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Anti-angiogenic agents elicit considerable immune modulatory effects within the tumor microenvironment, underscoring the rationale for synergistic clinical development of VEGF and immune checkpoint inhibitors in advanced gastric cancer (AGC). Early phase studies involving Asian patients demonstrated encouraging anti-tumor efficacies. We report the results of the REGOMUNE phase II study, in which Caucasian patients were administered regorafenib, a multi-tyrosine kinase inhibitor, in combination with avelumab, a PD-L1-targeting monoclonal antibody. This therapeutic regimen resulted in deep and durable responses in 19% of patients, with the median duration of response not yet reached. Notwithstanding, a significant proportion of AGC patients exhibited no therapeutic advantage, prompting investigations into mechanisms of inherent resistance. Comprehensive biomarker profiling elucidated that non-responders predominantly exhibited an augmented presence of M2 macrophages within the tumor microenvironment and a marked overexpression of S100A10 by neoplastic cells, a protein previously implicated in macrophage chemotaxis. Additionally, peripheral biomarker assessments identified elevated levels of cytokines, including CSF-1, IL-4, IL-8, and TWEAK, correlating with adverse clinical outcomes, thereby accentuating the role of macrophage infiltration in mediating resistance. These insights furnish an invaluable foundation for elucidating, and potentially circumventing, resistance mechanisms in current AGC therapeutic paradigms, emphasizing the integral role of tumor microenvironmental dynamics and immune modulation.
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Antígeno B7-H1 , Resistencia a Antineoplásicos , Proteómica , Neoplasias Gástricas , Microambiente Tumoral , Humanos , Microambiente Tumoral/efectos de los fármacos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Proteómica/métodos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Biomarcadores de Tumor , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Femenino , Masculino , Transcriptoma , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Persona de Mediana Edad , Perfilación de la Expresión GénicaRESUMEN
PURPOSE: To investigate circulating tumor DNA (ctDNA) RAS mutant (MT) incidence before salvage-line treatment and the clinicopathological features and molecular biological factors associated with the efficacy of anti-epithelial growth factor receptor (EGFR) monoclonal antibody (mAb) rechallenge for tissue RAS/BRAF wild type (WT) metastatic colorectal cancer (mCRC). METHODS: This multi-institutional retrospective observational study included 74 patients with mCRC with tissue RAS/BRAF WT refractory to first-line chemotherapy containing anti-EGFR mAb. ctDNA RAS status was assessed using the OncoBEAM™ RAS CRC Kit. We explored the clinicopathological features associated with ctDNA RAS status and the factors related to anti-EGFR mAb rechallenge efficacy in multivariate Cox proportional hazard regression. RESULTS: The incidence of RAS MT in ctDNA was 40.5% (30/74), which was associated with primary tumor resection (P = 0.016), liver metastasis (P < 0.001), and high tumor marker levels (P < 0.001). Among the 39 patients treated with anti-EGFR mAb rechallenge, those with ctDNA RAS WT showed significantly longer progression-free survival (PFS) than those with ctDNA RAS MT (median 4.1 vs. 2.7 months, hazard ratio [HR] = 0.39, P = 0.045). Patients who responded to first-line anti-EGFR mAb showed significantly longer PFS (HR = 0.21, P = 0.0026) and overall survival (OS) (HR = 0.23, P = 0.026) than those with stable disease. CONCLUSIONS: The incidence of ctDNA RAS MT mCRC was 40.5%, which was associated with liver metastases and high tumor volumes. Anti-EGFR mAb rechallenge may be effective for patients with mCRC who responded to first-line chemotherapy containing anti-EGFR mAb. No patients with RAS MT in ctDNA responded to anti-EGFR mAb rechallenge.
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Neoplasias Colorrectales , Receptores ErbB , Proteínas Proto-Oncogénicas B-raf , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Masculino , Femenino , Proteínas Proto-Oncogénicas B-raf/genética , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Adulto , Anciano de 80 o más Años , Mutación , ADN Tumoral Circulante/genética , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificaciónRESUMEN
The freezing-thawing (F/T) method for fusing giant unilamellar vesicles (GUVs) can provide substrates, enzymes and membrane material simultaneously and repetitively, and is useful for constructing a recursive model of an artificial cell. However, enzymatic efficiency after F/T is reduced due to rupture of the GUVs and leakage of the inner solution during F/T. Previously, liposomes composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and a negatively charged lipid, such as 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG), showed lower rupture and leakage rates during F/T. In this study, we investigated the effect of POPG on the supply of components required for T7 RNA polymerase reactions via F/T by flow cytometry analysis. We found that the addition of POPG to liposome preparations reduced the efficiency of RNA synthesis. In addition, DNA was concentrated during F/T and RNA synthesis occurred after F/T in liposomes composed of POPC and POPG. Our results provide new insights for more efficient supply of substrates and enzymes by the F/T method, thereby increasing the utility of the F/T method for the construction of recursive bioreactors.
