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1.
Nat Commun ; 12(1): 729, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526794

RESUMO

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.


Assuntos
/uso terapêutico , Linfócitos/imunologia , Neoplasias/tratamento farmacológico , Neutrófilos/imunologia , Idoso , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Seguimentos , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/mortalidade , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Estudos Retrospectivos
2.
Clin Cancer Res ; 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33509808

RESUMO

PURPOSE: Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown. EXPERIMENTAL DESIGN: Patients with melanoma were prospectively offered tumor sequencing of 341-468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables. RESULTS: A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; P < 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months. CONCLUSIONS: Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor-refractory melanoma.

3.
Nat Genet ; 53(1): 11-15, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398197

RESUMO

In multiple cancer types, high tumor mutational burden (TMB) is associated with longer survival after treatment with immune checkpoint inhibitors (ICIs). The association of TMB with survival outside of the immunotherapy context is poorly understood. We analyzed 10,233 patients (80% non-ICI-treated, 20% ICI-treated) with 17 cancer types before/without ICI treatment or after ICI treatment. In non-ICI-treated patients, higher TMB (higher percentile within cancer type) was not associated with better prognosis; in fact, in many cancer types, higher TMB was associated with poorer survival, in contrast to ICI-treated patients in whom higher TMB was associated with longer survival.


Assuntos
Mutação/genética , Neoplasias/diagnóstico , Neoplasias/genética , Idoso , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida
4.
J Immunother ; 44(1): 9-15, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33290361

RESUMO

Chronic lymphocytic leukemia (CLL) is associated with immune dysfunction and an increased risk of melanoma. For patients with metastatic melanoma, immunotherapy with checkpoint blocking antibodies is a standard of care. In patients with concomitant CLL and metastatic melanoma, it is not known whether CLL might influence the antimelanoma efficacy or immune-related toxicities of immune checkpoint blockade. Fifteen patients with locally advanced or metastatic melanoma and a concomitant diagnosis of CLL who received pembrolizumab or ipilimumab with or without nivolumab for the treatment of their melanoma at Memorial Sloan Kettering Cancer Center between January 1, 2010, and January 1, 2017, were retrospectively identified. Clinical characteristics including absolute lymphocyte counts during therapy were recorded along with a response to treatment (objective radiographic response, progression-free survival, and adverse events) for each patient. Of 9 response-evaluable patients treated with ipilimumab, 3 (33%) had a partial response, 1 (11%) had stable disease, and 5 (56%) developed progressive disease. Objective tumor responses were also observed with single-agent therapy pembrolizumab and with combination therapy of nivolumab and ipilimumab. Grade 3 or 4 toxicity was observed in 6 of 15 patients (40%), including diarrhea, transaminitis, rash, and hemolytic anemia. Although our retrospective assessment was limited, there was no evidence that CLL responded to the checkpoint blockade. This case series demonstrates that ipilimumab, pembrolizumab, and combined ipilimumab and nivolumab therapies show clinical activity in patients with melanoma and concomitant CLL, at rates consistent with those previously reported. This population may warrant closer surveillance for hematologic immune-related toxicities such as autoimmune hemolytic anemia.

5.
Clin Cancer Res ; 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33323400

RESUMO

PURPOSE: Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (n = 3), uveal (n = 2), and acral (n = 2) melanoma subtypes. EXPERIMENTAL DESIGN: Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression. RESULTS: For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance. CONCLUSIONS: In 4 patients who received immunotherapy, we found 1-3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective.

