Citations

Abstract Despite progress of immune checkpoint therapies, many cases of non-small cell lung cancer (NSCLC) are refractory or acquire resistance to current therapies. Antibody blockade of semaphorin 4D (SEMA4D, CD100) can overcome resistance mechanisms of immune exclusion and myeloid suppression. Importantly, combinations of anti-SEMA4D with various immunotherapies enhanced T cell infiltration and activity, leading to durable tumor regression in preclinical models. Pepinemab (VX15/2503) is a first-in-class humanized monoclonal antibody targeting SEMA4D. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the tumor immune microenvironment via pepinemab. Here, we present interim results of the Phase 2 portion of the CLASSICAL-Lung study. This phase 1b/2, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 subjects with advanced stage (IIIB/IV) NSCLC, including immunotherapy-naïve (ION) patients and patients whose tumors progressed during or following immunotherapy (IOF). Dose escalation was successfully completed, presented previously, and no concerning safety signals have been identified to date. Among 29 evaluable IOF patients, 2 experienced confirmed partial response (PR) with 66% and 52% tumor reduction following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease (SD), and at least 7 patients had durable clinical benefit of ≥ 23 weeks. Among 21 evaluable ION patients, 5 experienced PR, and 3 patients had clinical benefit ≥ 1 year. The disease control rate was 81%. Analysis of pre- and on-treatment biopsies demonstrated increased CD8+ T cell density correlating with response, with reduction or elimination of tumor in 10/11 biopsies from subjects with PR or SD. It was notable that 79% of patients who experienced PR or SD were reported to have tumors with negative or low PD-L1 expression. Enrollment is complete and this interim analysis suggest the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data, as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented. Citation Format: Jonathan W. Goldman, Terrence L. Fisher, Elizabeth Evans, John E. Leonard, Desa Rae Pastore, Crystal Mallow, Ernest Smith, Andreas Schröeder, Kevin Chin, Michael Shafique, Thaddeus Beck, Megan A. Baumgart, Ramaswamy Govindan, Nashat Gabrail, Rachel E. Sanborn, Alexander I. Spira, Nagashree Seetharamu, Yanyan Lou, Aaron S. Mansfield, Maurice Zauderer. Interim results from CLASSICAL-Lung, phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT191.

Abstract Introduction: Cer is an oral ALK/ROS1 inhibitor. Aberrancies in ALK and ROS1 have been observed in many cancer types and ALK inhibition has synergistic effects with chemotherapy in ALK or ROS1 rearranged tumors in preclinical models. We launched a Phase I study of Cer in combination with Gem-based chemotherapy in advanced solid tumors. Herein we present initial results of this study. Methods: Phase I, dose-escalation study of Cer in combination with A1: Gem 1000 mg IV D1/8/15 q28 days; A2: Gem 1000 mg IV + nanoparticle albumin-bound Paclitaxel 125 mg IV both D1/8/15 q28 days; A3: Gem 1000 mg IV + Cisplatin 60 mg IV D1/8 q21 days in pts with advanced, solid malignancies until disease progression, intolerable toxicity or withdrawal. A 3 + 3 dose-escalation design was used starting at Cer 450 mg once daily (DL1) in all arms; DL2 was 600 mg once daily. Primary objective was to determine the maximum tolerated dose (MTD) of Cer. Key inclusion criteria: diagnosis of advanced solid malignancy for which Gem-based treatment was appropriate, >18 years old, ECOG PS 0/1, adequate bone marrow/renal/liver function. Key exclusion criteria: interstitial lung fibrosis/disease, recent acute coronary event, CHF NYHA III/IV, corrected QTc > 450 ms. Pts in A3 could have up to 2 prior lines of therapy. Prior use of ALK inhibitors allowed. Plasma was collected for PK on C1D1, C2D1, and C1D15. Archival tumor tissue was tested for ALK/ROS1/JNK/MET by IHC. Results: Thirty-eight patients were enrolled with 21 evaluable for dose-limiting toxicity (DLT) in A1 and A3. A2 (n=4) closed to accrual for toxicity. Median age was 61 years. Seven pts (41%) had cholangiocarcinoma. A1 had one DLT (G3 ALT increase) in DL2; MTD was 600 mg. A3 had one DLT in DL1 (G3 acute renal failure) and two DLTs in DL2 (G3 thrombocytopenia and G3 dyspnea); MTD was 450 mg. G3-5 AEs in all pts: anemia (A1: 3/19, A3: 2/15), nausea (A1: 1/19, A3: 2/15), emesis (A1: 1/19, A3: 1/15), neutropenia (A1: 2/19, A3: 8/15), thrombocytopenia (A1: 1/19, A3: 4/15), hyperbilirubinemia (A3: 3/15), pneumonia (A1: 2/19), acute renal failure (A3: 1/15), fatigue (A3: 2/15). Fifteen patients were evaluable for response; the overall response rate was 20% with two PR (pt with head and neck carcinoma in A1 and pt with carcinoma of unknown primary in A3) - and one CR in a pt with cholangiocarcinoma (A3) lasting 10.3 months. Overall, disease control rate was 47%. Of 5 evaluable pts with cholangiocarcinoma 3 had clinical benefit. Median PFS 3.4 mo (A1)/4.8 mo (A3) and OS 13.7 mo (A1)/29.1 mo (A3). PK and IHC data will be presented at the conference. Conclusions: The MTD of Cer is 600 mg in combination with Gem and 450 mg in combination with Gem/Cisplatin. Further evaluation of Cer plus Gem-based chemotherapy is planned in ALK/ROS1 positive cholangiocarcinomas. Citation Format: Christos Fountzilas, Alex Adjei, Mateusz Opyrchal, Rachel Evans, Kristopher Attwood, Andrew Goey, John Wilton, Wen Wee Ma, Renuka Iyer. Ceritinib (Cer) in combination with gemcitabine (Gem)-based chemotherapy in patients (pts) with advanced solid tumors, a phase I study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT139.

