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1.
Proc Natl Acad Sci U S A ; 117(26): 15148-15159, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32541028

RESUMO

The potency of adoptive T cell therapies targeting the cell surface antigen CD19 has been demonstrated in hematopoietic cancers. It has been difficult to identify appropriate targets in nonhematopoietic tumors, but one class of antigens that have shown promise is aberrant O-glycoprotein epitopes. It has long been known that dysregulated synthesis of O-linked (threonine or serine) sugars occurs in many cancers, and that this can lead to the expression of cell surface proteins containing O-glycans comprised of a single N-acetylgalactosamine (GalNAc, known as Tn antigen) rather than the normally extended carbohydrate. Previously, we used the scFv fragment of antibody 237 as a chimeric antigen receptor (CAR) to mediate recognition of mouse tumor cells that bear its cognate Tn-glycopeptide epitope in podoplanin, also called OTS8. Guided by the structure of the 237 Fab:Tn-OTS8-glycopeptide complex, here we conducted a deep mutational scan showing that residues flanking the Tn-glycan contributed significant binding energy to the interaction. Design of 237-scFv libraries in the yeast display system allowed us to isolate scFv variants with higher affinity for Tn-OTS8. Selection with a noncognate human antigen, Tn-MUC1, yielded scFv variants that were broadly reactive with multiple Tn-glycoproteins. When configured as CARs, engineered T cells expressing these scFv variants showed improved activity against mouse and human cancer cell lines defective in O-linked glycosylation. This strategy provides CARs with Tn-peptide specificities, all based on a single scFv scaffold, that allows the same CAR to be tested for toxicity in mice and efficacy against mouse and human tumors.


Assuntos
Antígenos Glicosídicos Associados a Tumores/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/fisiologia , Sequência de Aminoácidos , Animais , Anticorpos , Linhagem Celular Tumoral , Evolução Molecular Direcionada , Epitopos/genética , Humanos , Camundongos , Modelos Moleculares , Mutação , Conformação Proteica , Receptores de Antígenos Quiméricos/genética
2.
Support Care Cancer ; 30(1): 897-906, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34401981

RESUMO

PURPOSE: Adults with acute myeloid leukemia (AML) face considerable distress and often have a poor prognosis. However, little is known about these patients' perceptions of prognosis and how this relates to emotional well-being (EWB). METHODS: We conducted a prospective, observational study of 50 adult patients with AML initiating chemotherapy, and surveyed them longitudinally for 6 months about their prognosis, treatment goals, quality of life, and EWB (by FACT-G). We derived a prognostic estimate for each patient based on data from published trials summarized in National Comprehensive Care Network Guidelines. We used descriptive statistics and longitudinal modeling to test the hypothesis that more accurate prognostic awareness is associated with worse EWB. RESULTS: Most patients (n = 43; 86%) had an objectively poor prognosis attributable to relapsed disease, complex karyotype, or FLT3 mutation. Yet, 74% of patients reported expecting a 50% or greater chance of cure. Patients with a poor prognosis more often had discordant prognostic estimates, compared to those with favorable risk AML (OR = 7.25, 95% CI 1.21, 43.37). Patient-reported prognostic estimates did not vary significantly over time. At baseline, patients who better understood their prognosis had worse EWB and overall quality-of-life scores (EWB 12 vs. 19.5; p = 0.01; FACT-G 65 vs. 75.5; p = 0.01). CONCLUSION: Patients with AML overestimate their prognosis, and awareness of a poor prognosis is associated with worse emotional well-being. Efforts are needed to improve patients' understanding of their prognosis, and to provide more psychosocial support and attention to well-being as part of high-quality leukemia care.


Assuntos
Leucemia Mieloide Aguda , Qualidade de Vida , Adulto , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Prognóstico , Estudos Prospectivos
3.
Am Heart J ; 233: 5-9, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33306993

RESUMO

Our analysis from a national registry shows that compared to cancer, cardiovascular disease patients referred to palliative care are a decade older, have worse functional status and clinician-estimated prognosis. Both groups have very high symptom burden, with cardiovascular disease patients experiencing more dyspnea while pain, nausea, and fatigue are more common in cancer.


