المؤلفون: Menzies, Alexander M, Long, Georgina V, Kohn, Amiee, Tawbi, Hussein, Weber, Jeffrey, Flaherty, Keith, McArthur, Grant A, Ascierto, Paolo A, Pfluger, Yanina, Lewis, Karl, Tsai, Katy K, Hamid, Omid, Prenen, Hans, Fein, Luis, Wang, Erjian, Guenzel, Carolin, Zhang, Fan, Kleha, Joseph F, di Pietro, Alessandra, Davies, Michael A

المصدر: Neuro-Oncology Advances ; ISSN 2632-2498

مصطلحات موضوعية: Surgery, Oncology, Neurology (clinical)

الوصف: Background POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases. Methods The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg BID plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg QD plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined. Results RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (n=10), 1 achieved complete response and 5 achieved partial responses (PR); brain metastasis response rate [BMRR] was 60% [95% CI: 26.2, 87.8]). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data. Conclusions Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2 and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.

الإتاحة: https://doi.org/10.1093/noajnl/vdae033Test

المؤلفون: Miaskowski, Christine, Paul, Steven M, Snowberg, Karin, Abbott, Maura, Borno, Hala T, Chang, Susan M, Chen, Lee May, Cohen, Bevin, Cooper, Bruce A, Hammer, Marilyn J, Kenfield, Stacey A, Kober, Kord M, Laffan, Angela, Levine, Jon D, Pozzar, Rachel, Rhoads, Kim, Tsai, Katy K, Van Blarigan, Erin L, Van Loon, Katherine

المصدر: Cancer. 127(17)

مصطلحات موضوعية: Behavioral and Social Science, Cancer, Depression, Mental Health, 2.3 Psychological, social and economic factors, Aetiology, Mental health, Good Health and Well Being, Anxiety, COVID-19, Humans, Loneliness, Neoplasms, Public Health Surveillance, Risk Factors, SARS-CoV-2, Social Isolation, Surveys and Questionnaires, anxiety, cancer, coronavirus disease 2019, depression, loneliness, sleep disturbance, social isolation, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis

الوصف: BackgroundLoneliness and social isolation are significant public health problems that are being exacerbated during the coronavirus disease 2019 pandemic. Little is known about the associations between loneliness and symptom burden in oncology patients before and during the pandemic. Study purposes include determining the prevalence of loneliness in a sample of oncology patients; evaluating for differences in demographic, clinical, and symptom characteristics between lonely and nonlonely patients; and determining which demographic, clinical, and symptom characteristics were associated with membership in the lonely group.MethodsA convenience sample (n = 606) completed online surveys that evaluated the severity of loneliness, social isolation, and common symptoms (ie, anxiety, depression, fatigue, sleep disturbance, cognitive dysfunction, and pain) in oncology patients. Parametric and nonparametric tests were used to evaluate for differences in scores between the lonely and nonlonely groups. Logistic regression analysis was used to determine risk factors for membership in the loneliness group.ResultsOf the 606 patients, 53.0% were categorized in the lonely group. The lonely group reported higher levels of social isolation, as well as higher symptom severity scores for all of the symptoms evaluated. In the multivariate model, being unmarried, having higher levels of social isolation, as well as higher levels of anxiety and depressive symptoms were associated with membership in the lonely group.ConclusionsStudy findings suggest that a significant number of oncology patients are experiencing loneliness, most likely as a result of mandate social distancing and isolation procedures. The symptom burden of these patients is extremely high and warrants clinical evaluation and interventions.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6qh9421kTest

المؤلفون: Pauken, Kristen E, Shahid, Osmaan, Lagattuta, Kaitlyn A, Mahuron, Kelly M, Luber, Jacob M, Lowe, Margaret M, Huang, Linglin, Delaney, Conor, Long, Jaclyn M, Fung, Megan E, Newcomer, Kathleen, Tsai, Katy K, Chow, Melissa, Guinn, Samantha, Kuchroo, Juhi R, Burke, Kelly P, Schenkel, Jason M, Rosenblum, Michael D, Daud, Adil I, Sharpe, Arlene H, Singer, Meromit

المصدر: Journal of Experimental Medicine. 218(4)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adenocarcinoma, Animals, Biomarkers, Tumor, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Colonic Neoplasms, Female, Humans, Melanoma, Mice, Mice, Inbred C57BL, Programmed Cell Death 1 Receptor, Receptors, Antigen, T-Cell, Single-Cell Analysis, Skin Neoplasms, Transcriptome, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences

الوصف: The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA and TCR sequencing to detect and characterize "tumor-matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors or melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared with nonmatching T cells in blood and were less exhausted than matching cells in tumors. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome, we identified candidate cell surface markers for TM cells in mice and patients and validated NKG2D, CD39, and CX3CR1 in mice. These data show that the TCR can be used to identify tumor-relevant cells for characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1wg2169bTest