Abstract Background Immunoglobulin G subclass 4 (IgG4) is hypothesized to play an immunomodulatory role, downregulating humoral immune responses. The role of this anti-inflammatory molecule in inflammatory bowel disease (IBD) has not been fully characterized. We sought to define alterations in serum IgG4 in patients with IBD and their association with multiyear disease severity. Methods We analyzed metadata derived from curated electronic health records from consented patients with IBD prospectively followed at a tertiary center over a 10-year time period. Patients with IBD with IgG4 serum levels available formed the study population. Demographics and multiyear clinical data were collected and analyzed. We stratified patients with IBD with low, normal, or high serum IgG4 levels. Results We found IgG4 characterized in 1193 patients with IBD and low IgG4 levels in 233 patients (20%) and elevated IgG4 levels in 61 patients (5%). An IgG4 deficiency did not significantly correlate with other antibody deficiencies. In a multiple Poisson regression analysis, low IgG4 was associated with more years on biologic agents (P = 0.002) and steroids (P = 0.049) and more hospital admissions (P < 0.001), clinic visits (P = 0.010), outpatient antibiotic prescriptions (P < 0.001), and CD-related surgeries (P = 0.011) during the study period after controlling for certain confounders. Elevated IgG4 was only associated with primary sclerosing cholangitis (P = 0.011). A cohort of patients with IgG4-deficient severe IBD received intravenous Ig replacement therapy, which benefited and was continued in 10 out of 11 individuals. Conclusions An IgG4 subclass deficiency, distinct from other antibody deficiencies, occurred commonly in a referral IBD population and was associated with multiple markers of disease severity. This is the first association of IgG4 subclass deficiency with an inflammatory disease process. Further work is needed to define the mechanistic role of IgG4 deficiency in this severe IBD subgroup.

Abstract Introduction: Acquired resistance to platinum remains a major clinical problem in ovarian cancer since systemic therapies have limited efficacy in this setting. There is growing evidence that the tumor microenvironment (TME) contributes to such resistance, as well as the pathogenesis of the disease. The study of the TME is limited by technical challenges of separating the epithelial from the stromal component. To overcome this limitation, we performed RNA sequencing (RNA-Seq) for three pairs of sensitive and induced resistant patient-derived xenograft models since the epithelial transcripts originate from human tissue and the stroma component is murine. Methods: To determine which TME genes might be contributing to chemotherapy resistance, three platinum-sensitive ovarian cancer PDX lines were treated repeatedly with carboplatin/paclitaxel until resistance occurred. Primary platinum-sensitive and induced platinum resistant tumors were characterized histologically by H&E and Masson Trichrome staining. The three pairs of sensitive and resistant PDX models were then subjected to RNA-Seq. Raw sequencing data were processed through Xenome to classify the reads into epithelial carcinoma (human) or TME (mouse) through Mayo Clinic’s internal RNA-Seq pipeline for transcriptome quantification. Differential expression analysis between induced resistant and sensitive models was carried out for both carcinoma and TME components using edgeR paired analysis. Gene set enrichment analysis was used to identify overrepresented biologic functions for differentially expressed genes between the pairs. Top significantly varied, differentially expressed genes between the pairs were validated using species-specific qPCR. Results: Histologic analysis of the matched sensitive/resistant pairs revealed a marked increase of the stromal component in the resistant tumors evident by H&E and Masson trichrome staining. A total number of 95 and 312 genes were differentially expressed in the epithelial and TME component, respectively (FDR<0.05; absolute log2 fold-change >1.5). The stemness marker SOX2 was significantly upregulated in the human component of the resistant tumors as confirmed by qPCR. Genes involved in stroma remodeling were upregulated in the “murine” component of the resistant tumors, and upregulation was confirmed by qPCR (normalized to a murine housekeeper gene). Gene set enrichment analysis showed that the upregulated genes in TME of resistant models were enriched for cytoskeleton related functions, while the downregulated genes were enriched for extracellular matrix-related functions. Conclusion: A bioinformatics strategy able to map human and murine reads separately may identify resistance mechanisms attributed to the two tumor subcompartments and could lead to strategies to potentially target each separately or concurrently. Citation Format: Valentina Zanfagnin, Yuanhang Liu, Pritha Chanana, Xiaonan Pritha, Beverly Long, Joe Pathoulas, Brad Evans, Jaime Davila, Chen Wang, Saravut John Weroha. Transcriptional profiling of tumor stroma using ovarian cancer PDX models with induced platinum-resistance [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B18.