6.
Semin Nucl Med ; 50(6): 584-603, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33059826

RESUMO

Imaging has played a critical role in the management of patients with cancer. Novel therapies are emerging rapidly; however, they are effective only in some patients. With the advent of new targeted therapeutics and immunotherapy, the limitations of conventional imaging methods are becoming more evident. FDG-PET imaging is restricted to the optimal assessment of immune therapies. There is a critical unmet need for pharmacodynamic and prognostic imaging biomarkers. Radiolabeled antibodies or small molecules can allow for specific assessment of targets in expression and concentration. Several such imaging agents have been under preclinical development. Early human studies with radiolabeled monoclonal antibodies or small molecules targeted to the epidermal growth factor receptor pathway have shown potential; targeted imaging of CA19.9 and CA-IX and are being further explored. Immune-directed imaging agents are highly desirable as biomarkers and preliminary studies with radiolabeled antibodies targeting immune mechanisms appear promising. While novel agents are being developed, larger well-designed studies are needed to validate the role of these agents as biomarkers in the clinical management of patients.

7.
J Transl Med ; 18(1): 346, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894202

RESUMO

The melanoma treatment landscape changed in 2011 with the approval of the first anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 checkpoint inhibitor and of the first BRAF-targeted monoclonal antibody, both of which significantly improved overall survival (OS). Since then, improved understanding of the tumor microenvironment (TME) and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. The approval of new immune and targeted therapies has further improved outcomes for patients with advanced melanoma and other combination modalities are also being explored such as chemotherapy, radiotherapy, electrochemotherapy and surgery. In addition, different strategies of drugs administration including sequential or combination treatment are being tested. Approaches to overcome resistance and to potentiate the immune response are being developed. Increasing evidence emerges that tissue and blood-based biomarkers can predict the response to a therapy. The latest findings in melanoma research, including insights into the tumor microenvironment and new biomarkers, improved understanding of tumor immune response and resistance, novel approaches for combination strategies and the role of neoadjuvant and adjuvant therapy, were the focus of discussions at the Melanoma Bridge meeting (5-7 December, 2019, Naples, Italy), which are summarized in this report.

8.
Eur J Radiol ; 131: 109250, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32905952

RESUMO

PURPOSE: To describe contrast-enhanced computed tomography (CECT), 18-Fluorine (18F)-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT and magnetic resonance imaging (MRI) findings of immune checkpoint inhibitor (ICI) associated pancreatitis in patients undergoing immunotherapy for solid malignant tumours. METHOD: In this retrospective study, 25 patients with clinical and/or biochemical evidence of pancreatitis who underwent CECT, MRI and 18F-FDG-PET/CT while being treated with ICIs were included. Imaging features of acute pancreatitis included: pancreatic enlargement, heterogeneous enhancement, peripancreatic stranding, fluid collection, pseudocyst, necrosis, atrophy and calcification. 18F-FDG PET/CT imaging was reviewed for pattern of abnormally increased pancreatic FDG uptake. ICI-associated pancreatitis diagnosis was based on clinical, imaging and biochemical findings. RESULTS: Imaging findings of ICI-associated pancreatitis included diffuse (n = 14) or focal (n = 11) pancreatic enlargement; heterogenous enhancement (n = 21); focal (n = 9) or diffuse (n = 15) peripancreatic infiltration on CECT and MRI. A pattern consistent with acute interstitial pancreatitis was present in 20/25 (80 %) patients, and a pattern consistent with autoimmune pancreatitis in 4/25 (16 %). A mixed pattern was present in one patient (4%). No patient developed necrotizing pancreatitis or a pseudocyst. The CT severity index was < 3 in all patients, consistent with mild pancreatitis. Focal pancreatic FDG uptake was noted in 2/3 (66 %) of patients. Acute imaging findings resolved with treatment in all 25 patients. Pancreatic atrophy developed in 11/25 (44 %). CONCLUSIONS: ICI-associated pancreatitis typically presents as either focal or diffuse acute interstitial pancreatitis. Post-pancreatitis atrophy is common. The ICI-associated pancreatitis cases in our study were mild, managed conservatively and did not result in local acute complications.