Assuntos
Doenças Cardiovasculares/terapia , Neoplasias/terapia , Cuidados Paliativos , Fatores Etários , Idoso , Dor do Câncer , Doenças Cardiovasculares/complicações , Efeitos Psicossociais da Doença , Dispneia/etiologia , Fadiga/etiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Náusea/etiologia , Neoplasias/complicações , Razão de Chances , Desempenho Físico Funcional , Prognóstico , Encaminhamento e Consulta , Sistema de Registros
4.
Exp Cell Res ; 393(2): 112014, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32439494

RESUMO

Understanding interactions between immune cells and their targets is an important step on the path to fully characterizing the immune system, and in doing so, learning how it combats disease. Many studies of these interactions have a narrow focus, often looking only at a binary result of whether or not a specific treatment was successful or only focusing on the interactions between two individual cells. Therefore, in an effort to more comprehensively study multicellular interactions among immune cells and their targets, we used in vitro longitudinal time-lapse imaging and developed an automated cell cluster analysis tool, or macro, to investigate the formation of cell clusters. In particular, we investigated the behavior of cancer-specific CD8+ and CD4+ T cells on how they interact around their targets: cancer cells and antigen-presenting cells. The macro that we established allowed us to examine these large-scale clustering behaviors taking place between those four cell types. Thus, we were able to distinguish directed immune cell clustering from random cell movement. Furthermore, this macro can be generalized to be applicable to systems consisting of any number of differently labeled species and can be used to track clustering behaviors and compare them to randomized simulations.


Assuntos
Comunicação Celular/fisiologia , Técnicas de Cultura de Células , Movimento Celular/fisiologia , Linfócitos T/citologia , Animais , Análise por Conglomerados , Camundongos Endogâmicos C57BL
5.
Carcinogenesis ; 41(11): 1605-1615, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-32221533

RESUMO

Human papillomavirus (HPV) infection is necessary but insufficient for progression of epithelial cells from dysplasia to carcinoma-in situ (CIS) to invasive cancer. The combination of mutant cellular and viral oncogenes that regulate progression of cervical cancer (CC) remains unclear. Using combinations of HPV16 E6/E7 (E+), mutant Kras (mKras) (K+) and/or loss of Pten (P-/-), we generated autochthonous models of CC without exogenous estrogen, carcinogen or promoters. Furthermore, intravaginal instillation of adenoCre virus enabled focal activation of the oncogenes/inactivation of the tumor suppressor gene. In P+/+ mice, E6/E7 alone (P+/+E+K-) failed to cause premalignant changes, while mKras alone (P+/+E-K+) caused persistent mucosal abnormalities in about one-third of mice, but no cancers. To develop cancer, P+/+ mice needed both E6/E7 and mKras expression. Longitudinal endoscopies of P+/+E+K+ mice predicted carcinoma development by detection of mucosal lesions, found on an average of 23 weeks prior to death, unlike longitudinal quantitative PCRs of vaginal lavage samples from the same mice. Endoscopy revealed that individual mice differed widely in the time required for mucosal lesions to appear after adenoCre and in the time required for these lesions to progress to cancer. These cancers developed in the transition zone that extends, unlike in women, from the murine cervix to the distal vagina. The P-/-E+K+ genotype led to precipitous cancer development within a few weeks and E6/E7-independent cancer development occurred in the P-/-E-K+ genotype. In the P-/-E+K- genotype, mice only developed CIS. Thus, distinct combinations of viral and cellular oncogenes are involved in distinct steps in cervical carcinogenesis.


Assuntos
Carcinógenos/toxicidade , Endoscopia/métodos , Estrogênios/toxicidade , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias Vaginais/patologia , Animais , Carcinogênese , Feminino , Papillomavirus Humano 16/isolamento & purificação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , PTEN Fosfo-Hidrolase/fisiologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias Vaginais/diagnóstico por imagem , Neoplasias Vaginais/etiologia , Neoplasias Vaginais/metabolismo
6.
Support Care Cancer ; 28(11): 5099-5107, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32040637