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Membrana Dobles de Lípidos , Liposomas , Congelación , ARNRESUMEN
BACKGROUND: Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations. METHODS: Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies. RESULTS: The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8+ T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the POLE gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial. CONCLUSIONS: We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.
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Neoplasias Colorrectales , Nivolumab , Humanos , Nivolumab/farmacología , Nivolumab/uso terapéutico , Linfocitos T CD8-positivos , Multiómica , Inmunoterapia , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , BiomarcadoresRESUMEN
PURPOSE: Determination of optimal treatment strategies for HER2-positive advanced gastric cancer (AGC) in randomized trials is necessary despite difficulties in direct comparison between trastuzumab deruxtecan (T-DXd) and nivolumab as third or later-line treatments. MATERIALS AND METHODS: This single-institution, retrospective study aimed to describe the real-world efficacy and safety of T-DXd and nivolumab as ≥ third line treatments for HER2-positive AGC between March 2016 and May 2022. Overall, 58 patients (median age, 64 years; 69% male) were eligible for the study (T-DXd group, n=20; nivolumab group, n=38). RESULTS: Most patients exhibited a HER2 3+ status (72%) and presented metastatic disease at diagnosis (66%). The response rates of 41 patients with measurable lesions in the T-DXd and nivolumab groups were 50% and 15%, respectively. The T-DXd and nivolumab groups had a median progression-free survival of 4.8 months (95% confidence interval [CI], 3.3, 7.0) and 2.3 months (95% CI, 1.5, 3.5), median overall survival (OS) of 10.8 months (95% CI, 6.9, 23.8) and 11.7 months (95% CI, 7.6, 17.1), and grade 3 or greater adverse event rates of 50% and 2%, respectively. Overall, 64% patients received subsequent treatment. Among 23 patients who received both regimens, the T-DXd-nivolumab and nivolumab-T-DXd groups had a median OS of 14.0 months (95% CI, 5.0, not reached) and 19.3 months (95% CI, 9.5, 25.1), respectively. CONCLUSIONS: T-DXd and nivolumab showed distinct efficacy and toxicity profiles as ≥ third line treatments for HER2-positive AGC. Considering the distinct features of each regimen, they may help clinicians personalize optimal treatment approaches for these patients.
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Renal impairment may be associated with an increased risk of hematologic events (AEs) in patients undergoing treatment with trifluridine/tipiracil (FTD/TPI). This study aimed to investigate the specific types of AEs linked to renal impairment in patients with metastatic colorectal cancer (mCRC) receiving FTD/TPI, using real-world data. Among the patients included in the REGOTAS study (a retrospective study of FTD/TPI versus regorafenib), those treated with FTD/TPI were evaluated. Creatinine clearance values of < 30, 30-60, 60-90, and > 90 mL/min were defined as severe, moderate, mild renal impairment, and normal renal function, respectively. Renal impairment was analyzed as a risk factor for grade 3 or higher AEs using a logistic regression model. Overall survival (OS) and progression-free survival (PFS) based on renal impairment were evaluated. A total of 309 patients were included in the analysis, with 124, 130, and 55 patients divided into the normal, mild, and moderate-to-severe groups, respectively. The risk of grade 3 or higher neutropenia was significantly higher in the moderate-to-severe group (odds ratio 3.47; 95% confidence interval 1.45-8.30; P = 0.005), but there was no significant increase in the risk of non-hematologic AEs in any of the groups. The OS and PFS of patients in the mild and moderate-to-severe groups were comparable to those in the normal group. Patients with mCRC and moderate/severe renal impairment receiving FTD/TPI therapy may develop severe neutropenia; however, FTD/TPI remains a viable treatment option due to its clinical benefit.