Purpose To assess if the choice of acetaminophen formulation (intravenous vs oral) when administered preoperatively for ambulatory cystoscopy procedures is associated with differences in anesthetic outcomes. Methods Medical records of adult patients undergoing ambulatory cystoscopy procedures at an outpatient procedural center from July 1, 2014, through November 30, 2017, were abstracted. The association between anesthetic outcomes (severe pain, rescue opioids, postoperative nausea, and vomiting) and acetaminophen formulation was assessed. Propensity-adjusted analyses were performed using inverse probability of treatment weighting to account for potential confounders. Results During the study time frame, there were 611 intravenous and 2955 oral acetaminophen administrations for cystoscopy procedures. Postoperative bladder spasms were a major contributor to severe pain and complicated 1036 cases, with similar rates between intravenous (N = 183, 29.9%) and oral (N = 853, 28.9%) formulations, P = .625. After adjusting for bladder spasms, intravenous acetaminophen was associated with longer anesthesia recovery (estimate 5.2 [95% CI 0.5-9.9] minutes, P = .030), use of rescue opioids (odds ratio 1.33 [1.07-1.66], P = .012), and postoperative nausea and vomiting (1.40 [1.02-1.93], P = .037), but not severe pain (1.07 [0.81-1.40], P = .640). Conclusion Preoperative intravenous acetaminophen compared to oral acetaminophen for ambulatory cystoscopy procedures was not associated with better anesthetic outcomes. Bladder spasms were a major contributor to postoperative pain.

PURPOSE Radical prostatectomy (RP) alone is often inadequate in curing men with clinically localized, high-risk prostate cancer (PC). We hypothesized that chemohormonal therapy (CHT) with androgen-deprivation therapy plus docetaxel before RP would improve biochemical progression–free survival (BPFS) over RP alone. PATIENTS AND METHODS Men with clinically localized, high-risk PC were assigned to RP alone or neoadjuvant CHT with androgen deprivation plus docetaxel (75 mg/m 2 body surface area every 3 weeks for 6 cycles) and RP. The primary end point was 3-year BPFS. Biochemical failure was defined as a serum prostate-specific antigen level > 0.2 ng/mL that increased on 2 consecutive occasions that were at least 3 months apart. Secondary end points included 5-year BPFS, overall BPFS, local recurrence, metastasis-free survival (MFS), PC-specific mortality, and overall survival (OS). RESULTS In total, 788 men were randomly assigned. Median follow-up time was 6.1 years. The overall rates of grade 3 and 4 adverse events during chemotherapy were 26% and 19%, respectively. No difference was seen in 3-year BPFS between neoadjuvant CHT plus RP and RP alone (0.89 v 0.84, respectively; 95% CI for the difference, −0.01 to 0.11; P = .11). Neoadjuvant CHT was associated with improved overall BPFS (hazard ratio [HR], 0.69; 95% CI, 0.48 to 0.99), improved MFS (HR, 0.70; 95% CI, 0.51 to 0.95), and improved OS (HR, 0.61; 95% CI, 0.40 to 0.94) compared with RP alone. CONCLUSION The primary study end point, 3-year BPFS, was not met. Although some improvement was seen in secondary end points, any potential benefit must be weighed against toxicity. Our data do not support the routine use of neoadjuvant CHT and RP in patients with clinically localized, high-risk PC at this time.

Hypertrophic cardiomyopathy (HCM) is a prevalent and untreatable cardiovascular disease with a highly complex clinical and genetic causation. HCM patients bearing similar sarcomeric mutations display variable clinical outcomes, implying the involvement of gene modifiers that regulate disease progression. As individuals exhibiting mutations in mitochondrial DNA (mtDNA) present cardiac phenotypes, the mitochondrial genome is a promising candidate to harbor gene modifiers of HCM. Herein, we sequenced the mtDNA of isogenic pluripotent stem cell-cardiomyocyte models of HCM focusing on two sarcomeric mutations. This approach was extended to unrelated patient families totaling 52 cell lines. By correlating cellular and clinical phenotypes with mtDNA sequencing, potentially HCM-protective or -aggravator mtDNA variants were identified. These novel mutations were mostly located in the non-coding control region of the mtDNA and did not overlap with those of other mitochondrial diseases. Analysis of unrelated patients highlighted family-specific mtDNA variants, while others were common in particular population haplogroups. Further validation of mtDNA variants as gene modifiers is warranted but limited by the technically challenging methods of editing the mitochondrial genome. Future molecular characterization of these mtDNA variants in the context of HCM may identify novel treatments and facilitate genetic screening in cardiomyopathy patients towards more efficient treatment options.