Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden

BACKGROUND: Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma. METHODS: Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8+ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario. RESULTS: PD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity. CONCLUSIONS: In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden

Streamlining Cross-Institutional Processes: the Next Great Frontier for Supplying High-Quality Biospecimens to Translational Researchers

Translational cancer research is continuously in need of high-quality biospecimens and clinically associated data to enable research projects. While many have recognized the benefits of a process approach to manage researchers’ requests, most are less cognizant about which processes are to be considered, which sub-processes and activities are contained in each process, and how the processes interact with each other and with traditional functional silos. In order to provide a strategic and operational description of each of the four functional units of our Biospecimen Repository Facility (BRF), illustrations of the interfaces among the processes and a semi-standardized method for effective request fulfillment for development and implementation is presented. The method follows a customer service approach that integrates the BRF patient consent, biospecimen collection and distribution capabilities, operational logistics as well as the Departments of Pathology, Surgery and Clinical Data Management. The method is constantly tested and remains semi-standardized in order to be efficient, flexible to adjust based on marketing plans and changes in the oncology research land-scape, and monitored to be tracked and flagged when not meeting expected requirements. The implementation of this method has reduced wait times, ensured commitment to provide biospecimens and data based on feasibility and inventory, and researchers’ requests executed and fulfilled in an organized and efficient manner

Breaking Barriers: Cultivating a Collaborative Infrastructure in a Hybrid Academic Community Cancer Center

Cultivating an internal collaborative infrastructure is critical for the success of new initiatives that require multi-departmental and multidisciplinary services. Ensuring that the Bio-specimen Repository Facility (BRF) program at Miami Cancer Institute is logistically positioned to continuously enroll participants, collect fit-for-purpose biospecimens, and annotate them with clinical information is critical to support translational research. Five pivotal departments were identified for developing collaborative efforts: Surgery, Infusion Services, Laboratory, Pathology and the Oncology Data Warehouse team. Here we present the dynamic workflows established for patients consented in the clinical areas of Infusion and Surgery, for routine and specific biospecimen collection in the Laboratory and Pathology Departments and for complex data extraction by the Oncology Data Warehouse team. We also dis-cuss strategies used by BRF leadership to interconnect departments and encourage cooperation by focusing on the common goal, presenting issues as a problem-solving opportunity, assigning cross-functional liaisons, developing multi-functional teams for critical launches and nurturing effective communication strategies for increased productivity

Trolox enhances anti-leukemic effects of arsenic trioxide: the role of oxidative stress