RESUMO

PURPOSE: Utilization of electronic patient-reported outcomes (ePROs) in the clinic can improve quality of life and prolong survival in cancer care. However, there remain unanswered questions regarding trends in missing data and the potential effect on real-time patient care. METHODS: This study utilized a prospectively collected dataset of ePROs from oncology clinics that administered the Patient Care Monitor 2.0 (PCM), a validated symptoms survey assessing 78 items for men, and 86 for women. We tabulated the frequency of missing items, by item and domain (emotional, functional and physical symptom-related), and examined these by age, gender, education, race and marital status. RESULTS: Within 20,986 encounters, there were responses to at least 1 PCM item from 6933 unique patients. The highest frequency of missing answers occurred for: "attend a paid job" (10.7%), "reduced sexual enjoyment" (3.8%), and "run" (3.7%). By domain, 12.3% of functional, 8.4% of physical symptom-related, and 1.6% of emotional constructs contained at least one missing item. For functional and physical symptom-related items, missingness was most common in patients >60 years old. CONCLUSION: The frequency of missingness was highest for functional items, like attending a paid job, suggesting that some respondents (e.g., retirees without a paid job) skipped questions that were less applicable to them. More universal issues for cancer patients, such as emotional well-being, had much lower frequencies of missingness. This suggests differential item completion that warrants further study to understand the inherent drivers. Identifying causes of missingness could improve the clinical utility of ePROs and highlight opportunities to personalize care.


Assuntos
Interpretação Estatística de Dados , Registros Eletrônicos de Saúde , Neoplasias/diagnóstico , Neoplasias/terapia , Medidas de Resultados Relatados pelo Paciente , Adulto , Coleta de Dados/métodos , Bases de Dados Factuais , Feminino , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Neoplasias/psicologia , Qualidade de Vida , Inquéritos e Questionários
7.
Support Care Cancer ; 27(10): 3897-3904, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30762144

RESUMO

PURPOSE: Pruritus is a common symptom in cutaneous malignancies, but its impact on patients with solid tumors is unclear. We explored the impact and management of pruritus in patients with solid tumors, using patient-reported outcomes (PRO) data from a real-world registry. METHODS: From 2006 to 2011, patients seen in the Duke Cancer Institute reported their symptoms via the Patient Care Monitor v2.0, a validated PRO tool that includes a 0-10-point question about pruritus severity. From > 25,000 encounters, 203 patients reported severe pruritus (> 6/10) on at least one visit and 506 total visits were abstracted where patients reported either moderate or severe pruritus (> 3/10). From this cohort, we abstracted demographics, diagnosis, stage, cancer therapy, anti-pruritic therapy, and clinicians' responses. RESULTS: Mean age was 59.8 (SD 13.3), 134 (66%) were female, 125 (62%) were Caucasian, and 65 (32%) were African American. Breast cancer was the most common tumor (36.5%), followed by lung cancer (23.2%). Mean pruritus severity score was 6.8 (SD 1.8) for patients on chemotherapy, 6.9 (SD 1.8) for patients on targeted therapy alone or in combination, and 7.1(SD 1.8) for patients off treatment. Overall, 67% of patients reported at least two episodes of moderate-severe pruritus (mean # of visits 4.2 (SD 2.7)). Despite frequent report of severe and persistent pruritus, this was mentioned in just 28% of clinician notes and an intervention was recommended/prescribed in only 7% of visits. CONCLUSIONS: Pruritus is an under-addressed symptom in patients with solid tumors. Additional research is needed to understand the burden of pruritus in affected populations.


Assuntos
Neoplasias da Mama/patologia , Neoplasias Pulmonares/patologia , Prurido/diagnóstico , Autorrelato/estatística & dados numéricos , Neoplasias Cutâneas/patologia , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prurido/complicações , Prurido/terapia , Inquéritos e Questionários
8.
Support Care Cancer ; 26(5): 1437-1445, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29151174

RESUMO

PURPOSE: Shared decision-making in acute myeloid leukemia (AML) requires understanding patients' longitudinal experiences of illness, but little is known about the impact of remission status on patient-reported outcomes (PROs). We aimed to explore the association between remission status and PROs 6-12 months following induction chemotherapy. METHODS: Forty-two patients completed three validated instruments characterizing symptom burden (Patient Care Monitor v2.0), distress (NCCN Distress Thermometer), and QOL (FACT-Leu), as part of a longitudinal observational study. We used regression models to explore the relationship between remission status and PROs, and explore differences by initial disease type (de novo versus secondary/relapsed AML). RESULTS: Those with secondary or relapsed AML at study onset had marked impairments in all measures compared to de novo AML patients. After 6 months, their mean distress score was 4.8 (> 4.0 warrants intervention), they reported a mean of 14.1 moderate/severe symptoms and had a mean QOL score of 113.6, compared to 1.0, 1.7, and 155.2, respectively, for those with de novo AML (p < .0001). Similarly, patients in relapse had a mean distress score of 5.3, a mean of 12.8 moderate/severe symptoms, and a mean QOL score of 113.4, compared to 1.8, 5.7, and 143.8, respectively, among those in remission (p < .005). These patterns persisted after adjusting for baseline differences (p < .0001). CONCLUSION: Remission is associated with markedly better patient well-being in AML. Patients with secondary or relapsed AML face more severe symptom burden, distress, and QOL issues after induction. Interventions are needed to improve AML patients' experiences of illness.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida/psicologia , Indução de Remissão/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Support Care Cancer ; 26(4): 1197-1205, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29101469