المؤلفون: Miaskowski, Christine, Paul, Steven M, Snowberg, Karin, Abbott, Maura, Borno, Hala, Chang, Susan, Chen, Lee May, Cohen, Bevin, Cooper, Bruce A, Hammer, Marilyn J, Kenfield, Stacey A, Laffan, Angela, Levine, Jon D, Pozzar, Rachel, Tsai, Katy K, Van Blarigan, Erin L, Van Loon, Katherine

المصدر: Supportive Care in Cancer. 29(4)

مصطلحات موضوعية: Health Services and Systems, Health Sciences, Basic Behavioral and Social Science, Rare Diseases, Behavioral and Social Science, Clinical Research, Cancer, 7.3 Management and decision making, Management of diseases and conditions, 7.1 Individual care needs, Good Health and Well Being, Adult, Aged, COVID-19, COVID-19 Testing, Educational Status, Female, Health Knowledge, Attitudes, Practice, Humans, Infection Control, Male, Middle Aged, Neoplasms, Patients, Perception, Quarantine, SARS-CoV-2, Surveys and Questionnaires, United States, Perceptions, Fears, Mitigation procedures, Symptoms, Medical and Health Sciences, Psychology and Cognitive Sciences, Oncology & Carcinogenesis, Biomedical and clinical sciences, Health sciences, Psychology

الوصف: PurposeNo information is available on cancer patients' knowledge of and experiences with COVID-19. We undertook an evaluation of differences in COVID-19 symptom occurrence rates, COVID-19 testing rates, clinical care activities, knowledge of COVID-19, and use of mitigation procedures between patients who were and were not receiving active cancer treatment.MethodsPatients enrolled were > 18 years of age; had a diagnosis of cancer; and were able to complete the emailed study survey online.ResultsOf the 174 patients who participated, 27.6% (n = 48) were receiving active treatment, 13.6% were unemployed because of COVID-19, 12.2% had been tested for COVID-19, and 0.6% had been hospitalized for COVID-19. Patients who were not on active treatment reported a higher mean number of COVID-19 symptoms (3.1 (± 4.2) versus 1.9 (± 2.6)), and patients who reported a higher number of COVID-19 symptoms were more likely to be tested. Over 55% of the patients were confident that their primary care provider could diagnose COVID-19, and the majority of the patients had high levels of adherence with the use of precautionary measures (e.g., social distancing, use of face coverings).ConclusionThe high level of COVID-19 symptoms and the significant overlap of COVID-19 and cancer-related symptoms pose challenges for clinicians who are assessing and triaging oncology patients for COVID-19 testing. For patients on active treatment, clinicians face challenges with how to assess and manage symptoms that, prior to COVID-19, would be ascribed to acute toxicities associated with cancer treatments or persistent symptoms in cancer survivors.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/63g6j8swTest

المؤلفون: Levine, Lauren S, Mahuron, Kelly M, Tsai, Katy K, Wu, Clinton, Mattis, Daiva M, Pauli, Mariela L, Oglesby, Arielle, Lee, James C, Spitzer, Matthew H, Krummel, Matthew F, Algazi, Alain P, Rosenblum, Michael D, Alvarado, Michael, Daud, Adil I

المصدر: Annals of Surgical Oncology. 27(11)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Patient Safety, Cancer, Immunization, Clinical Research, Vaccine Related, CTLA-4 Antigen, Humans, Immune Checkpoint Inhibitors, Immunotherapy, Kaplan-Meier Estimate, Melanoma, Neoadjuvant Therapy, Programmed Cell Death 1 Receptor, Tumor Microenvironment, Oncology & Carcinogenesis, Oncology and carcinogenesis

الوصف: BackgroundThe frequency of "exhausted" or checkpoint-positive (PD-1+CTLA-4+) cytotoxic lymphocytes (Tex) in the tumor microenvironment is associated with response to anti-PD-1 therapy in metastatic melanoma. The current study determined whether pretreatment Tex cells in locally advanced melanoma predicted response to neoadjuvant anti-PD-1 blockade.MethodsPretreatment tumor samples from 17 patients with locally advanced melanoma underwent flow cytometric analysis of pretreatment Tex and regulatory T cell frequency. Patients who met the criteria for neoadjuvant checkpoint blockade were treated with either PD-1 monotherapy or PD-1/CTLA-4 combination therapy. Best overall response was evaluated by response evaluation criteria in solid tumors version 1.1, with recurrence-free survival (RFS) calculated by the Kaplan-Meier test. The incidence and severity of adverse events were tabulated by clinicians using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.ResultsOf the neoadjuvant treated patients, 10 received anti-PD-1 monotherapy and 7 received anti-CTLA-4/PD-1 combination therapy. Of these 17 patients, 12 achieved a complete response, 4 achieved partial responses, and 1 exhibited stable disease. Surgery was subsequently performed for 11 of the 17 patients, and 8 attained a complete pathologic response. Median RFS and overall survival (OS) were not reached. Immune-related adverse events comprised four grade 3 or 4 events, including pneumonitis, transaminitis, and anaphylaxis.ConclusionThe results showed high rates of objective response, RFS, and OS for patients undergoing immune profile-directed neoadjuvant immunotherapy for locally advanced melanoma. Furthermore, the study showed that treatment stratification based upon Tex frequency can potentially limit the adverse events associated with combination immunotherapy. These data merit further investigation with a larger validation study.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2tv559t6Test

