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BACKGROUND: Immunotherapy (IO) and oral anticancer agents (OAA) have improved outcomes for metastatic renal cell carcinoma (mRCC) but there is a need to understand real-world costs from the perspective of payers and patients. METHODS: We used retrospective fee-for-service Medicare 100% claims data to study patients diagnosed with mRCC in 2015-2019. We identified initial treatment type and costs (the year after diagnosis) and analyzed differences in monthly and 12-month costs over time and between OAA, IO, and combination groups and the association between OOP costs and adherence. RESULTS: We identified 15,407 patients with mRCC (61% male; 85% non-Hispanic white). 6,196 received OAA, IO or combination OAA/IO as initial treatment. OAA use decreased (from 31% to 11%) with a simultaneous rise in patients receiving IO (3% to 26%) or combination IO/OAA therapy (1% to 11%). Medicare payments for all patients with mRCC increased by 41%, from $60,320 (95% CI: 58,260-62,380) in 2015 to $85,130 (95% CI: 82,630-87,630) in 2019. Payments increased in patients who received OAA, IO or combination OAA/IO but were stable in those with other/no treatment. Initial higher OOP responsibility ($200-$1000) was associated with 13% decrease in percent days covered in patients receiving OAA in the first 90 days of treatment, compared to those whose OOP responsibility was <$200. CONCLUSION: From 2015-2019, costs for Medicare patients with mRCC rose substantially due to more patients receiving IO or IO/OAA combined therapy and increases in costs among those receiving those therapies. Increased OOP costs was associated with decreased adherence.
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Importance: Area-level measures of sociodemographic disadvantage may be associated with racial and ethnic disparities with respect to receipt of treatment for metastatic renal cell carcinoma (mRCC) but have not been investigated previously, to our knowledge. Objective: To assess the association between area-level measures of social vulnerability and racial and ethnic disparities in the treatment of US Medicare beneficiaries with mRCC from 2015 through 2019. Design, Setting, and Participants: This retrospective cohort study included Medicare beneficiaries older than 65 years who were diagnosed with mRCC from January 2015 through December 2019 and were enrolled in fee-for-service Medicare Parts A, B, and D from 1 year before through 1 year after presumed diagnosis or until death. Data were analyzed from November 22, 2022, through January 26, 2024. Exposures: Five different county-level measures of disadvantage and 4 zip code-level measures of vulnerability or deprivation and segregation were used to dichotomize whether an individual resided in the most vulnerable quartile according to each metric. Patient-level factors included age, race and ethnicity, sex, diagnosis year, comorbidities, frailty, Medicare and Medicaid dual enrollment eligibility, and Medicare Part D low-income subsidy (LIS). Main Outcomes and Measures: The main outcomes were receipt and type of systemic therapy (oral anticancer agent or immunotherapy from 2 months before to 1 year after diagnosis of mRCC) as a function of patient and area-level characteristics. Multivariable regression analyses were used to adjust for patient factors, and odds ratios (ORs) from logistic regression and relative risk ratios (RRRs) from multinomial logistic regression are reported. Results: The sample included 15â¯407 patients (mean [SD] age, 75.6 [6.8] years), of whom 9360 (60.8%) were men; 6931 (45.0%), older than 75 years; 93 (0.6%), American Indian or Alaska Native; 257 (1.7%), Asian or Pacific Islander; 757 (4.9%), Hispanic; 1017 (6.6%), non-Hispanic Black; 12â¯966 (84.2%), non-Hispanic White; 121 (0.8%), other; and 196 (1.3%), unknown. Overall, 8317 patients (54.0%) received some type of systemic therapy. After adjusting for individual factors, no county or zip code-level measures of social vulnerability, deprivation, or segregation were associated with disparities in treatment. In contrast, patient-level factors, including female sex (OR, 0.78; 95% CI, 0.73-0.84) and LIS (OR, 0.48; 95% CI, 0.36-0.65), were associated with lack of treatment, with particularly limited access to immunotherapy for patients with LIS (RRR, 0.25; 95% CI, 0.14-0.43). Associations between individual-level factors and treatment in multivariable analysis were not mediated by the addition of area-level metrics. Disparities by race and ethnicity were consistently and only observed within the most vulnerable areas, as indicated by the top quartile of each vulnerability deprivation index. Conclusions and Relevance: In this cohort study of older Medicare patients diagnosed with mRCC, individual-level demographics, including race and ethnicity, sex, and income, were associated with receipt of systemic therapy, whereas area-level measures were not. However, individual-level racial and ethnic disparities were largely limited to socially vulnerable areas, suggesting that efforts to improve racial and ethnic disparities may be most effective when targeted to socially vulnerable areas.