RESUMO

PURPOSE: The research on cancer treatment decision-making focuses on dyads; the full "triad" of patients, oncologists, and caregivers remains largely unstudied. We investigated how all members of this triad perceive and experience decisions related to treatment for advanced cancer. METHODS: At an academic cancer center, we enrolled adult patients with advanced gastrointestinal or hematological malignancies, their caregivers, and their oncologists. Triad members completed a semi-structured qualitative interview and a survey measuring decisional conflict and perceived influence of the other triad members on treatment decisions. RESULTS: Seventeen patients, 14 caregivers, and 10 oncologists completed the study. Patients and caregivers reported little decisional regret and voiced high satisfaction with their decisions, but levels of decisional conflict were high. We found sizeable disagreement among triad members' perceptions and preferences. For example, patients and oncologists disagreed about the caregiver's influence on the decision 56% of the time. In addition, many patients and caregivers preferred to defer to their oncologist about treatment decisions, felt like no true decision existed, and disagreed with their oncologist about how many treatment options had been presented. CONCLUSIONS: Patients, caregivers, and oncologists have discordant perceptions of the cancer treatment decision-making process, and bring different preferences about how they want to make decisions. These data suggest that oncologists should assess patients' and caregivers' decisional preferences, explicitly signal that a decision needs to be made whenever approaching an important crossroads in treatment and ensure that patients and caregivers understand the full range of presented options.


Assuntos
Cuidadores/psicologia , Tomada de Decisões/ética , Neoplasias/terapia , Oncologistas/psicologia , Pacientes/psicologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Percepção , Projetos Piloto , Inquéritos e Questionários
10.
Microcirculation ; 22(4): 267-75, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25689594

RESUMO

OBJECTIVE: We investigated whether hemodynamic optimization of systemic tissue perfusion based on PPV and CI improves microcirculatory perfusion when compared to a MAP-based strategy in patients undergoing elective abdominal surgery. METHODS: Patients were randomized into a PPV/CI guided group (n = 13, target PPV <12%, CI >2.5 L/min/m(2) , and MAP >70 mmHg) or MAP-guided group (n = 18, target MAP >70 mmHg). PPV, CI, and MAP were measured using noninvasive arterial blood pressure measurements. Sublingual microcirculatory perfusion was measured at one, two, and three hours following anesthesia induction, and quantified as TVD, PVD or the proportion of perfused vessels. Data were analyzed using ANOVA RM. RESULTS: Patients in the PPV/CI group required more fluid administration than control patients (1927 ± 747 mL versus 1283 ± 582 mL, respectively; p = 0.01). Despite this difference, we observed similar values for TVD (RM; F(1.28) = 0.01; p = 0.92), PVD (RM; F(1.28) = 0.09; p = 0.77) and the proportion of perfused vessels (RM; F(1.28) = 0.01; p = 0.76) in both groups. CONCLUSION: Hemodynamic optimization of systemic tissue perfusion is not associated with improvement of microcirculatory perfusion compared to a MAP-guided protocol in patients undergoing abdominal surgery.


Assuntos
Procedimentos Cirúrgicos Eletivos , Hemodinâmica , Microcirculação , Assistência Perioperatória , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Perfusão
11.
Support Care Cancer ; 23(8): 2341-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25586527

RESUMO

PURPOSE: Patients with cancer anorexia-cachexia syndrome (CACS) suffer a significant symptom burden, impaired quality of life (QoL), and shorter survival. Measurement of QoL impairments related to CACS is thereby important both in clinical practice and in research. We aimed to further validate the Functional Assessment of Anorexia-Cachexia Therapy (FAACT) scale in an advanced lung cancer population. METHODS: We tested the performance of the FAACT and its anorexia-cachexia subscale (ACS) within a dataset of patients with advanced non-small cell lung cancer (aNSCLC), using standard statistical methods. We then compared the performance of commonly used QoL measures stratified by CACS status and by patient self-report of appetite and weight loss. RESULTS: The FAACT and its ACS demonstrate internal validity consistent with acceptable published ranges for other QoL scales (Cronbach alpha = 0.9 and 0.79, respectively). Correlation coefficients demonstrate moderate correlations in the expected directions between FAACT and ACS and scales that measure related constructs. Comparing patients with and without CACS, the ACS is more sensitive to change than other QoL instruments (mean score 33.1 vs. 37.2, p = 0.011, ES = 0.58). CONCLUSION: In patients with aNSCLC, the FAACT and its ACS performed well compared with other instruments, further supporting their validity and value in clinical research. FAACT and ACS scores covaried with symptoms and other QoL changes that are typical hallmarks of CACS, lending further support to their use as QoL endpoints in clinical trials among patients with CACS.


