Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD81) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD81 T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of 89 Zr-IAB22M2C, a radiolabeled minibody against CD81 T cells, for targeted imaging of CD81 T cells in patients with cancer. Methods: The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of 89 Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1-2, 6-8, 24, 48, and 96-144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Results: 89 Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time-activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24-48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most 89 Zr-IAB22M2C-positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Conclusion: 89 Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD81 T-cell-rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD81 T-cell accumulation within tumors. Further evaluation is under way.
Arcus, and he has a patent filed by his institution related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. R. Korn serves as CMIO of ImaginAb. A. Mascioni is employed by ImaginAb. W. Le serves as VP of Operations at ImaginAb. I. Wilson serves as CEO of ImaginAb. M. Gordon receives consulting fees from ImaginAb and Imaging Endpoints. A. Wu receives consulting fees from ImaginAb. G. Ulaner receives consulting fees from ImaginAb and is a member of the Scientific Advisory Board for ImaginAb. J. Wolchock has equity in Tizona Pharmaceuticals, Adaptive Biotechnologies, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, and Georgiamune. M. Postow receives grant/research support from ImaginAb. N. Pandit-Taskar has served as a consultant for or been on an advisory board and has received honoraria for ImaginAb, and receives grant/research support from ImaginAb. No other potential conflict of interest relevant to this article was reported.
Adenosquamous carcinoma of the pancreas (ASCP) is a rare entity. Like adenocarcinoma of the pancreas, overall survival is poor. Characteristics of ASCP include central tumor necrosis, along with osteoclasts and hypercalcemia. Various theories exist as to why this histological subtype exists, as normal pancreas tissue has no benign squamous epithelium. Due to the rarity of this disease, limited molecular analysis has been performed, and those reports indicate unique molecular features of ASCP. In this paper, we characterize 23 patients diagnosed with ASCP through molecular profiling using immunohistochemistry staining, fluorescent in situ hybridization, chromogenic in situ hybridization, and gene sequencing, Additionally, we provide a comprehensive literature review of what is known to date of ASCP. Molecular characterization revealed overexpression in MRP1 (80%), MGMT (79%), TOP2A (75), RRM1 (42%), TOPO1 (42%), PTEN (45%), CMET (40%), and C-KIT (10%) among others. One hundred percent of samples tested were positive for KRAS mutations. This analysis shows heretofore unsuspected leads to be considered
IMPORTANCE Genomes of metastatic pancreatic cancers frequently contain intrachromosomal aberrations, indicating a DNA repair deficiency associated with sensitivity to DNA damaging agents, such as platinum. OBJECTIVE To determine response rate following treatment with nab-paclitaxel plus gemcitabine plus platinum-based cisplatin for patients with metastatic pancreatic ductal adenocarcinoma (PDA). DESIGN, SETTING, AND PARTICIPANTS This was a single-arm, open-label, phase 1b/2 clinical trial of nab-paclitaxel plus gemcitabine plus cisplatin treatment in which 25 patients with previously untreated metastatic PDA were enrolled. The trial was conducted from December 2013 to July 2016 at 3 US sites, with the last patient receiving study treatment at the end of October 2016, and the study closing January 2018. INTERVENTIONS Patients were treated with nab-paclitaxel plus gemcitabine plus various doses of cisplatin, 25 mg/m 2 , 37.5 mg/m 2 , and 50 mg/m 2 , on days 1 and 8 of a 21-day cycle. MAIN OUTCOMES AND MEASURES Primary end point was complete response rate as assessed by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and levels of carbohydrate antigen 19-9 (or in nonexpressers, carbohydrate antigen 125 or carcinoembryonic antigen). Efficacy analysis included evaluable patients (those who received at least 1 dose of study treatment and had at least 1 postbaseline tumor assessment). RESULTS Of 25 patients enrolled in the study, the median (range) age was 65.0 (47.0-79.0) years, 14 (56%) were men, and most (24) were white (96%). The maximum tolerable dose of cisplatin was 25 mg/m 2. The most common treatment-related adverse events grade 3 or higher were thrombocytopenia (17 patients [68%]), anemia (8 patients [32%]), and neutropenia (6 patients [24%]). Fatal events occurred for 3 patients (12%); 2 were related to study participation. A median (range) of 8 (1-15) cycles was completed. The RECIST responses in 24 evaluable patients included 2 complete responses (8%), which was below the primary end point of 25%, 15 partial responses (62%), 4 stable disease (17%), and 3 progressive disease (12%), with median overall survival of 16.4 (95% CI, 10.2-25.3) months; 16 patients (64%) were alive at 1 year, 10 (40%) at 2 years, 4 (16%) at 3 years, and 1 (4%) at 4 plus years. Overall survival ranged from 36 to 59 months. Median progression-free survival was 10.1 (95% CI, 6.0-12.5) months. Thus, the overall response rate was 71%, and the disease control rate was 88%. CONCLUSIONS AND RELEVANCE This triple drug regimen showed substantial clinical activity in this small study. Although the primary end point was not reached, the high overall response rate, disease control rate, and median survival time among patients with advanced PDA treated with this combination are encouraging. The regimen is being studied in patients with PDA in the neoadjuvant setting and in patients with advanced biliary cancers.
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