9.
J Am Acad Dermatol ; 83(5): 1239-1253, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32461079

RESUMO

As the incidence of cutaneous malignancies continues to rise and their treatment with immunotherapy expands, dermatologists and their patients are more likely to encounter immune checkpoint inhibitors. While the blockade of immune checkpoint target proteins (cytotoxic T-lymphocyte-associated protein-4, programmed cell death-1, and programmed cell death ligand-1) generates an antitumor response in a substantial fraction of patients, there is a critical need for reliable predictive biomarkers and approaches to address refractory disease. The first article of this Continuing Medical Education series reviews the indications, efficacy, safety profile, and evidence supporting checkpoint inhibition as therapeutics for metastatic melanoma, cutaneous squamous cell carcinoma, and Merkel cell carcinoma. Pivotal studies resulting in the approval of ipilimumab, pembrolizumab, nivolumab, cemiplimab, and avelumab by regulatory agencies for various cutaneous malignancies, as well as ongoing clinical research trials, are discussed.

10.
J Immunother Cancer ; 8(1)2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32238470

RESUMO

As the field of cancer immunotherapy continues to advance at a fast pace, treatment approaches and drug development are evolving rapidly to maximize patient benefit. New agents are commonly evaluated for activity in patients who had previously received a programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor as standard of care or in an investigational study. However, because of the kinetics and patterns of response to PD-1/PD-L1 blockade, and the lack of consistency in the clinical definitions of resistance to therapy, the design of clinical trials of new agents and interpretation of results remains an important challenge. To address this unmet need, the Society for Immunotherapy of Cancer convened a multistakeholder taskforce-consisting of experts in cancer immunotherapy from academia, industry, and government-to generate consensus clinical definitions for resistance to PD-(L)1 inhibitors in three distinct scenarios: primary resistance, secondary resistance, and progression after treatment discontinuation. The taskforce generated consensus on several key issues such as the timeframes that delineate each type of resistance, the necessity for confirmatory scans, and identified caveats for each specific resistance classification. The goal of this effort is to provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance.

11.
J Immunother Cancer ; 8(1)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32152222

RESUMO

BACKGROUND: Immune checkpoint inhibitors (CIs) have revolutionized treatment of advanced melanoma, leading to an emerging population of long-term survivors. Survivors' quality of life (QOL) and symptom burden are poorly understood. We set out to evaluate symptom burden and QOL in patients with advanced melanoma alive more than 1 year after initiating CI therapy. METHODS: Cross-sectional surveys, accompanied by chart review of patients with advanced melanoma treated with CIs at Memorial Sloan Kettering Cancer Center, completed therapy, and were alive >1 year after treatment initiation. Surveys were administered between February and August 2018. Surveys included: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, EuroQOL, items from Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events and Fatigue Severity Scale. RESULTS: We included 90 patients. The most common CI regimens were ipilimumab plus nivolumab (53%) and pembrolizumab (41%); most patients (71%) were not treated in clinical trials. Median time from CI therapy initiation was 40 months and from last dose was 28 months. Fatigue was reported by 28%, with higher fatigue scores in women than men; 12% reported difficulty sleeping. Aching joints (17%) and muscles (12%) were fairly common. Level of functioning was generally high. Overall QOL was excellent though 40% reported 'some or moderate' problems with anxiety/depression and 31% with pain/discomfort. CONCLUSIONS: After CI therapy, long-surviving advanced melanoma patients commonly report fatigue but otherwise have moderate symptom burden and good QOL. Ensuring appropriate symptom management will optimize clinical outcomes for these patients.