Assuntos
Anorexia/diagnóstico , Caquexia/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/complicações , Neoplasias Pulmonares/complicações , Anorexia/etiologia , Caquexia/etiologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Feminino , Humanos , Estudos Longitudinais , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida
12.
BMC Health Serv Res ; 14: 315, 2014 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-25038783

RESUMO

BACKGROUND: Concerns about unsustainable costs in the US Medicare program loom as the number of retirees increase and experiences serious and costly illnesses like cancer. Engagement of stakeholders, particularly cancer patients and their families, in prioritizing insured services offers a valuable strategy for informing Medicare coverage policy. We designed and evaluated a decision exercise that allowed cancer patients and family members to choose Medicare benefits for advanced cancer patients. METHODS: The decision tool, Choosing Health plans All Together (CHAT) was modified to select services for advanced cancer patients. Patients with a cancer history (N = 246) and their family members (N = 194) from North Carolina participated in 70 CHAT sessions. Variables including participants' socio-demographic characteristics, health status, assessments of the exercise and results of group benefit selections were collected. Routine descriptive statistics summarized participant characteristics and Fisher's exact test compared group differences. Qualitative analysis of group discussions were used to ascertain reasons for or against selecting benefits. RESULTS: Patients and family members (N = 440) participated in 70 CHAT exercises. Many groups opted for such services as palliative care, nursing facilities, and services not currently covered by the Medicare program. In choosing among four levels of cancer treatment coverage, no groups chose basic coverage, 27 groups (39%) selected intermediate coverage, 39 groups (56%) selected high coverage, and 4 groups (6%) chose the most comprehensive cancer coverage. Reasons for or against benefit selection included fairness, necessity, need for prioritizing, personal experience, attention to family needs, holistic health outlook, preference for comfort, freedom of choice, and beliefs about the proper role of government. Participants found the exercise very easy (59%) or fairly easy (39%) to understand and very informative (66%) or fairly informative (31%). The majority agreed that the CHAT exercise led to fair decisions about priorities for coverage by which they could abide. CONCLUSIONS: It is possible to involve cancer patients and families in explicit discussions of their priorities for affordable advanced cancer care through the use of decision tools designed for this purpose. A key question is whether such a conversation is possible on a broader, national level.


Assuntos
Comportamento de Escolha , Técnicas de Apoio para a Decisão , Família/psicologia , Medicare , Neoplasias/psicologia , Neoplasias/terapia , Demografia , Feminino , Prioridades em Saúde , Necessidades e Demandas de Serviços de Saúde , Humanos , Benefícios do Seguro , Masculino , North Carolina , Estados Unidos
13.
Clin Cancer Res ; 30(8): 1642-1654, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38190111

RESUMO

PURPOSE: To achieve eradication of solid tumors, we examined how many neoantigens need to be targeted with how many T-cell receptors (TCR) by which type of T cells. EXPERIMENTAL DESIGN: Unmanipulated, naturally expressed (autochthonous) neoantigens were targeted with adoptively transferred TCR-engineered autologous T cells (TCR-therapy). TCR-therapy used CD8+ T-cell subsets engineered with TCRs isolated from CD8+ T cells (CD8+TCR-therapy), CD4+ T-cell subsets engineered with TCRs isolated from CD4+ T cells (CD4+TCR-therapy), or combinations of both. The targeted tumors were established for at least 3 weeks and derived from primary autochthonous cancer cell cultures, resembling natural solid tumors and their heterogeneity as found in humans. RESULTS: Relapse was common with CD8+TCR-therapy even when targeting multiple different autochthonous neoantigens on heterogeneous solid tumors. CD8+TCR-therapy was only effective against homogenous tumors artificially derived from a cancer cell clone. In contrast, a combination of CD8+TCR-therapy with CD4+TCR-therapy, each targeting one neoantigen, eradicated large and established solid tumors of natural heterogeneity. CD4+TCR-therapy targeted a mutant neoantigen on tumor stroma while direct cancer cell recognition by CD8+TCR-therapy was essential for cure. In vitro data were consistent with elimination of cancer cells requiring a four-cell cluster composed of TCR-engineered CD4+ and CD8+ T cells together with antigen-presenting cells and cancer cells. CONCLUSIONS: Two cancer-specific TCRs can be essential and sufficient to eradicate heterogeneous solid tumors expressing unmanipulated, autochthonous targets. We demonstrate that simplifications to adoptive TCR-therapy are possible without compromising efficacy.