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Neoplasias del Colon , Neoplasias Colorrectales , Demencia Frontotemporal , Neutropenia , Neoplasias del Recto , Humanos , Uracilo/uso terapéutico , Estudios Retrospectivos , Trifluridina/efectos adversos , Demencia Frontotemporal/tratamiento farmacológico , Neoplasias Colorrectales/patología , Timina/uso terapéutico , Pirrolidinas/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Combinación de Medicamentos , Factores de Riesgo , Neutropenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
The PI3K-Akt-mTOR (PAM) pathway is implicated in tumor progression in many tumor types, including metastatic gastric cancer (GC). The initial promise of PAM inhibitors has been unrealized in the clinic, presumably due, in part, to the up-regulation of Akt signaling that occurs when the pathway is inhibited. Here we present that DIACC3010 (formerly M2698), an inhibitor of two nodes in the PAM pathway, p70S6K and Akt 1/3, blocks the pathway in in vitro and in vivo preclinical models of GC while providing a mechanism that inhibits signaling from subsequent Akt up-regulation. Utilizing GC cell lines and xenograft models, we identified potential markers of DIACC3010-sensitivity in Her2-negative tumors, i.e., PIK3CA mutations, low basal pERK, and a group of differentially expressed genes (DEGs). The combination of DIACC3010 and trastuzumab was evaluated in Her2-positive cell lines and models. Potential biomarkers for the synergistic efficacy of the combination of DIACC3010 + trastuzumab also included DEGs as well as a lack of up-regulation of pERK. Of 27 GC patient-derived xenograft (PDX) models tested in BALB/c nu/nu mice, 59% were sensitive to DIACC3010 + trastuzumab. Of the 21 HER2-negative PDX models, DIACC3010 significantly inhibited the growth of 38%. Altogether, these results provide a path forward to validate the potential biomarkers of DIACC3010 sensitivity in GC and support clinical evaluation of DIACC3010 monotherapy and combination with trastuzumab in patients with HER2- negative and positive advanced GCs, respectively.
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Neoplasias Gástricas , Animales , Ratones , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Proteínas Quinasas S6 Ribosómicas 70-kDa , Proteínas Proto-Oncogénicas c-akt , Fosfatidilinositol 3-Quinasas , Inhibidores de Proteínas Quinasas , Inhibidores de la Angiogénesis , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Few studies have focused on the impact of single-organ pulmonary metastases on progression-free survival and overall survival in patients with metastatic colorectal cancer. Recognizing differences in prognosis and chemotherapeutic efficacy based on metastasized organs may help in optimizing treatment strategies. The exploratory study was conducted to evaluate the comparative clinical outcomes and prognoses of patients with metastatic colorectal cancer presenting with single-organ pulmonary metastases and treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy. METHODS: This retrospective study included 289 patients with metastatic colorectal cancer treated with second-line folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors. The response rate, disease control rate, progression-free survival, and overall survival were assessed in the participants. RESULTS: Among the 289 patients enrolled, 26 (9.0%) had single-organ pulmonary metastasis with left-sided primary locations, lower levels of tumor markers at the initiation point of chemotherapy, a significantly higher disease control rate (96.2% vs. 76.7%, P = .02), and a longer progression-free survival (median 29.6 months vs. 6.1 months, P < .001) and overall survival (median 41.1 months vs. 18.7 months, P < .001) than patients with other forms of metastatic colorectal cancer. Multivariate analysis showed that single-organ pulmonary metastasis was an independent predictor of longer progression-free survival (hazard ratio 0.35, P = .00075) and overall survival (hazard ratio 0.2, P = .006). CONCLUSION: Single-organ pulmonary metastasis was a strong predictor of progression-free survival and overall survival in patients with metastatic colorectal cancer treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy; this provides preliminary evidence for medical guidelines and clinical decision-making on novel therapeutic strategies for these patients.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias Pulmonares , Neoplasias del Recto , Humanos , Irinotecán/uso terapéutico , Neoplasias Colorrectales/patología , Factor A de Crecimiento Endotelial Vascular , Camptotecina , Pronóstico , Leucovorina , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fluorouracilo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Neoplasias Pulmonares/etiología , Metástasis de la Neoplasia/tratamiento farmacológicoRESUMEN