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Carcinoma de Células Renais , Disparidades em Assistência à Saúde , Neoplasias Renais , Medicare , Humanos , Masculino , Feminino , Idoso , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/etnologia , Estados Unidos , Estudos Retrospectivos , Medicare/estatística & dados numéricos , Neoplasias Renais/terapia , Neoplasias Renais/etnologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde/etnologia , Idoso de 80 Anos ou mais , Vulnerabilidade Social , Populações Vulneráveis/estatística & dados numéricos , Fatores SocioeconômicosRESUMO
Therapeutic approaches for clear cell renal cell carcinoma (ccRCC) remain limited; however, chimeric antigen receptor (CAR) T-cell therapies may offer novel treatment options. CTX130, an allogeneic CD70-targeting CAR T-cell product, was developed for the treatment of advanced or refractory ccRCC. We report that CTX130 showed favorable preclinical proliferation and cytotoxicity profiles and completely regressed RCC xenograft tumors. We also report results from 16 patients with relapsed/refractory ccRCC who received CTX130 in a phase I, multicenter, first-in-human clinical trial. No patients encountered dose-limiting toxicity, and disease control was achieved in 81.3% of patients. One patient remains in a durable complete response at 3 years. Finally, we report on a next-generation CAR T construct, CTX131, in which synergistic potency edits to CTX130 confer improved expansion and efficacy in preclinical studies. These data represent a proof of concept for the treatment of ccRCC and other CD70+ malignancies with CD70- targeted allogeneic CAR T cells. Significance: Although the role of CAR T cells is well established in hematologic malignancies, the clinical experience in solid tumors has been disappointing. This clinical trial demonstrates the first complete response in a patient with RCC, reinforcing the potential benefit of CAR T cells in the treatment of solid tumors.
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Ligante CD27 , Carcinoma de Células Renais , Imunoterapia Adotiva , Neoplasias Renais , Humanos , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/imunologia , Animais , Neoplasias Renais/terapia , Neoplasias Renais/imunologia , Imunoterapia Adotiva/métodos , Camundongos , Feminino , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos Quiméricos/imunologia , Idoso , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , AdultoRESUMO
In 2022, the American Council for Graduate Medical Education (ACGME) recommended that core faculty (CF) in medical subspecialty fellowships receive at least 0.1 full-time equivalent (FTE) salary support, with plans to enforce compliance in July 2023. After early feedback raised concerns about potential unintended consequences, ACGME deferred enforcement to July 2024. Hence, there is an urgent need to understand the ramifications of providing FTE support for CF. In 2020, the Yale hematology and medical oncology (HO) fellowship program began providing 0.1 FTE support to all CF. Perceptions regarding this were assessed via surveys distributed to all CF in 2021 and 2022 and to all HO fellows in 2021. The vast majority (83.3%) of CF survey respondents reported improved job satisfaction and an increased sense of involvement in the fellowship program as a result of the new 0.1 FTE-supported CF program. Most CF increased attendance at fellowship conferences, devoted more time to mentorship, and increased participation in recruitment. In free text comments, CF respondents described that providing 0.1 FTE support made them "feel rewarded," gave them "a sense of commitment" to the fellowship, and helped "offset clinical requirements." HO fellows reported "a positive impact" of the new program with faculty being "more present at lectures." The median number of times faculty were available to interview fellowship applicants rose markedly after introduction of the program. The FTE-supported CF program was viewed enthusiastically by fellows and faculty, resulting in increased CF involvement in fellowship education and recruitment.