Assuntos
Antígenos de Neoplasias , Neoplasias , Humanos , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Imunoterapia Adotiva/métodos
14.
J Immunother Cancer ; 11(5)2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37258040

RESUMO

BACKGROUND: Treatment of some blood cancers with T cells that express a chimeric antigen receptor (CAR) against CD19 have shown remarkable results. In contrast, CAR-T cell efficacy against solid tumors has been difficult to achieve. METHODS: To examine the potential of CAR-T cell treatments against ovarian cancers, we used the mouse ovarian cancer cell line ID8 in an intraperitoneal model that exhibits disseminated solid tumors in female C57BL/6J mice. The CAR contained a single-chain Fv from antibody 237 which recognizes a Tn-glycopeptide-antigen expressed by ID8 due to aberrant O-linked glycosylation in the absence of the transferase-dependent chaperone Cosmc. The efficacy of four Tn-dependent CARs with varying affinity to Tn antigen, and each containing CD28/CD3ζ cytoplasmic domains, were compared in vitro and in vivo in this study. RESULTS: In line with many observations about the impact of aberrant O-linked glycosylation, the ID8Cosmc knock-out (ID8Cosmc-KO) exhibited more rapid tumor progression compared with wild-type ID8. Despite the enhanced tumor growth in vivo, 237 CAR and a mutant with 30-fold higher affinity, but not CARs with lower affinity, controlled advanced ID8Cosmc-KO tumors. Tumor regression could be achieved with a single intravenous dose of the CARs, but intraperitoneal administration was even more effective. The CAR-T cells persisted over a period of months, allowing CAR-treated mice to delay tumor growth in a re-challenge setting. The most effective CARs exhibited the highest affinity for antigen. Antitumor effects observed in vivo were associated with increased numbers of T cells and macrophages, and higher levels of cleaved caspase-3, in the tumor microenvironment. Notably, the least therapeutically effective CAR mediated tonic signaling leading to antigen-independent cytokine expression and it had higher levels of the immunosuppressive cytokine interleukin10. CONCLUSION: The findings support the development of affinity-optimized CAR-T cells as a potential treatment for established ovarian cancer, with the most effective CARs mediating a distinct pattern of inflammatory cytokine release in vitro. Importantly, the most potent Tn-dependent CAR-T cells showed no evidence of toxicity in tumor-bearing mice in a syngeneic, immunocompetent system.


Assuntos
Neoplasias Ovarianas , Receptores de Antígenos Quiméricos , Humanos , Feminino , Camundongos , Animais , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T , Imunoterapia Adotiva/métodos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos C57BL , Citocinas/metabolismo , Microambiente Tumoral
15.
Curr Opin Immunol ; 74: 25-31, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34619458

RESUMO

Certain aspects of experimental tumor models in mice most accurately reflect the biology and immunology of cancer in patients. A survey of experimental cancer immunotherapy papers published in 2020 shows most do not achieve cancer shrinkage although treatment is initiated at an early time point after cancer cell injection, which does not reflect cancer immunotherapy in patients. Even then, few current experimental approaches eradicate the injected malignant cells, most only delay outgrowth. The value of targeting mutation-encoded tumor-specific antigens becomes increasingly evident while problems of finding normal gene-encoded tumor-associated antigens as safe, effective targets persist. It might be time to refocus on realistic experimental settings and truly cancer-specific targets. These antigens are associated with the least risk of side effects.