PURPOSE: As circulating tumor DNA (ctDNA) measurement becomes more widespread, the "NeoRAS" phenomenon, where tissue rat sarcoma viral oncogene homolog (RAS) status converts from mutant (MT) to wild-type (WT) after treatment in metastatic colorectal cancer (mCRC), is gaining attention because ineffective epidermal growth factor receptor (EGFR) inhibitors may made effective. This study investigated its incidence and clinicopathological characteristics. PATIENTS AND METHODS: In total, 107 mCRC patients (refractory or intolerant to previous chemotherapies) with tissue RAS MT were enrolled in four institutions from June 2021 to August 2022. The RAS status in ctDNA was assessed using OncoBEAM™ RAS CRC assay. Clinicopathologic features were compared between patients according to their RAS status in ctDNA, whether WT conversion was noted or not. RESULTS: The incidence rate of NeoRAS WT mCRC was 21.5% (23/107). According to tissue RAS mutation sites, NeoRAS WT frequency in patients with KRAS mutation in exon 2 was significantly lower than those in exon 3 and 4 or NRAS (18.2% [18/99] vs 62.5% [5/8], P = 0.011). Regarding clinical background, there were significant differences in NeoRAS WT frequency between male vs female patients (30.6% [19/62] vs 8.9% [4/45], P = 0.008), and absence vs presence of liver metastasis (38.6% [17/44] vs 9.5% [6/63], P < 0.001). Comparing the two groups divided by the median value, NeoRAS WT was associated with smaller tumor diameter (>60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P < 0.001), lower carcinoembryonic antigen level (>38.2 ng/ml vs ≤, 11.3% [6/53] vs 31.5% [17/54], P = 0.018), and lower carbohydrate antigen 19-9 level (>158.0 U/ml vs ≤, 9.4% [5/53] vs 33.3% [18/54], P = 0.004). In the logistic regression multivariate analysis, liver metastasis absence (Odds ratio [OR], 4.62; P = 0.019), smaller tumor diameter (OR, 7.92; P = 0.012), and tissue RAS MT in other than KRAS exon 2 (OR, 9.04; P = 0.026) were significantly related to the conversion to NeoRAS WT in ctDNA. CONCLUSIONS: Original RAS variants in tissue, tumor diameter, and liver metastasis are related to conversion to NeoRAS WT mCRC in ctDNA.
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PURPOSE: We previously reported preliminary activity of regorafenib plus nivolumab (REGONIVO) or lenvatinib plus pembrolizumab (LENPEM) in advanced gastric cancer (AGC). Meanwhile, several studies demonstrated liver metastases are less responsive to immunotherapy. PATIENTS AND METHODS: Combined efficacy outcomes with a longer follow-up in a phase Ib trial of REGONIVO and a phase II trial of LENPEM were examined in AGC with or without liver metastases (REGONIVO plus LENPEM cohort). We also investigated the efficacy of anti-PD-1 monotherapies (anti-PD-1 monotherapy cohort). A comparison of the immune microenvironment between gastric primary tumors and liver metastases was also conducted by multiplex IHC. RESULTS: In the REGONIVO plus LENPEM cohort, with a median follow-up of 14.0 months, objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were 46%, 7.8 months, and 15.6 months in patients with liver metastases, while 69%, 6.9 months, and 15.5 months in those without. In the anti-PD-1 monotherapy cohort, with a median follow-up of 27.6 months, ORR, mPFS, and mOS were 9%, 1.4 months, and 6.4 months in patients with liver metastases, while 22%, 2.3 months, and 9.0 months in those without. Multiplex IHC revealed liver metastases were associated with an abundance of immune-suppressive cells, such as tumor-associated macrophages and regulatory T cells, with fewer CD8+ T cells compared with gastric primary tumors. CONCLUSIONS: Anti-PD-1 antibodies plus regorafenib or lenvatinib for AGC showed promising antitumor activity with a longer follow-up, irrespective of liver metastases status, despite a more immune-suppressive tumor microenvironment in liver metastases.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Hepáticas , Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Inmunoterapia , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Nivolumab/uso terapéutico , Supervivencia sin Progresión , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Resultado del Tratamiento , Microambiente TumoralRESUMEN
PURPOSE: Preoperative chemoradiotherapy (CRT) and surgical resection are the standard treatment for locally advanced rectal cancer (LARC). Combining immune checkpoint inhibitors with radiation suggests a promising approach for enhancing efficacy. We investigated the efficacy of CRT followed by nivolumab and surgery in patients with LARC. PATIENTS AND METHODS: In phase I, we investigated the feasibility of sequentially combined CRT, 5 cycles of nivolumab, and radical surgery. In phase II, patients with microsatellite stable (MSS) and microsatellite instability-high (MSI-H) LARC were evaluated. RESULTS: Three patients in phase I received full courses of CRT and nivolumab without dose modification; the schedule was recommended for phase II. A pathologic complete response (pCR) was centrally confirmed in 30% [11/37; 90% confidence interval (CI), 18%-44%] and 60% (3/5) of the MSS and exploratory MSI-H cohorts, respectively. While immune-related severe adverse events were observed in 3 patients, no treatment-related deaths were observed. In 38 patients with MSS who underwent surgery, pCR rates of 75% (6/8) and 17% (5/30; P = 0.004, Fisher exact test) were observed in those with programmed cell death ligand 1 (PD-L1) tumor proportion score ≥1% and <1%, respectively; IHC staining was performed using pre-CRT samples. In 24 patients with MSS, pre-CRT samples were analyzed by flow cytometry; pCR rates of 78% (7/9) and 13% (2/15; P = 0.003, Fisher exact test) were observed for CD8+ T cell/effector regulatory T cell (CD8/eTreg) ratios of ≥2.5 and <2.5, respectively, in tumor-infiltrating lymphocytes. CONCLUSIONS: CRT followed by consolidation nivolumab could increase pCR. PD-L1 expression and an elevated CD8/eTreg ratio were positive predictors in patients with MSS LARC.