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Docentes de Medicina , Bolsas de Estudo , Humanos , Inquéritos e Questionários , Salários e Benefícios , Satisfação no Emprego , Oncologia/educação , Educação de Pós-Graduação em Medicina , Mentores , Hematologia/educação , Seleção de Pessoal , Feminino , MasculinoRESUMO
Disparities in metastatic renal cell carcinoma (mRCC) outcomes persist in the era of oral anticancer agents (OAAs) and immunotherapies (IOs). We examined variation in the utilization of mRCC systemic therapies among US Medicare beneficiaries from 2015 to 2019. Logistic regression models evaluated the association between therapy receipt and demographic covariates including patient race, ethnicity, and sex. In total, 15 407 patients met study criteria. After multivariable adjustment, non-Hispanic Black race and ethnicity was associated with reduced IO (adjusted relative risk ratio [aRRR] = 0.76, 95% confidence interval [CI] = 0.61 to 0.95; P = .015) and OAA receipt (aRRR = 0.76, 95% CI = 0.64 to 0.90; P = .002) compared with non-Hispanic White race and ethnicity. Female sex was associated with reduced IO (aRRR = 0.73, 95% CI = 0.66 to 0.81; P < .001) and OAA receipt (aRRR = 0.74, 95% CI = 0.68 to 0.81; P < .001) compared with male sex. Thus, disparities by race, ethnicity, and sex were observed in mRCC systemic therapy utilization for Medicare beneficiaries from 2015 to 2019.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Masculino , Feminino , Idoso , Estados Unidos/epidemiologia , Carcinoma de Células Renais/tratamento farmacológico , Medicare , Neoplasias Renais/tratamento farmacológico , Etnicidade , BrancosRESUMO
PURPOSE: To summarize contemporary and emerging strategies for the diagnosis and management of metastatic hormone sensitive prostate cancer (mHSPC), focusing on diagnostic testing and therapeutics. METHODS: Literature review using PUBMED-Medline databases as well as clinicaltrials.gov to include reported or ongoing clinical trials on treatment for mHSPC. We prioritized the findings from phase III randomized clinical trials, systematic reviews, meta-analyses and clinical practice guidelines. RESULTS: There have been significant changes to the diagnosis and staging evaluation of mHSPC with the integration of increasingly accurate positron emission tomography (PET) imaging tracers that exceed the performance of conventional computerized tomography (CT) and bone scan. Germline multigene testing is recommended for the evaluation of patients newly diagnosed with mHSPC given the prevalence of actionable alterations that may create candidacy for specific therapies. Although androgen deprivation therapy (ADT) remains the backbone of treatment for mHSPC, approaches to first-line treatment include the integration of multiple agents including androgen receptor synthesis inhibitors (ARSI; abiraterone) Androgen Receptor antagonists (enzalutamide, darolutamide, apalautamide), and docetaxel chemotherapy. The combination of ADT, ARSI, and docetaxel chemotherapy has recently been evaluated in a randomized trial and was associated with significantly improved overall survival including in patients with a high burden of disease. The role of local treatment to the prostate with radiation has been evaluated in randomized trials with additional studies underway evaluating the role of cytoreductive radical prostatectomy. CONCLUSION: The staging and initial management of patients with mHSPC has undergone significant advances in the last decade with advancements in the diagnosis, treatment and sequencing of therapies.