Assuntos
Neoplasias Experimentais , Neoplasias , Animais , Antígenos de Neoplasias , Humanos , Imunoterapia , Camundongos , Mutação , Neoplasias/terapia
16.
JCO Oncol Pract ; 17(2): e94-e100, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33439744

RESUMO

PURPOSE: Advance care planning (ACP) is a process in which patients share their values, goals, and preferences regarding future medical care. ACP can improve care quality, yet may be challenging to address for patients with cancer. We sought to characterize key components of ACP in patients with cancer as compared with patients with noncancer serious illness referred to palliative care (PC). METHODS: We performed a retrospective cross-sectional analysis of initial outpatient PC visits from the Quality Data Collection Tool for PC database from 2015 to 2019. Quality Data Collection Tool is a web-based point-of-care specialty PC registry to track quality metrics. RESULTS: We analyzed 1,604 patients with cancer and 1,094 patients without cancer: 44% of patients were female, 87% were White, and 98% were non-Hispanic. The average age was 72.2 years (standard deviation [SD] 15.4). Patients with cancer were on average younger than patients without cancer (66.5 [SD: 13.9] v 80.5 [SD: 13.8]) and had a higher Palliative Performance Scale (PPS) (59.5 [SD: 22.4] v 33.4 [SD: 25.1]). In our unadjusted comparison, patients with cancer were less likely to be DNR/DNI (37% v 53%; P < .0001) and less likely to have an advance directive (53% v 73%; < .0001); rates of healthcare proxy identification were similar (92.8% v 94.5%; P = .10). These differences did not persist when we accounted for age, race, sex, and PPS, with age being the primary explanatory factor. CONCLUSION: Despite having serious illness meriting PC referral, many patients with cancer in our study lacked advance directives. This highlights both the important role of oncologists in facilitating ACP and the utility of PC playing a complementary role.


Assuntos
Planejamento Antecipado de Cuidados , Neoplasias , Idoso , Estudos Transversais , Feminino , Humanos , Neoplasias/terapia , Cuidados Paliativos , Encaminhamento e Consulta , Estudos Retrospectivos
17.
Cancer Immunol Res ; 8(2): 192-202, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31831634

RESUMO

Burnet postulated that the diversity of T-cell receptors (TCR) allows T cells to protect against the development of cancers that display antigens with a similar, seemingly endless diversity. To test this hypothesis, we developed a strategy in which a single breeding pair of mice gives rise to four groups of sibling mice. Three of the four groups had a similar number of CD8+ T cells, but TCR diversity was either broad, significantly reduced, or absent when expressing only one type of TCR. The fourth group had no T cells. All mice shared the same housing, and, therefore, their microbial environment was similar. Only slight differences in the intestinal flora were observed under these conditions. An undisturbed broad TCR repertoire was required for the rejection of inoculated cancers displaying the natural antigenic heterogeneity of primary tumors, whereas even one type of TCR was sufficient to protect against artificial cancers stably expressing cognate antigens. The three groups of mice with limited or no TCR repertoire showed an increased risk of developing primary tumors after chemical induction. However, the risk of early death or morbidity in these cohorts of mice was significantly higher than in mice with a diverse TCR repertoire, and it remains unknown whether mice with reduced TCR diversity, who died early without cancer, would have developed tumors with higher, lower, or equal probability after induction. Together, TCR diversity seems crucial to overcome the natural genetic instability of cancers and their antigenic heterogeneity, which impacts the design of cellular therapies.


Assuntos
Transplante de Neoplasias/métodos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias/imunologia , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/metabolismo , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética
18.
J Pain Symptom Manage ; 59(5): e6-e13, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31778784

RESUMO

CONTEXT: Many clinical disciplines report high rates of burnout, which leads to low quality of care. Palliative care clinicians routinely manage patients with significant suffering, aiming to improve quality of life. As a major role of palliative care clinicians involves educating patients and caregivers regarding identifying priorities and balancing stress, we wondered how clinician self-management of burnout matches against the emotionally exhaustive nature of the work. OBJECTIVES: We sought to understand the prevalence and predictors of burnout using a discipline-wide survey. METHODS: We asked American Academy of Hospice and Palliative Medicine clinician members to complete an electronic survey querying demographic factors, job responsibilities, and the Maslach Burnout Inventory. We performed univariate and multivariable regression analyses to identify predictors of high rates of burnout. RESULTS: We received 1357 responses (response rate 30%). Overall, we observed a burnout rate of 38.7%, with higher rates reported by nonphysician clinicians. Most burnout stemmed from emotional exhaustion, with depersonalization comprising a minor portion. Factors associated with higher odds of burnout include nonphysician clinical roles, working in smaller organizations, working longer hours, being younger than 50 years of age, and working weekends. We did not observe different rates between palliative care clinicians and hospice clinicians. Higher rated self-management activities to mitigate burnout include participating in interpersonal relationships and taking vacations. CONCLUSION: Burnout is a major issue facing the palliative care clinician workforce. Strategies at the discipline-wide and individual levels are needed to sustain the delivery of responsive, available, high-quality palliative care for all patients with serious illness.