Arsenic trioxide (As2O3) has considerable efficacy in the treatment of acute promyelocytic leukemia (APL), inducing partial differentiation and promoting apoptosis of malignant promyelocytes. Although initial studies focused on the role of the characteristic APL fusion protein, PML-RARα, in mediating the response to As2O3, recent investigations indicate that its cytotoxic activities are mediated by mechanisms independent of this fusion protein. As2O3 affects numerous intracellular targets mainly through the accumulation of free radicals and consequent induction of oxidative stress and causes a wide range of alterations leading to apoptosis. The intracellular oxidative status has been shown to be important for As2O3 sensitivity. Hematologic cancers other than APL and, solid tumors are less responsive to As2O3 monotherapy in part because their increased redox buffering capacity. Thus, the use of As2O3 in other malignancies is limited by the toxicity of concentrations required to induce apoptosis. The primary goal of the work presented in this thesis was a search for agents that could enhance As2O3 efficacy in malignant cells, but not in normal cells. We demonstrated that trolox (6–hydroxy–2,5,7,8–tetramethylchroman–2–carboxylic acid), a widely known antioxidant, enhances As2O3-mediated apoptosis in APL, P388 murine lymphoma, myeloma and breast cancer cells through the potentiation of As2O3-induced oxidative stress. We performed in vivo experiments in P388 tumor-bearing mice, and show that As2O3 treatment prolonged survival, and the addition of trolox provided a significant further increase in life span and decreased the number of animal with visible macrometastasis. Importantly, trolox protected normal blood mononuclear cells and non-malignant hepatocytes from As2O3-mediated cytotoxicity in vitro and protected non-tumors and tumors-bearing animals from arsenic-induced hepatotoxicity. We next investigated the mechanisms responsible for the opposite effLe trioxyde d’arsenic (As2O3) induit l’apoptose ainsi qu’une différentiation partielle des promyélocytes malins et de cette façon, il est considérablement efficace dans le traitement de la leucémie promyelocytic aigüe (APL). Les premières études sur le trioxyde d’arsenic ont mis en lumière l’importance de la protéine de fusion PML-RAR. Cependant, plusieurs études récentes démontrent que l’acitvité cytotoxiques de l’As2O3 dépend de mécanismes indépendants de PML-RAR. Entres autres, la présence d’As2O3 dans la cellule engendre une accumulation de radicaux libre qui affecte de nombreuses cibles intracellulaires et provoque une variété de changement qui vont mener à l’apoptose. L’équilibre oxydatif intracellulaire à démontré être important pour la sensibilité des cellules cancéreuse face à l’As2O3. Les cancers hématologiques autres que l’APL ainsi que les tumeurs solides semblent moins sensibles à l’As2O3 puisqu’elles possèdent une grande capacité d’oxydoréduction. L’utilisation de l’As2O3 contre plusieurs cancers est par conséquent limitée; les doses effectives pour induire l’apoptose étant toxique pour les cellules saines. L’objectif de la recherche présenté dans cette thèse est d’augmenter l’efficacité de l’As2O3 par le biais de thérapies combinatoires.Un antioxydant largement reconnu, le trolox (acide 6-hydroxy-2,5,7,8-tétraméthylchroman-2-carboxilique) augmente l’effet de l’As2O3 sur l’apoptose dans des cellules APL, de myélome, de cancer du sein en potentialisant le stress oxydatif. Par des expériences in vivo, nous observons que l’As2O3 prolonge la survie de souris possédant les tumeurs P388. De plus, la combinatoire avec le trolox augmente significativement la durée de vie de ces souris et diminue la quantité de candidats présentant des macrométastases. D’une autre part, des études in vitro montre que le trolox protège les cellules mononuc

Recruiting Terminally Ill Patients into Non-Therapeutic Oncology Studies: views of Health Professionals

Abstract Background Non-therapeutic trials in which terminally ill cancer patients are asked to undergo procedures such as biopsies or venipunctures for research purposes, have become increasingly important to learn more about how cancer cells work and to realize the full potential of clinical research. Considering that implementing non-therapeutic studies is not likely to result in direct benefits for the patient, some authors are concerned that involving patients in such research may be exploitive of vulnerable patients and should not occur at all, or should be greatly restricted, while some proponents doubt whether such restrictions are appropriate. Our objective was to explore clinician-researcher attitudes and concerns when recruiting patients who are in advanced stages of cancer into non-therapeutic research. Methods We conducted a qualitative exploratory study by carrying out open-ended interviews with health professionals, including physicians, research nurses, and study coordinators. Interviews were audio-recorded and transcribed. Analysis was carried out using grounded theory. Results The analysis of the interviews unveiled three prominent themes: 1) ethical considerations; 2) patient-centered issues; 3) health professional issues. Respondents identified ethical issues surrounding autonomy, respect for persons, beneficence, non-maleficence, discrimination, and confidentiality; bringing to light that patients contribute to science because of a sense of altruism and that they want reassurance before consenting. Several patient-centered and health professional issues are having an impact on the recruitment of patients for non-therapeutic research. Facilitators were most commonly associated with patient-centered issues enhancing communication, whereas barriers in non-therapeutic research were most often professionally based, including the doctor-patient relationship, time constraints, and a lack of education and training in research. Conclusions This paper aims to contribute to debates on the overall challenges of recruiting patients to non-therapeutic research. This exploratory study identified general awareness of key ethical issues, as well as key facilitators and barriers to the recruitment of patients to non-therapeutic studies. Due to the important role played by clinicians and clinician-researchers in the recruitment of patients, it is essential to facilitate a greater understanding of the challenges faced; to promote effective communication; and to encourage educational research training programs.</p