12.
Clin Cancer Res ; 26(13): 3193-3201, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32205463

RESUMO

PURPOSE: Preclinical data suggest that radiotherapy (RT) is beneficial in combination with immune checkpoint blockade. Clinical trials have explored RT with single-agent immune checkpoint blockade, but no trials have reported RT with the combination of nivolumab and ipilimumab. PATIENTS AND METHODS: We conducted a phase 1 study of patients with stage IV melanoma receiving nivolumab and ipilimumab with two different dose-fractionation schemes of RT. Patients had at least one melanoma metastasis that would benefit from palliative RT and one metastasis that would not be irradiated. Nivolumab 1 mg/kg + ipilimumab 3 mg/kg and extracranial RT with a dose of 30 Gy in 10 fractions was administered in Cohort A, and then 27 Gy in 3 fractions was administered in Cohort B. The primary outcome was safety. RESULTS: Twenty patients were treated (10 in each cohort). The rates of treatment-related grade 3-4 adverse events in Cohort A and B were 40% and 30%, respectively. There were no grade ≥3 adverse events attributed to RT. Patients responded to treatment outside of the irradiated volume (Cohort A 5/10; Cohort B 1/9). No evaluable patients had progression of irradiated metastases. Immunologic changes were seen in the peripheral blood with increases in T-cell receptor diversity in some responding patients. CONCLUSIONS: RT with nivolumab and ipilimumab was safe compared with historical data of nivolumab and ipilimumab alone. Immunologic effects were observed in the peripheral blood. Randomized studies are ongoing to assess whether RT increases the efficacy of nivolumab and ipilimumab.

13.
Oncologist ; 25(2): 140-149, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32043775

RESUMO

BACKGROUND: Checkpoint inhibitor therapy is widely known to cause a number of immune-related adverse events. One rare adverse effect that is emerging is eosinophilic fasciitis, a fibrosing disorder causing inflammatory infiltration of subcutaneous fascia. It is characterized clinically by edema and subsequent induration and tightening of the skin and subcutaneous tissues. The condition is rare, yet at our institutions we have seen four cases in the past 3 years. We describe our 4 cases and review 11 other cases reported in the literature. CASE PRESENTATION: We present four cases of eosinophilic fasciitis following treatment with programmed cell death protein 1 or programmed cell death-ligand 1 blockade. All patients had extremity involvement with characteristic skin changes ranging from peripheral edema to induration, tightening, and joint limitation. The patients had varying degrees of peripheral eosinophilia. In two of our patients, the diagnosis was made by full-thickness skin biopsy showing lymphocytic infiltration of the subcutaneous fascia, with CD4+ T cells predominating in one case and CD8+ T cells in the other. In the other two cases, the diagnosis was made on the basis of characteristic imaging findings in the context of clinical features consistent with the diagnosis. All four patients were treated with glucocorticoids with varying degrees of success; immunotherapy had to be discontinued in all four. Patients with advanced melanoma who experienced this adverse effect had either a partial response or a complete response to therapy. CONCLUSION: Eosinophilic fasciitis can occur as a result of checkpoint inhibitor therapy. Although a tissue diagnosis is the gold standard, imaging studies may facilitate the diagnosis in the presence of consistent clinical features, but a degree of suspicion is key to recognizing the condition early. Therapy requires a collaborative approach by oncology, rheumatology, and dermatology; physical therapy is an important adjunct in treatment. For advanced melanoma, it may be a good prognostic indicator. IMPLICATIONS FOR PRACTICE: It is important for clinicians to recognize that eosinophilic fasciitis is a potential immune-related adverse event (irAE) as a consequence of immune checkpoint inhibitor therapy. The presentation is quite stereotypical; the diagnosis can be made by imaging in the absence of a full-thickness skin biopsy. Early intervention is important to limit morbidity. This irAE may be a good prognostic sign among patients with melanoma.