Assuntos
Esgotamento Profissional , Hospitais para Doentes Terminais , Esgotamento Profissional/epidemiologia , Esgotamento Psicológico , Humanos , Cuidados Paliativos , Prevalência , Qualidade de Vida , Inquéritos e Questionários
19.
JAMA Netw Open ; 2(5): e192375, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31050773

RESUMO

Importance: Use of palliative care (PC) for patients with cardiovascular disease (CVD) has increased recently. However, it is unknown if patients are receiving earlier referrals to PC. Objective: To assess characteristics and trends of patients with CVD referred to PC. Design, Setting, and Participants: Cohort study in which analysis of data from the multicenter Quality Data Collection Tool for Palliative Care registry from January 2, 2015, through December 29, 2017, included patients with CVD 18 years or older referred to initial PC consultation who had a documented palliative performance score (PPS) . Exposures: Patients with CVD who presented for an initial PC visit. Main Outcomes and Measures: The primary outcome was PPS. Secondary outcomes included symptoms and end-of-life documentation. Results: Among 1801 patients (mean [SD] age, 77.7 [13.7] years) from 16 sites in the analysis, 875 (48.6%) were women and 1339 (74.3%) were white. A low PPS score (0%-30%), consistent with bedbound status, was recorded for 521 patients (28.9%), with no change through time. The most common moderate to severe symptoms were poor well-being, tiredness, anorexia, and dyspnea. Year of encounter was associated with improved symptoms of pain (odds ratio, 1.25; 95% CI, 1.05-1.50) and with constipation (odds ratio, 1.32; 95% CI, 1.03-1.69). No change through time was noted in other symptoms or end-of-life documentation. Although the proportion of referrals from general medicine increased from 43.2% (167 of 387) in 2015 to 52.9% (410 of 775) in 2017, the proportion of referrals from cardiologists decreased from 16.5% (64 of 387) in 2015 to 10.5% (81 of 775) in 2017. The proportion of patients referred to PC who were black decreased from 11.9% (46 of 387) in 2015 to 6.3% (49 of 775) in 2017. While 69.5% of all patients with CVD (1252 of 1801) had a primary diagnosis of heart failure, the proportion of non-heart failure CVD diagnoses, such as coronary artery disease and valvular heart disease, increased from 25.6% (99 of 387) in 2015 to 30.1% (233 of 775) in 2017. Conclusions and Relevance: Patients with CVD demonstrated significant symptom burden, and there was no evidence in the registry of change in the PPSs of patients with CVD referred to PC through time. Cardiologists provided comparatively fewer referrals to PC for patients with CVD, and this proportion decreased through time. The proportion of racial and ethnic minorities referred to PC was small and decreased through time. These findings reinforce the need for cardiologists to be more engaged with PC and consider referring appropriate patients with CVD sooner.


Assuntos
Doenças Cardiovasculares/terapia , Cuidados Paliativos/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiologia/estatística & dados numéricos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Progressão da Doença , Feminino , Medicina Geral/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Índice de Gravidade de Doença
20.
Health Aff (Millwood) ; 38(6): 910-918, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31158018

RESUMO

Specialized palliative care teams improve outcomes for the steadily growing population of people living with serious illness. However, few studies have examined whether the specialty palliative care workforce can meet the growing demand for its services. We used 2018 clinician survey data to model risk factors associated with palliative care clinicians leaving the field early, and we then projected physician numbers from 2019 to 2059 under four scenarios. Our modeling revealed an impending "workforce valley," with declining physician numbers that will not recover to the current level until 2045, absent policy change. However, sustained growth in the number of fellowship positions over ten years could reverse the worsening workforce shortage. There is an immediate need for policies that support high-value, team-based palliative care through expansion in all segments of the specialty palliative care workforce, combined with payment reform to encourage the deployment of sustainable teams.


Assuntos
Previsões , Política de Saúde , Necessidades e Demandas de Serviços de Saúde , Mão de Obra em Saúde/tendências , Cuidados Paliativos/tendências , Médicos , Mão de Obra em Saúde/estatística & dados numéricos , Cuidados Paliativos na Terminalidade da Vida , Humanos , Médicos/estatística & dados numéricos , Médicos/provisão & distribuição , Fatores de Risco
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