingham score and coronary calcification. Results: A total of 145 scans were included (79 women; mean age = 56.9 ± 13.7 years). Inter-reader agreement was excellent with intraclass correlation coefficient (r) = 0.964 (95% confidence interval [CI] = 0.903–0.987; P < 0.001). There was a weak but significant positive correlation between MUS and presence of coronary calcifications (Spearman rho = 0.20; P = 0.016). MUS was higher in patients with heart disease or risk factors (n = 83, mean MUS 2.03, 95% CI = 1.85–2.21) compared to those without (n = 23, mean MUS 1.40, 95% CI = 1.17–1.62; P < 0.001), although the cardiac disease group was older with a higher percentage of men (62.0 years, 57.8% men compared to 47.6 years, 13.0% men; P value <0.0001 for both comparisons). Conclusion: For patients undergoing ⁶⁸Ga-DOTATATE PET/CT scan, an elevated MUS might indicate an underlying heart disease.