Citations

One of the signicant obstacles to donor heart utilization is that increasingly prolonged cold ischemic times are associated with worsened short- and long-term outcomes. As a result, most transplant centers aim to limit cold ischemic times to less than four hours. The TransMedics Organ Care System (OCS) (Trans Medics, Andover MA) is a portable ex vivo perfusion system designed to store a donor heart in a beating, metabolically active state, until it reaches the recipient, thereby allowing extended time outside the body while minimizing the effects of cold storage. We present a case of a heart transplant recipient supported with the Impella 5.5 as a bridge to transplantation who received a donation after circulatory death (DCD) heart supported by OCS. To our knowledge, this is the rst report of such a case.

Abstract Background Glioblastoma is the most common and devastating primary brain cancer. Radiotherapy is standard of care; however, it is associated with brain radiation toxicity (BRT). This study used a multi-omics approach to determine whether BRT-related genes (RGs) harbor survival prognostic value and whether their encoded proteins represent novel therapeutic targets for glioblastoma. Methods RGs were identified through analysis of single-nucleotide variants associated with BRT (R-SNVs). Functional relationships between RGs were established using Protein-Protein Interaction networks. The influence of RGs and their functional groups on glioblastoma prognosis was evaluated using clinical samples from the Glioblastoma Bio-Discovery Portal database and validated using the Chinese Glioma Genome Atlas dataset. The identification of clusters of radiotoxic and putative pathogenic variants in proteins encoded by RGs was achieved by computational 3D structural analysis. Results We identified the BRT-related 15CAcBRT molecular signature with prognostic value in glioblastoma, by analysis of the COMT and APOE protein functional groups. Its external validation confirmed clinical relevance independent of age, MGMT promoter methylation status, and IDH mutation status. Interestingly, the genes IL6, APOE, and MAOB documented significant gene expression levels alteration, useful for drug repositioning. Biological networks associated with 15CAcBRT signature involved pathways relevant to cancer and neurodegenerative diseases. Analysis of 3D clusters of radiotoxic and putative pathogenic variants in proteins coded by RGs unveiled potential novel therapeutic targets in neuro-oncology. Conclusions 15CAcBRT is a BRT-related molecular signature with prognostic significance for glioblastoma patients and represents a hub for drug repositioning and development of novel therapies.

Abstract Background: Cholangiocarcinoma is an aggressive malignancy with limited systemic therapeutics. We have recently identified LCK, a non-receptor tyrosine kinase, as a potential therapeutic target in select subtypes of cholangiocarcinoma. Proteomic profiling in other cancer types has proven beneficial in predicting response to systemic therapies. Herein, we present proteomic profiling of cholangiocarcinoma can predict sensitivity to a novel LCK inhibitor in patient derived xenograft models. Methods: Proteins from 28 unique cholangiocarcinoma patient derived xenograft models (PDX) were isolated, labeled with tandem mass tags (TMT) and then analyzed by liquid chromatography and mass spectroscopy (LC/MS). Phosphopeptides were separately evaluated both by Immobilized Metal Affinity Chromatography and pY-enrichment techniques. Following normalization, the global proteome, serine/threonine phosphoproteome, and tyrosine phosphoproteome were analyzed and a proteomic signature was created for each tumor. These signatures were compared to PDX models with known response profiles to NTRC0652-0, an LCK inhibitor (1 resistant and 1 sensitive). The top 200 differentially abundant proteins (log2FC 2.6) were then utilized to develop a sensitive and a resistant signature. Correlation indices were then calculated across the 28 PDX model library. An additional predicted resistant and predicted sensitive model was expanded. Tumor bearing mice were randomized based on tumor volume to either treatment with NTRC (30mg/kg PO daily), n=5, or vehicle, n=4, (10% Kolliphor, 10% DMSO, 80% Water, 2 mol equivalents HCl). Tumors were measured weekly with calipers and then weighed at the end of the study. Results: In the top 200 differentially abundant proteins that represented the proteomic signature there was over representation of proteins with decreased abundance. There were only 12 proteins with higher abundance in the sensitive model as compared to the resistant. Utilizing the signature developed from the global proteomics data, nine tumors were predicted to be sensitive while 17 were predicted to be resistant to NTRC. PDX115 is a an intrahepatic CCA PDX known to contain an IDH1 mutation and was predicted to be resistant by modeling. The model was resistant to single agent NTRC with no demonstrable effect on tumor growth in vivo. PDX175 is a distal CCA PDX and was predicted to be sensitive by modeling. In vivo growth was inhibited by NTRC as compared to vehicle treated mice following two weeks of treatment (983% vs 435%, p=0.03). Additionally, final tumor weight was significantly lower in NTRC treated mice (0.651 g vs 0.317 g, p=0.04). Conclusion: Cholangiocarcinoma proteomic signatures can be used to predict therapeutic response to a novel LCK inhibitor in preclinical models. Whether or not this could be applied to other treatment modalities in cholangiocarcinoma remains to be determined. Citation Format: Ryan Watkins, Roberto Alva-Ruiz, Caitlin Conboy, Dong-Gi Mun, Erik Jessen, Diep Vu, Jos de Man, Rogier Buijsman, Akhilesh Pandey, Mitesh Borad, Gregory Gores, Rory Smoot. Proteomic profiling of cholangiocarcinoma predicts response to a novel small molecule inhibitor in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3094.