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Nivolumab , Neoplasias del Recto , Antígeno B7-H1/genética , Quimioradioterapia , Humanos , Inestabilidad de Microsatélites , Repeticiones de Microsatélite/genética , Terapia Neoadyuvante , Nivolumab/uso terapéutico , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/terapiaRESUMEN
The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.
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Regulación Neoplásica de la Expresión Génica , Ácido Láctico/metabolismo , Receptor de Muerte Celular Programada 1/genética , Linfocitos T Reguladores/metabolismo , Microambiente Tumoral/genética , Animales , Biomarcadores de Tumor , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucólisis , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Proteínas de Punto de Control Inmunitario/metabolismo , Inmunofenotipificación , Ácido Láctico/farmacología , Activación de Linfocitos , Recuento de Linfocitos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Ratones , Terapia Molecular Dirigida , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacosRESUMEN
Six strains of Gram-stain-negative, obligately anaerobic, non-spore-forming, non-motile rods were isolated from human faeces. Based on phylogenetic characteristics, the six isolates were included in the family Ruminococcaceae, and divided into three groups. The six isolates showed 16S rRNA gene sequence similarity values lower than 96.2â% to the closely related species, Oscillibacter ruminantium GH1T, Oscillibacter valericigenes Sjm18-20T and Dysosmobacter welbiomis J115T. Coherently with the 16S rRNA gene sequence results, the in silico DNA-DNA hybridization and average nucleotide identity values clearly indicated that strains MM35T, MM50T and MM59T belong to different species from the closely related three species. Based on phenotypic features and phylogenetic positions, three novel species, Vescimonas coprocola gen. nov., sp. nov., Vescimonas fastidiosa gen. nov., sp. nov. and Pusillimonas faecalis gen. nov., sp. nov. are proposed. The type strain of V. coprocola is strain MM50T (=JCM 34012T=DSM 111893T). The type strain of V. fastidiosa is strain MM35T (=JCM 34016T=DSM 111899T). The type strain of P. faecalis is strain MM59T (=JCM 34011T=DSM 111669T). The DNA G+C contents estimated according to the whole genomes of strains MM35T, MM50T and MM59T were 56.4, 58.2 and 55.2 mol%, respectively.
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Clostridiales/clasificación , Heces/microbiología , Filogenia , Técnicas de Tipificación Bacteriana , Composición de Base , Clostridiales/aislamiento & purificación , ADN Bacteriano/genética , Humanos , Hibridación de Ácido Nucleico , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Primary tumor location (PTL) is an important prognostic and predictive factor in the first-line treatment of metastatic colorectal cancer (mCRC). Although regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have been introduced recently, the clinical impact of PTL in these treatments is not well understood. MATERIALS AND METHODS: We retrospectively evaluated patients with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, angiogenesis inhibitors, anti-epidermal growth factor receptor therapy (if RAS wild-type), and no prior use of REG and FTD/TPI. The impact of PTL on overall survival (OS) was evaluated using Cox proportional hazard models based on baseline characteristics. RESULTS: A total of 550 patients (223 patients in the REG group and 327 patients in the FTD/TPI group) were included in this study, with 122 patients with right-sided tumors and 428 patients with left-sided tumors. Although the right-sided patients had significantly shorter OS compared with the left-sided patients by univariate analysis (p = 0.041), a multivariate analysis revealed that PTL was not an independent prognostic factor (hazard ratio, 0.95; p = 0.64). In a subgroup analysis, the OS was comparable between the REG and FTD/TPI groups regardless of PTL (p for interactions = 0.60). CONCLUSIONS: In the present study, PTL is not a prognostic and predictive factor in patients with mCRC under later-line REG or FTD/TPI therapy.