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Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Docetaxel , Antagonistas de Androgênios/uso terapêutico , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hormônios/uso terapêuticoRESUMO
BACKGROUND: The IO Score is a 27-gene immuno-oncology (IO) classifier that has previously predicted benefit to immune checkpoint inhibitor (ICI) therapy in triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). It generates both a continuous score and a binary result using a defined threshold that is conserved between breast and lung. Herein, we aimed to evaluate the IO Score's binary threshold in ICI-naïve TCGA bladder cancer patients (TCGA-BLCA) and assess its clinical utility in metastatic urothelial cancer (mUC) using the IMvigor210 clinical trial treated with the ICI, atezolizumab. METHODS: We identified a list of tumor immune microenvironment (TIME) related genes expressed across the TCGA breast, lung squamous and lung adenocarcinoma cohorts (TCGA-BRCA, TCGA-LUSQ, and TCGA-LUAD, 939 genes total) and then examined the expression of these 939 genes in TCGA-BLCA, to identify patients as having high inflammatory gene expression. Using this as a test of classification, we assessed the previously established threshold of IO Score. We then evaluated the IO Score with this threshold in the IMvigor210 cohort for its association with overall survival (OS). RESULTS: In TCGA-BLCA, IO Score positive patients had a strong concordance with high inflammatory gene expression (p < 0.0001). Given this concordance, we applied the IO Score to the ICI treated IMvigor210 patients. IO Score positive patients (40%) had a significant Cox proportional hazard ratio (HR) of 0.59 (95% CI 0.45-0.78 p < 0.001) for OS and improved median OS (15.6 versus 7.5 months) compared to IO Score negative patients. The IO Score remained significant in bivariate models combined with all other clinical factors and biomarkers, including PD-L1 protein expression and tumor mutational burden. CONCLUSION: The IMvigor210 results demonstrate the potential for the IO Score as a clinically useful biomarker in mUC. As this is the third tumor type assessed using the same algorithm and threshold, the IO Score may be a promising candidate as a tissue agnostic marker of ICI clinical benefit. The concordance between IO Score and inflammatory gene expression suggests that the classifier is capturing common features of the TIME across cancer types.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos como Assunto , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/patologia , Microambiente TumoralRESUMO
BACKGROUND: Despite recent changes in the treatment landscape, there remains an unmet need for effective, tolerable, chemotherapy-free treatments for patients with advanced/metastatic urothelial carcinoma (mUC), especially cisplatin-ineligible patients. OBJECTIVE: To evaluate the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab in patients with advanced/mUC from the phase 2 multicenter PIVOT-02 study. DESIGN, SETTING, AND PARTICIPANTS: This open-label, multicohort phase 1/2 study enrolled patients with previously untreated locally advanced/surgically unresectable or mUC (N = 41). INTERVENTION: Patients received BEMPEG 0.006 mg/kg plus nivolumab 360 mg intravenously every 3 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objectives were safety and the objective response rate (ORR) in patients with measurable disease at baseline and at least one postbaseline tumor response assessment (response-evaluable). Secondary objectives were overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses via univariate logistic regression were performed to test the association between potential biomarkers (CD8+ tumor-infiltrating lymphocytes, tumor mutational burden, and IFN-γ gene expression profile) and response. RESULTS AND LIMITATIONS: The ORR was 35% (13/37 evaluable patients) and the complete response rate was 19% (7/37 patients); the median duration of response was not reached. Median PFS was 4.1 mo (95% confidence interval [CI] 2.1-8.7) and median OS was 23.7 mo (95% CI 15.8-not reached). Overall, 40/41 patients (98%) experienced at least one treatment-related adverse event (TRAE); grade 3/4 TRAEs occurred in 11 patients (27%), most commonly pyrexia (4.9%; 2 patients). Exploratory biomarker analyses showed no association between biomarkers and response. Limitations include the small sample size and single-arm design. CONCLUSIONS: BEMPEG plus nivolumab was well tolerated and showed antitumor activity as first-line treatment in patients with locally advanced/mUC. PATIENT SUMMARY: We investigated an immune-stimulating prodrug called bempegaldesleukin plus the antibody nivolumab as the first therapy for patients with advanced or metastatic cancer of the urinary tract. This combination had manageable treatment-related side effects and was effective in a subset of patients. This trial is registered at ClinicalTrials.gov as NCT02983045.