14.
J Clin Oncol ; 38(15): 1655-1663, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32053428

RESUMO

PURPOSE: To analyze long-term outcomes after treatment discontinuation of anti-programmed death-1 (anti-PD-1) therapy in a cohort of patients with melanoma with the longest follow-up yet available to our knowledge, including a majority of patients treated outside of a clinical trial. We also assessed efficacy of retreatment with anti-PD-1 therapy with or without ipilimumab in relapsing patients. METHODS: We retrospectively analyzed all patients with nonuveal, unresectable stage III/IV melanoma treated with single-agent anti-PD-1 therapy at Memorial Sloan Kettering from 2009-2018 who had discontinued treatment and had at least 3 months of follow-up after discontinuation (n = 396). Overall survival for patients with complete response (CR) was calculated from time of CR. Time to treatment failure for patients with CR was time from CR to the next melanoma treatment or death. RESULTS: CRs were seen in 102 of 396 patients (25.8%). The median number of months of treatment after CR was zero (range, stopped before CR to 26 months after CR). With a median follow-up of 21.1 months from time of CR in patients who did not relapse, the probability of being alive and not needing additional melanoma therapy at 3 years was 72.1%. There was no significant association between treatment duration and relapse risk. In multivariable analysis, CR was associated with M1b disease and cutaneous versus mucosal or acral primaries. Among the 78 patients (of 396) retreated after disease progression, response was seen in 5 of 34 retreated patients with single-agent anti-PD-1 therapy and 11 of 44 patients escalated to anti-PD-1 plus ipilimumab. CONCLUSION: In our cohort, most patients discontinued treatment at the time of CR. Most CRs were durable but the probability of treatment failure was 27% at 3 years. Responses to retreatment were infrequent. The optimal duration of treatment after CR is not yet established.

15.
Clin Cancer Res ; 26(9): 2085-2086, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32102949

RESUMO

The impact on survival of steroids and TNFα blockade to treat immune-related toxicity from checkpoint blockade with ipilimumab, nivolumab/pembrolizumab, or combined ipilimumab and nivolumab was assessed using data from a large national database. Using steroids was associated with better survival than the use of TNFα-blocking antibodies such as infliximab.See related article by Verheijden et al., p. 2268.

16.
Cancer ; 126(1): 76-85, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31584709

RESUMO

BACKGROUND: An elevated neutrophil-to-lymphocyte ratio (NLR) is associated with poor survival in patients with cancer, including those who receive immunotherapies. The authors sought to investigate NLR as a biomarker of treatment outcomes in patients with melanoma who were treated with PD-1 inhibition. METHODS: Patients undergoing initial treatment with PD-1 inhibitor monotherapy for stage IV melanoma at a single center from 2012 to 2015 were included. Clinical characteristics and the NLR at baseline and before subsequent treatment cycles were collected. The time to treatment failure (TTF) and overall survival (OS) were evaluated using Kaplan-Meier and landmark analyses. RESULTS: Among 224 study patients, 63 (28%) had a baseline NLR ≥5. The baseline NLR was significantly associated with Eastern Cooperative Oncology Group performance status and the number of involved metastatic sites. With a median follow-up of 39 months in survivors, a baseline NLR ≥5 was independently associated with shorter OS (hazard ratio, 2.0; 95% CI, 1.3-2.9) and TTF (hazard ratio, 1.7; 95% CI, 1.2-2.4). An NLR increase ≥30% during the first 2 cycles of treatment was associated with worse OS (median, 47 vs 13.5 months; P < .001) and a trend toward shorter TTF (12.8 vs 5.9 months; P = .05). A combined baseline NLR ≥5 and an NLR increase ≥30% identified a small cohort with markedly shortened OS (median, 5.8 months) and TTF (median, 1.8 months). CONCLUSIONS: Elevated baseline NLR and an increased NLR early during treatment are prognostic for TTF and OS in patients who have melanoma treated with PD-1 inhibitor monotherapy. Combined, these biomarkers can widely risk-stratify patients for treatment failure and survival.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Melanoma/tratamento farmacológico , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Linfócitos/efeitos dos fármacos , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutrófilos/efeitos dos fármacos , Receptor de Morte Celular Programada 1/imunologia
17.
J Nucl Med ; 61(4): 512-519, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586002

RESUMO

Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of 89Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. Methods: The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of 89Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1-2, 6-8, 24, 48, and 96-144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Results: 89Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time-activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24-48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most 89Zr-IAB22M2C-positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Conclusion: 89Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell-rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.