Abstract Background: Cemiplimab is the first treatment approved in the US (as cemiplimab-rwlc) for patients with metastatic basal cell carcinoma (mBCC) or locally advanced disease (laBCC) after hedgehog inhibitor (HHI) treatment or for whom an HHI is not appropriate. Cemiplimab provided substantial clinical benefit and an acceptable safety profile in patients with laBCC who discontinued HHI therapy due to progressive disease (PD), intolerance, or no better than stable disease (SD) after 9 months (NCT03132636). Here, we present the primary analysis of the mBCC cohort. Methods: Patients with mBCC (nodal or distant) post-HHI treatment received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until PD. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Key secondary endpoints included safety and tolerability, ORR per investigator (INV) assessment, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and complete response (CR) rate (data cutoff date: May 20, 2021). Results: Fifty-four patients were enrolled (70.4% male; median age 63.5 years [range, 38−90]; Eastern Cooperative Oncology Group performance status 0 [66.7%] and 1 [33.3%]). Median duration of follow-up was 8.4 months (range 1.5-36.2). ORR per ICR was 24.1% (95% confidence interval [CI], 13.5-37.6); with 1 CR and 12 partial responses (PRs). ORR per INV was 25.9% (95% CI, 15.0-39.7), with 2 CRs and 12 PRs. Among responders, median time to response per ICR was 4.0 months (range, 2.0−10.5). Estimated median DOR per ICR was 16.7 months (95% CI, 9.8-not evaluable). Disease control rate was 63.0% (95% CI, 48.7-75.7) per ICR and 70.4% (95% CI, 56.4-82.0) per INV. Median OS was not reached. Median PFS per ICR was 8.3 months (95% CI, 4.2-15.9). The most common treatment-related adverse events were fatigue (37.0%), diarrhea (14.8%), pruritus (13.0%), hyperthyroidism (9.3%), and arthralgia (9.3%) as well as hypothyroidism, asthenia, constipation, and maculo-papular rash (7.4% each). There were no treatment-related deaths. Conclusions: Cemiplimab provided clinically meaningful antitumor activity, including durable responses, and an acceptable safety profile in patients with mBCC who had progressed on or were intolerant to HHI therapy. Citation Format: Karl Lewis, Ketty Peris, Aleksander Sekulic, Alexander J. Stratigos, Lara Dunn, Zeynep Eroglu, Anne Lynn S. Chang, Michael R. Migden, Suk-Young Yoo, Kosalai Mohan, Ebony Coates, Emmanuel Okoye, Timothy Bowler, Jean-François Baurain, Oliver Bechter, Axel Hauschild, Marcus O. Butler, Leonel Hernandez-Aya, Lisa Licitra, Rogerio I. Neves, Emily S. Ruiz, Frank Seebach, David M. Weinreich, George D. Yancopoulos, Israel Lowy, Priscila Goncalves, Matthew G. Fury. Primary analysis of phase 2 results for cemiplimab in patients with metastatic basal cell carcinoma who progressed on or were intolerant to hedgehog inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT165.

Immunotherapy has redefined the treatment of cancer patients and it is constantly generating new advances and approaches. Among the multiple options of immunotherapy, bispecific antibodies (bsAbs) represent a novel thoughtful approach. These drugs integrate the action of the immune system in a strategy to redirect the activation of innate and adaptive immunity toward specific antigens and specific tumor locations. Here we discussed some basic aspects of the design and function of bsAbs, their main challenges and the state-of-the-art of these molecules in the treatment of hematological and solid malignancies and future perspectives.

11541 Background: Ripretinib (R) is a switch-control tyrosine kinase inhibitor (TKI) indicated for the treatment of patients (pts) with advanced gastrointestinal stromal tumor (GIST) after prior treatment with ≥3 TKIs. In the INTRIGUE study (NCT03673501) there was no significant difference in median PFS (primary endpoint) between R and sunitinib (S). We present exploratory analyses of tolerability data and selected pt reported outcomes (PROs). Methods: Pts were randomized 1:1 to R 150 mg QD or S 50 mg QD 4 weeks on/2 weeks off.Dose modification was allowed for toxicity management. The event of interest was severe or life-threatening (grade ≥3) treatment-related adverse event prior to progression (sTRAE). Days with at least one sTRAE were summed for all treated pts and for pts with ≥1 sTRAE event. PROs were assessed using questions from EORTC QLQ-C30 and Dermatology Life Quality Index (DLQI) at cycle 1 (C1) day 1 (D1), D15, and D29; D1 and D29 of all other cycles; as well as at end of treatment. Differences in PRO scores between baseline and later assessments were calculated across visits. Long-term data will be presented. Results: Pts receiving R (n = 223) versus (vs) S (n = 221) experienced fewer sTRAEs (24% vs 51%, respectively). For all treated pts, the mean time with sTRAEs was 11 days for R and 42 days for S (ratio 0.27, P<0.0001). For pts with ≥1 sTRAE, the mean number of days with a sTRAE was 48 days for R vs 81 days for S (ratio 0.59, p = 0.037). Completion of PRO assessments across the two treatment arms was similar (baseline: R [n = 199], S [n = 199]; C1 D29: R [n = 167], S [n = 177]). Significant differences in self-reported functioning and symptoms were observed by C1 D29. For PROs relating to commonly reported sTRAEs, except constipation, pts in the R arm reported better outcomes than pts in the S arm. Pts in the R arm reported significantly (p<0.05) less decline compared to baseline in pt-reported role function as well as less increase, or improvement, in symptoms of fatigue, appetite loss, diarrhea, nausea/vomiting, and pain vs pts in the S arm. Moderate or severe effect of skin toxicity on pt life, as measured by DLQI in the R arm (n = 165) and in the S arm (n = 175), was observed in 6.6% of pts in the R arm vs 14.8% of pts in the S arm (p = 0.015). Conclusions: In the INTRIGUE study the total number of days with sTRAEs was fewer for pts receiving R vs S. Pts in the R arm also reported significantly less decline in pt-reported role function and less increase in symptoms related to commonly reported sTRAEs, except constipation, vs pts in the S arm. Medical writing provided by Costello Medical. Clinical trial information: NCT03673501.