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Carcinoma de Células de Transição , Pró-Fármacos , Neoplasias da Bexiga Urinária , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/secundário , Humanos , Interleucina-2/uso terapêutico , Nivolumabe/efeitos adversos , Pró-Fármacos/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/etiologiaRESUMO
BACKGROUND: Immune checkpoint inhibitor-based combinations have expanded the treatment options for patients with renal cell carcinoma (RCC); however, tolerability remains challenging. The aim of this study was to evaluate the safety and efficacy of the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) as first-line therapy in patients with advanced clear-cell RCC. METHODS: This was an open-label multicohort, multicenter, single-arm phase 1/2 study; here, we report results from the phase 1/2 first-line RCC cohort (N=49). Patients received BEMPEG 0.006 mg/kg plus NIVO 360 mg intravenously every 3 weeks. The primary objectives were safety and objective response rate (ORR; patients with measurable disease at baseline and at least one postbaseline tumor response assessment). Secondary objectives included overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses: association between baseline biomarkers and ORR. RESULTS: At a median follow-up of 32.7 months, the ORR was 34.7% (17/49 patients); 3/49 patients (6.1%) had a complete response. Of the 17 patients with response, 14 remained in response for >6 months, and 6 remained in response for >24 months. Median PFS was 7.7 months (95% CI 3.8 to 13.9), and median OS was not reached (95% CI 37.3 to not reached). Ninety-eight per cent (48/49) of patients experienced ≥1 treatment-related adverse event (TRAE) and 38.8% (19/49) had grade 3/4 TRAEs, most commonly syncope (8.2%; 4/49) and increased lipase (6.1%; 3/49). No association between exploratory biomarkers and ORR was observed. Limitations include the small sample size and single-arm design. CONCLUSIONS: BEMPEG plus NIVO showed preliminary antitumor activity as first-line therapy in patients with advanced clear-cell RCC and was well tolerated. These findings warrant further investigation.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais , Neoplasias Renais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Feminino , Humanos , Interleucina-2/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Nivolumabe/uso terapêuticoRESUMO
PURPOSE: Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma. METHODS: A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers. RESULTS: At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response. CONCLUSION: BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Interleucina-2/análogos & derivados , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Polietilenoglicóis/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Europa (Continente) , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Interleucina-2/efeitos adversos , Interleucina-2/uso terapêutico , Masculino , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nivolumabe/efeitos adversos , Polietilenoglicóis/efeitos adversos , Intervalo Livre de Progressão , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Fatores de Tempo , Estados UnidosRESUMO
PURPOSE OF REVIEW: This review will discuss current understanding and management approaches of Intraductal carcinoma of the prostate (IDC-P). IDC-P is a histological finding characterized by neoplastic cells that expand but do not invade prostate ducts. RECENT FINDINGS: The presence of IDC-P on a prostate biopsy is almost always associated with an invasive disease component and is independently associated with worse clinical outcomes in both early and late disease. These tumors are enriched for mutations in homologous DNA recombination repair (HRR) leading to high genomic instability. Multiparametric MRI with targeted biopsy may aid in diagnosis. Given the poor clinical outcomes associated with this histologic entity, its presence in biopsies should warrant consideration of aggressive management.
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Carcinoma Ductal/genética , Reparo de Erro de Pareamento de DNA/genética , Predisposição Genética para Doença/genética , Instabilidade de Microssatélites , Mutação , Neoplasias da Próstata/genética , Carcinoma Ductal/patologia , Carcinoma Ductal/terapia , Humanos , Masculino , Gradação de Tumores , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Transdução de Sinais/genéticaRESUMO
This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8+ T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.See related commentary by Rouanne et al., p. 1097.This article is highlighted in the In This Issue feature, p. 1079.
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Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/administração & dosagem , Interleucina-2/análogos & derivados , Neoplasias Renais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Nivolumabe/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Melanoma/genética , Melanoma/imunologia , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Polietilenoglicóis/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Resultado do Tratamento , Adulto JovemRESUMO
High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rß). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.
