RESUMO
BACKGROUND: For some cancer operations, center volume is associated with improved patient outcomes. Whether this association is true for cytoreductive surgery/heated intraperitoneal chemotherapy (CRS/HIPEC) is unclear. Given the rapidly expanding use of CRS/HIPEC, the aim of this analysis was to determine whether a volume-outcome relationship exists for this strategy. METHODS: The Vizient Clinical Database® was queried for CRS/HIPEC cases from January 2020 through December 2022. Low-, medium-, and high-volume designations were made by sorting hospitals by case volume and creating equal tertiles based on total number of cases. Analysis was performed via one-way ANOVA with post-hoc Tukey test, as indicated. RESULTS: In the 36-month study period, 5165 cases were identified across 149 hospitals. Low- (n = 113), medium- (n = 25), and high-volume (n = 11) centers performed a median of 4, 21, and 47 cases per annum, respectively. Most cases were performed for appendiceal (39.3%) followed by gynecologic neoplasms (20.4%). Groups were similar with respect to age, gender, race, comorbidities, and histology. Low-volume centers were more likely to utilize the ICU post-operatively (59.6% vs. 40.5% vs. 36.3%; p = 0.02). No differences were observed in morbidity (9.4% vs. 7.1% vs. 9.0%, p = 0.71), mortality (0.9% vs. 0.6% vs. 0.7%, p = 0.93), length of stay (9.3 vs. 9.4 vs. 10 days, p = 0.83), 30-day readmissions (5.6% vs. 5.6% vs. 5.6%, p = 1.0), or total cost among groups. CONCLUSIONS: No association was found between CRS/HIPEC hospital volume and post-operative outcomes. These data suggest that in academic medical centers with HIPEC programs, outcomes for commonly treated cancers are not associated with hospital volume.
Assuntos
Neoplasias do Apêndice , Hipertermia Induzida , Neoplasias Peritoneais , Humanos , Feminino , Neoplasias Peritoneais/patologia , Estudos Retrospectivos , Quimioterapia Intraperitoneal Hipertérmica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hospitais , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Neoplasias do Apêndice/patologia , Terapia Combinada , Taxa de SobrevidaRESUMO
Circulating T cells from peripheral blood (PBL) can provide a rich and noninvasive source for antitumor T cells. By single-cell transcriptomic profiling of 36 neoantigen-specific T cell clones from 6 metastatic cancer patients, we report the transcriptional and cell surface signatures of antitumor PBL-derived CD8+ T cells (NeoTCRPBL). Comparison of tumor-infiltrating lymphocyte (TIL)- and PBL-neoantigen-specific T cells revealed that NeoTCRPBL T cells are low in frequency and display less-dysfunctional memory phenotypes relative to their TIL counterparts. Analysis of 100 antitumor TCR clonotypes indicates that most NeoTCRPBL populations target the same neoantigens as TILs. However, NeoTCRPBL TCR repertoire is only partially shared with TIL. Prediction and testing of NeoTCRPBL signature-derived TCRs from PBL of 6 prospective patients demonstrate high enrichment of clonotypes targeting tumor mutations, a viral oncogene, and patient-derived tumor. Thus, the NeoTCRPBL signature provides an alternative source for identifying antitumor T cells from PBL of cancer patients, enabling immune monitoring and immunotherapies.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Humanos , Estudos Prospectivos , Antígenos de Neoplasias , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Linfócitos do Interstício Tumoral , Receptores de Antígenos de Linfócitos TRESUMO
BACKGROUND: Cellular immunotherapies using autologous tumor-infiltrating lymphocytes (TIL) can induce durable regression of epithelial cancers in selected patients with treatment-refractory metastatic disease. As the genetic engineering of T cells with tumor-reactive T-cell receptors (TCRs) comes to the forefront of clinical investigation, the rapid, scalable, and cost-effective detection of patient-specific neoantigen-reactive TIL remains a top priority. METHODS: We analyzed the single-cell transcriptomic states of 31 neoantigen-specific T-cell clonotypes to identify cell surface dysfunction markers that best identified the metastatic transcriptional states enriched with antitumor TIL. We developed an efficient method to capture neoantigen-reactive TCRs directly from resected human tumors based on cell surface co-expression of CD39, programmed cell death protein-1, and TIGIT dysfunction markers (CD8+ TILTP). RESULTS: TILTP TCR isolation achieved a high degree of correlation with single-cell transcriptomic signatures that identify neoantigen-reactive TCRs, making it a cost-effective strategy using widely available resources. Reconstruction of additional TILTP TCRs from tumors identified known and novel antitumor TCRs, showing that at least 39.5% of TILTP TCRs are neoantigen-reactive or tumor-reactive. Despite their substantial enrichment for neoantigen-reactive TCR clonotypes, clonal dynamics of 24 unique antitumor TILTP clonotypes from four patients indicated that most in vitro expanded TILTP populations failed to demonstrate neoantigen reactivity, either by loss of neoantigen-reactive clones during TIL expansion, or through functional impairment during cognate neoantigen recognition. CONCLUSIONS: While direct usage of in vitro-expanded CD8+ TILTP as a source for cellular therapy might be precluded by profound TIL dysfunction, isolating TILTP represents a streamlined effective approach to rapidly identify neoantigen-reactive TCRs to design engineered cellular immunotherapies against cancer.