المؤلفون: Algazi, Alain P, Twitty, Christopher G, Tsai, Katy K, Le, Mai, Pierce, Robert, Browning, Erica, Hermiz, Reneta, Canton, David A, Bannavong, Donna, Oglesby, Arielle, Francisco, Murray, Fong, Lawrence, Pittet, Mikael J, Arlauckas, Sean P, Garris, Christopher, Levine, Lauren P, Bifulco, Carlos, Ballesteros-Merino, Carmen, Bhatia, Shailender, Gargosky, Sharron, Andtbacka, Robert HI, Fox, Bernard A, Rosenblum, Michael D, Daud, Adil I

المصدر: Clinical Cancer Research. 26(12)

مصطلحات موضوعية: Clinical Research, Cancer, Clinical Trials and Supportive Activities, Adult, Aged, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Case-Control Studies, Female, Follow-Up Studies, Humans, Interleukin-12, Male, Melanoma, Middle Aged, Prognosis, Programmed Cell Death 1 Receptor, Prospective Studies, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: PurposeTumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).Patients and methodsTavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.ResultsThe combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.ConclusionsThe combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/59t2b8v3Test

المؤلفون: Greaney, Samantha K, Algazi, Alain P, Tsai, Katy K, Takamura, Kathryn T, Chen, Lawrence, Twitty, Christopher G, Zhang, Li, Paciorek, Alan, Pierce, Robert H, Le, Mai H, Daud, Adil I, Fong, Lawrence

المصدر: Cancer Immunology Research. 8(2)

مصطلحات موضوعية: Clinical Trials and Supportive Activities, Cancer, Clinical Research, Inflammatory and immune system, Adjuvants, Immunologic, Antigens, Neoplasm, Biomarkers, CD8-Positive T-Lymphocytes, Electroporation, Humans, Immunity, Cellular, Immunotherapy, Interferon-gamma, Interleukin-12, Melanoma, Neoplasm Staging, Patient Safety, Plasmids, Skin Neoplasms, Treatment Outcome, Tumor Microenvironment, Immunology, Oncology and Carcinogenesis, Pharmacology and Pharmaceutical Sciences

الوصف: Whereas systemic IL12 is associated with potentially life-threatening toxicity, intratumoral delivery of IL12 through tavokinogene telseplasmid electroporation (tavo) is safe and can induce tumor regression at distant sites. The mechanism by which these responses are mediated is unknown but is presumed to result from a cellular immune response. In a phase II clinical trial of tavo (NCT01502293), samples from 29 patients with cutaneous melanoma with in-transit disease were assessed for immune responses induced with this treatment. Within the blood circulating immune cell population, we found that the frequencies of circulating PD-1+ CD4+ and CD8+ T cells declined with treatment. Circulating immune responses to gp100 were also detected following treatment as measured by IFNγ ELISpot. Patients with a greater antigen-specific circulating immune response also had higher numbers of CD8+ T cells within the tumor. Clinical response was also associated with increased intratumoral CD3+ T cells. Finally, intratumoral T-cell clonality and convergence were increased after treatment, indicating a focusing of the T-cell receptor repertoire. These results indicated that local treatment with tavo can induce a systemic T-cell response and recruit T cells to the tumor microenvironment.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/28b0z9wrTest

المؤلفون: Jacob, Saya, Micu, Markee, Quandt, Zoe, Tsai, Katy K, Yaghoubi, Shahriar, Daud, Adil

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2023-sitc2023.0775Test

المؤلفون: Bommareddy, Praveen K, Monteagudo, Alina, Milhem, Mohammed, Sacco, Joseph J, Bowles, Tawnya Lynn, Tsai, Katy K, In, Gino K, Muñoz-Couselo, Eva, VanderWalde, Ari M, Chesney, Jason Alan, Michels, Judith, Samson, Adel, Beasley, Georgia M, Wise-Draper, Trisha M, Schadendorf, Dirk, Mahmoud, Fade, Wong, Michael K, Hong, Walter, Hou, Jeannie W, Clack, Aaron, Coffin, Robert S, Middleton, Mark R, Chmielowski, Bartosz

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2023-sitc2023.0705Test

المؤلفون: Migden, Michael R, Chai-Ho, Wanxing, Daniels, Gregory A, Wise-Draper, Trisha M, Kheterpal, Meenal, Tang, Jennifer C, Bolotin, Diana, Verschraegen, Claire, Poklepovic, Andrew S, Khan, Shaheer A, Ibrahim, Sherrif F, Zeitouni, Nathalie C, Medina, Theresa, Tsai, Katy K, Tucci, Chris, Navia, Susan, Donthireddy, Laxminarasimha, Bommareddy, Praveen K, Hou, Jeannie W, Davar, Diwakar

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2023-sitc2023.0777Test