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Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/análogos & derivados , Melanoma/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Pró-Fármacos/administração & dosagem , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/administração & dosagem , Interleucina-2/agonistas , Interleucina-2/imunologia , Ipilimumab/administração & dosagem , Ativação Linfocitária/efeitos dos fármacos , Melanoma/genética , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Adoptive cell therapy (ACT) with autologous tumor infiltrating lymphocytes (TIL) has been studied for patients with advanced metastatic cancers (primarily melanoma) for decades and has changed significantly during that period. Treatment with TIL includes ex vivo cell activation and expansion followed by re-infusion of these cells into the patient. After cell infusion, patients receive Interleukin-2 (IL-2). Objective response rates up to 52% have been seen in patients with metastatic melanoma. Efforts to improve TIL therapy include better selection and expansion of tumor-reactive lymphocytes, optimization of IL-2 or other T cell activating cytokine dosing, and, potentially, genetic manipulation of the immune cell product. Here we describe methods involved in the collection, expansion, and treatment with TIL for patients with metastatic melanoma.
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Protocolos Clínicos , Imunoterapia Adotiva/métodos , Melanoma/imunologia , Melanoma/terapia , Humanos , Depleção Linfocítica , Linfócitos do Interstício Tumoral/imunologiaRESUMO
Cell-mediated cytotoxicity is a critical function of the immune system in mounting defense against pathogens and cancers. Current methods that allow direct evaluation of cell-mediated cytotoxicity suffer from a wide-range of drawbacks. Here, we present a novel strategy to measure cytotoxicity that is direct, sensitive, rapid, and highly adaptable. Moreover, it allows accurate measurement of viability of both target and effector cells. Target cells are fluorescently labeled with a non-toxic, cell-permeable dye that covalently binds to cell proteins, including nuclear proteins. The labeled target cells are incubated with effector cells to begin killing. Following the killing reaction, the cell mixture is incubated with another dye that specifically stains proteins of dead cells, including nuclear proteins. In the final step, cell nuclei are released by Triton X-100, and analyzed by flow cytometry. This results in four nuclear staining patterns that separate target and effector nuclei as well as nuclei of live and dead cells. Analyzing nuclei, instead of cells, greatly reduces flow cytometry errors caused by the presence of target-effector cell aggregates. Target killing time can often be reduced to 2â¯h and the assay can be done in a high throughput format. We have successfully validated this assay in a variety of cytotoxicity scenarios including those mediated by NK-92 cells, Chimeric Antigen Receptor (CAR)-T cells, and Tumor Infiltrating Lymphocytes (TIL). Therefore, this technique is broadly applicable, highly sensitive and easily administered, making it a powerful tool to assess immunotherapy-based, cell-mediated cytotoxicity.
Assuntos
Testes Imunológicos de Citotoxicidade/métodos , Citotoxicidade Imunológica , Citometria de Fluxo , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Núcleo Celular/imunologia , Núcleo Celular/patologia , Ensaios de Triagem em Larga Escala , Humanos , Imunoterapia Adotiva , Masculino , Melanoma/imunologia , Melanoma/patologia , Camundongos Endogâmicos C57BL , Valor Preditivo dos Testes , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Reprodutibilidade dos Testes , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Fatores de Tempo , Fluxo de TrabalhoRESUMO
NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor ßγ to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. SIGNIFICANCE: We believe that IL2- and IL2 pathway-targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.See related commentary by Sullivan, p. 694.This article is highlighted in the In This Issue feature, p. 681.