Assuntos
Antígenos de Neoplasias , Neoplasias , Humanos , Linfócitos T CD8-Positivos , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T , Linfócitos do Interstício TumoralRESUMO
Adoptive cellular therapy (ACT) targeting neoantigens can achieve durable clinical responses in patients with cancer. Most neoantigens arise from patient-specific mutations, requiring highly individualized treatments. To broaden the applicability of ACT targeting neoantigens, we focused on TP53 mutations commonly shared across different cancer types. We performed whole-exome sequencing on 163 patients with metastatic solid cancers, identified 78 who had TP53 missense mutations, and through immunologic screening, identified 21 unique T-cell reactivities. Here, we report a library of 39 T-cell receptors (TCR) targeting TP53 mutations shared among 7.3% of patients with solid tumors. These TCRs recognized tumor cells in a TP53 mutation- and human leucocyte antigen (HLA)-specific manner in vitro and in vivo. Twelve patients with chemorefractory epithelial cancers were treated with ex vivo-expanded autologous tumor-infiltrating lymphocytes (TIL) that were naturally reactive against TP53 mutations. However, limited clinical responses (2 partial responses among 12 patients) were seen. These infusions contained low frequencies of mutant p53-reactive TILs that had exhausted phenotypes and showed poor persistence. We also treated one patient who had chemorefractory breast cancer with ACT comprising autologous peripheral blood lymphocytes transduced with an allogeneic HLA-A*02-restricted TCR specific for p53R175H. The infused cells exhibited an improved immunophenotype and prolonged persistence compared with TIL ACT and the patient experienced an objective tumor regression (-55%) that lasted 6 months. Collectively, these proof-of-concept data suggest that the library of TCRs targeting shared p53 neoantigens should be further evaluated for the treatment of patients with advanced human cancers. See related Spotlight by Klebanoff, p. 919.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Neoplasias , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Genes Codificadores dos Receptores de Linfócitos T , Humanos , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/genética , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologiaRESUMO
The accurate identification of antitumor T cell receptors (TCRs) represents a major challenge for the engineering of cell-based cancer immunotherapies. By mapping 55 neoantigen-specific TCR clonotypes (NeoTCRs) from 10 metastatic human tumors to their single-cell transcriptomes, we identified signatures of CD8+ and CD4+ neoantigen-reactive tumor-infiltrating lymphocytes (TILs). Neoantigen-specific TILs exhibited tumor-specific expansion with dysfunctional phenotypes, distinct from blood-emigrant bystanders and regulatory TILs. Prospective prediction and testing of 73 NeoTCR signature-derived clonotypes demonstrated that half of the tested TCRs recognized tumor antigens or autologous tumors. NeoTCR signatures identified TCRs that target driver neoantigens and nonmutated viral or tumor-associated antigens, suggesting a common metastatic TIL exhaustion program. NeoTCR signatures delineate the landscape of TILs across metastatic tumors, enabling successful TCR prediction based purely on TIL transcriptomic states for use in cancer immunotherapy.
Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos do Interstício Tumoral/imunologia , Metástase Neoplásica , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Transcriptoma , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Redes Reguladoras de Genes , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , RNA-Seq , Análise de Célula ÚnicaAssuntos
Antibacterianos/farmacologia , Cirurgia Colorretal/estatística & dados numéricos , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Procedimentos Cirúrgicos Eletivos/métodos , Cuidados Pré-Operatórios/métodos , Infecção da Ferida Cirúrgica/prevenção & controle , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Infecção da Ferida Cirúrgica/epidemiologia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Given the lack of consensus in the surgical treatment of anal adenocarcinoma, practice-patterns demonstrate utilization of organ-preserving techniques. The adequacy of local excision compared to abdominoperineal resection (APR) as a surgical approach for stage II disease is unknown. Our study examines the utilization of local excision in the treatment of stage II anal adenocarcinoma, rates of R0 resection, and differences in overall survival compared to APR. MATERIALS AND METHODS: Using the National Cancer Database (2004-2016), we retrospectively analyzed patients diagnosed with clinical stage II anal adenocarcinoma who received chemoradiation and surgery. Patient cohorts were assigned based on the surgical procedure they received. Propensity score matching was used to offset selection bias and confounding factors. Treatment approach, pathologic margin status, and overall survival were assessed. RESULTS: Overall, 359 patients underwent resection of clinical stage II anal adenocarcinoma and received chemoradiation therapy. Of these patients, 87 (24%) underwent local excision, whereas 272 (76%) received an abdominoperineal resection. In a propensity score-matched cohort, patients who underwent local excision were less likely to achieve an R0 resection (40% vs 90%), and more likely to receive adjuvant instead of neoadjuvant chemoradiation. Overall survival was not significantly different between the propensity-matched groups. Surgical approach and pathologic margin status were not independently associated with overall survival. CONCLUSIONS: Among patients with clinical stage II anal adenocarcinoma who received chemotherapy and radiation, complete resection was significantly less likely with local excision compared to abdominoperineal resection, however, overall survival was not affected. Prospective studies of neoadjuvant chemoradiation followed by local excision are warranted.
Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/terapia , Neoplasias do Ânus/patologia , Neoplasias do Ânus/terapia , Quimiorradioterapia , Protectomia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ânus/mortalidade , Estudos de Coortes , Feminino , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pontuação de Propensão , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Small bowel neuroendocrine tumors (SB-NET) frequently metastasize to regional lymphatic or distant sites. Although most prognostication of SB-NET focuses on lymph node involvement, findings from studies of neuroendocrine tumors from other primary sites have suggested that preoperative serum chromogranin-A (CgA) levels may provide a more accurate metric. METHODS: Using the National Cancer Database (2004-2016), we analyzed patients with locoregional SB-NET who underwent curative resection including an adequate lymphadenectomy (n = 1,274). A statistically optimized cut-point was used to dichotomize CgA cohort based on preoperative serum CgA levels. RESULTS: We determined that a CgA ≥139 ng/mL identified patients with significantly shorter estimated mean overall survival (6.6 years vs 7.6 years, log-rank P = .00001). These patients were also older (63 vs 57 years, P < .001) and had higher rates of poorly differentiated tumors (2.1% vs 0.7%, P = .04) or primary tumors >1 cm (88.2% vs 79.2%, P = .001). Clinical features associated with shorter overall survival included preoperative CgA ≥139 ng/mL (HR = 2.19, 95% CI 1.22-3.92; P = .009), age at diagnosis (HR = 1.06, 95% CI 1.03-1.09; P < .001), Charlson-Deyo score ≥2 (HR = 3.93, 95% CI 1.71-9.01; P = .001), and poorly differentiated tumors (HR = 11.22, 95% CI 4.16-30.24; P < .001). Neither lymph node metastasis nor T-stage were independently associated with shorter overall survival in patients with locoregional SB-NET. CONCLUSION: Elevated preoperative serum CgA is an adverse prognostic marker associated with shorter overall survival in patients with locoregional SB-NET.
Assuntos
Cromogranina A/sangue , Neoplasias do Íleo/sangue , Neoplasias do Jejuno/sangue , Tumores Neuroendócrinos/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Humanos , Neoplasias do Íleo/mortalidade , Neoplasias do Íleo/cirurgia , Neoplasias do Jejuno/mortalidade , Neoplasias do Jejuno/cirurgia , Estimativa de Kaplan-Meier , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/cirurgia , Valor Preditivo dos Testes , Período Pré-Operatório , Prognóstico , Adulto JovemRESUMO
BACKGROUNDTherapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.METHODSWe recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients' tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer.RESULTSThe vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRASG12D mutation. We observed no objective clinical responses in the 4 patients treated in this trial.CONCLUSIONThis vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.TRIAL REGISTRATIONPhase I/II protocol (NCT03480152) was approved by the IRB committee of the NIH and the FDA.FUNDINGCenter for Clinical Research, NCI, NIH.
Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Neoplasias Gastrointestinais , Imunidade Celular , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas p21(ras) , RNA Mensageiro , Linfócitos T/imunologia , Substituição de Aminoácidos , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/terapia , Humanos , Masculino , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/imunologia , RNA Mensageiro/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/imunologiaRESUMO
The RAS family of proteins is at the apex of several pathways implicated in a multitude of epithelial cancers but has remained stubbornly resistant to the wave of targeted small molecules and antibodies that have revolutionized clinical oncology. KRAS, the most commonly mutated of the isoforms, represents an attractive target for treatment, given its ubiquity, central role as a driver mutation, and association with poor prognosis. This review is a comprehensive summary of the existing approaches to targeting KRAS spanning small-molecule inhibitors, cancer vaccines, and with a focus on trials in adoptive cell therapy. Here we explain how the limitations of existing drugs and nonspecific immune-based therapies are circumvented with techniques in modern immunotherapy. The successes outlined represent the most promising path to finally targeting the prototypical "undruggable" RAS oncogene family.