Assuntos
Antígenos CD8/imunologia , Imunoconjugados/química , Imunoconjugados/farmacocinética , Neoplasias/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Radioisótopos , Zircônio , Adulto , Idoso , Idoso de 80 Anos ou mais , Transporte Biológico , Feminino , Humanos , Imunoconjugados/sangue , Imunoconjugados/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias/metabolismo , Neoplasias/patologia , Distribuição Tecidual
18.
Clin Infect Dis ; 70(2): 193-199, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30874791

RESUMO

BACKGROUND: Cancer patients are at a higher risk for developing influenza (flu)- related complications. It is unclear if the flu vaccine exacerbates immune events in patients treated with immune checkpoint inhibitors (ICIs). METHODS: We conducted an institutional review board-IRB-approved retrospective review of advanced cancer patients on ICIs who received the flu vaccine during three 3 consecutive seasons: 2014-2015, 2015-2016, and 2016-2017. The primary outcome assessed was any "new onset" immune-related adverse event (IRAE). A subset analysis of vaccinated patients newly treated with anti-programmed cell death protein 1 (PD-1) agents (nivolumab or pembrolizumab) was conducted to assess overall IRAE rates for comparison with published clinical trials. RESULTS: During the three 3 seasons, 370 patients met criteria for ICI and vaccination within ~ twoapproximately 2 months (65 days). The most common underlying cancers were lung (46%) and melanoma (19%); 61% of patients received an anti-PD-1 agent only. In the entire cohort, 20% experienced an IRAE (any grade); incidence of grade 3 or 4 toxicity was 8%. No grade 5 events occurred. In the subset of 170 patients newly treated with anti-PD-1 agents, the overall IRAE rate was 18% and, grade 3/4 events occurred in 7.6%. Influenza was diagnosed in 2 patients. CONCLUSIONS: No increase in incidence or severity of IRAEs was detected in patients on ICIs who received the inactivated influenza vaccine within ~ approximately 2 months of ICI. For newly treated patients on anti-PDI-1 agents, IRAE rates were comparable to those from published clinical trials and did not vary with order of administration. Routine seasonal flu vaccination is encouraged in patients on ICIs.

19.
Ann Surg Oncol ; 27(4): 1180-1188, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31848819

RESUMO

INTRODUCTION: Checkpoint inhibitors have improved outcomes in metastatic melanoma, with 4-year overall survival (OS) of 46% for anti-PD-1 alone or 53% in combination with anti-CTLA-4. However, the median progression free survival is 6.9 and 11.5 months, respectively. Many who progress have gone on to alternative treatments, including surgery, yet the outcome of patients selected for surgery after checkpoint blockade remains unclear. METHODS: Patients who were treated with checkpoint blockade from 2003 to 2017, followed by metastasectomy, were identified from a prospectively maintained institutional melanoma database. Response to immunotherapy was assessed at the time of surgery. Patients were categorized as having responding, isolated progressing, or multiple progressing lesions. RESULTS: Of the 237 total patients identified, 208 (88%) had stage IV disease, and 29 (12%) had unresectable stage III disease at the start of immunotherapy. Median OS following first resection was 21 months. Median follow-up among survivors was 23 months. Complete resection at the first operation (n = 87, 37%) was associated with improved survival compared with patients with incomplete resection (n = 150, 63%) [median OS not reached (NR) vs. 10.8 months, respectively; 95% CI: 7.3, 14.8; p < 0.0001]. Patients resected for an isolated progressing or responding tumor had a longer median survival compared with those with multiple progressing lesions (NR vs. 7.8 months, 95% CI: 6.2, 11.2; p < 0.0001). CONCLUSIONS: Patients selected for surgical resection following checkpoint blockade have a relatively favorable survival, especially if they had a response to immunotherapy and undergo complete resection of isolated progressing or responding disease.

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