Assuntos
Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-2/análogos & derivados , Interleucina-2/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Polietilenoglicóis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Interleucina-2/farmacocinética , Interleucina-2/uso terapêutico , Neoplasias/etiologia , Neoplasias/patologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: Renal cell carcinoma (RCC) was recognized as an immunologically sensitive cancer over 30 years ago. The first therapies to affect the course of RCC were cytokines (interferon alfa-2B and interleukin-2). Subsequently, drugs that inhibit HIF (hypoxia-inducible factor)/VEGF (vascular endothelial growth factor) signaling demonstrated overall survival advantages (tyrosine kinase inhibitors and mTor inhibitors). RECENT FINDINGS: In the last 3 years, the immune checkpoint inhibitors (ICIs) have become the standard of care treatments in the first and second lines for RCC. Emerging data show that combinations of ICI, HIF signaling inhibitors, and cytokines are potentially powerful regimens. How to combine and sequence these types of therapies and how to integrate new approaches into the management of RCC are now the key questions for the field. Treatment of RCC is likely to change dramatically in the next few years.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Imunoterapia/tendências , Neoplasias Renais/tratamento farmacológico , Carcinoma de Células Renais/imunologia , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologiaRESUMO
BACKGROUND: Sorafenib, an oral tyrosine kinase inhibitor, may enhance the antitumor activity of platinum-based chemotherapy in transitional-cell carcinoma. This study investigated the safety and clinical outcome of adding sorafenib to gemcitabine and carboplatin for patients with advanced transitional-cell carcinoma. PATIENTS AND METHODS: Subjects with metastatic or unresectable chemotherapy-naive TCC with Eastern Cooperative Oncology Group performance status 0 or 1 received gemcitabine (1000 mg/m2 on days 1 and 8) and carboplatin (area under the curve of 5 on day 1) with sorafenib (400 mg 2 times a day on days 2-19 every 21 days) for 6 cycles. Subjects with stable disease or partial or complete response continued to receive sorafenib until disease progression. The primary end point was progression-free survival (PFS) at 5 months with a secondary end point of response (partial or complete). RESULTS: Seventeen subjects were enrolled. The median number of cycles of gemcitabine and carboplatin with sorafenib provided was 4.4. A total of 15, 5, and 8 subjects required reductions of gemcitabine, carboplatin, and sorafenib, respectively. Thirteen subjects (76%) required multiple dose reductions. Eleven subjects (65%) were free of progression at 5 months. The overall response rate was 54% (95% confidence interval [CI], 0.28-077), with 4 patients experiencing complete response (24%; 95% CI, 0.07-0.50) and 5 partial response (29%; 95% CI, 0.10-0.56); 7 subjects (41%) had stable disease. Median PFS was 9.5 months (95% CI, 0.43-1.26), and median overall survival was 25.2 months (95% CI, 0.96-5.65). One-year PFS was 31%, and 1-year overall survival was 72%. Eleven subjects (65%) discontinued treatment because of toxicity. There were no toxic deaths. CONCLUSION: Gemcitabine and carboplatin with sorafenib showed clinical activity in advanced TCC, with some prolonged progression-free intervals. However, gemcitabine and carboplatin with sorafenib was associated with significant toxicity, causing discontinuation of therapy in most patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos , Análise de Sobrevida , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/patologia , GencitabinaRESUMO
PURPOSE OF REVIEW: Over the last 10 years, harnessing of the immune system to attack tumors has been one of the major breakthroughs in cancer, primarily through the use of immune checkpoint inhibitors (ICIs). This review will summarize current immune treatments in urologic malignancies and ongoing trials with novel combinations and in different disease settings. RECENT FINDINGS: Patients with urologic malignancies such as kidney and bladder cancer have benefited significantly from these advances with the approval of ICIs in both of these diseases. In addition, older immune therapies have also been used in these malignancies. For example, kidney cancers, which are traditionally unresponsive to chemotherapy, can respond to immune activation by cytokines. Prostate cancers, too, have immune therapies, such as sipuleucel-T, a dendritic cell vaccine. Combining ICIs with these older treatments as well as with molecularly targeted therapies and chemotherapies are currently underway. SUMMARY: The ICIs have changed the way urologic malignancies are treated and newer combinations are likely to alter the therapeutic landscape in these diseases dramatically in the coming years.
Assuntos
Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Neoplasias Renais/terapia , Neoplasias Urológicas/terapia , Humanos , Masculino , Urologia/tendênciasRESUMO
Unbiased genetic screens are an excellent way to discover novel genes involved in specific biological processes in vivo. Modifier screens, whether to suppress or enhance a phenotype, are a powerful way to find proteins that modulate biological processes responsible for specific phenotypes. However, modification of phenotypes that are only partially penetrant, which is often the case, are often extremely difficult to screen this way in a traditional F2 or non-clonal genetic screen. Here we describe an F3 or clonal screen in the nematode Caenorhabditis elegans to search for genes that modify partially penetrant phenotypes. Specifically we describe a screen to search for modifiers of genes that cause defects in migration of a specific developmentally regulated cell, the distal tip cell.