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BACKGROUND/AIM: In later-line treatment of metastatic colorectal cancer (mCRC), trifluridine/tipiracil is often selected because regorafenib is difficult to use in patients with comorbidities such as thrombosis, hemorrhage, or cardiac events. However, the safety and efficacy of trifluridine/tipiracil in these patients is not clear. PATIENTS AND METHODS: The clinical outcomes of trifluridine/tipiracil were retrospectively investigated in patients who were ineligible for regorafenib because of comorbidities. RESULTS: Among the 27 patients who received trifluridine/tipiracil, many had comorbidities of deep venous thrombosis or hemorrhage. The median overall survival was 12.4 months, and the median progression-free survival was 2.8 months. The median overall survival was 7.7 months in 19 patients without subsequent regorafenib. Grade 3 or higher toxicities were found in 51% of patients. No treatment discontinuation because of comorbidities was observed. CONCLUSION: Trifluridine/tipiracil can be safely administered while maintaining efficacy in patients who were ineligible for regorafenib.
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Adenocarcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Pirrolidinas/uso terapéutico , Timina/uso terapéutico , Trifluridina/uso terapéutico , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Adulto , Anciano , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Comorbilidad , Combinación de Medicamentos , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Selección de Paciente , Compuestos de Fenilurea/uso terapéutico , Supervivencia sin Progresión , Piridinas/uso terapéutico , Pirrolidinas/efectos adversos , Estudios Retrospectivos , Terapia Recuperativa , Análisis de Supervivencia , Timina/efectos adversos , Resultado del Tratamiento , Trifluridina/efectos adversosRESUMEN
Patients with colorectal cancers (CRCs) generally exhibit improved survival through intensive lymph node (LN) dissection. However, recent progress in cancer immunotherapy revisits the potential importance of regional LNs, where T cells are primed to attack tumor cells. To elucidate the role of regional LN, we investigated the immunological status of nonmetastatic regional LN lymphocytes (LNLs) in comparison with those of the tumor microenvironment (tumor-infiltrating lymphocytes; TILs) using flow cytometry and next-generation sequencing. LNLs comprised an intermediate level of the effector T cell population between peripheral blood lymphocytes (PBLs) and TILs. Significant overlap of the T cell receptor (TCR) repertoire was observed in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) CRCs with high tumor mutation burden (TMB), although limited TCRs were shared between nonmetastatic LNs and primary tumors in microsatellite stable/MMR proficient (MSS/pMMR) CRC patients with low TMB. In line with the overlap of the TCR repertoire, an excessive LN dissection did not provide a positive impact on long-term prognosis in our MSI-H/dMMR CRC cohort (n = 130). We propose that regional LNs play an important role in antitumor immunity, particularly in MSI-H/dMMR CRCs with high TMB, requiring care to be taken regarding excessive nonmetastatic LN dissection in MSI-H/dMMR CRC patients.
Asunto(s)
Neoplasias Colorrectales/inmunología , Ganglios Linfáticos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Microambiente Tumoral/inmunología , Anciano , Linfocitos T CD4-Positivos/inmunología , Estudios de Cohortes , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Reparación de la Incompatibilidad de ADN/genética , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/inmunología , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Masculino , Células T de Memoria/inmunología , Inestabilidad de Microsatélites , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
Background: The survival benefits of regorafenib (REG) and trifluridine/tipiracil hydrochloride (TFTD) have been demonstrated in chemorefractory patients with metastatic colorectal cancer (mCRC). However, the effects of crossover administration of REG and TFTD on patient survival remain unclear. The present study evaluated the association between exposure to REG and TFTD and overall survival (OS) in patients with mCRC using data from the REGOTAS study. Patients and Methods: We analyzed patients registered in the REGOTAS study, which retrospectively compared the efficacy and safety of use of REG or TFTD as later-line chemotherapy for chemorefractory mCRC patients. We compared the survival outcomes of cohort A (treated using both REG and TFTD) and cohort B (treated using either REG or TFTD). Results: A total of 550 patients (cohort A, n = 252; cohort B, n = 298) met the inclusion criteria. The median OS was significantly increased in cohort A compared with cohort B [9.6 months (95% confidence interval (CI), 8.9-10.9 months) vs. 5.2 months (95% CI, 4.4-6.0 months), P < 0.001]. Multivariate analysis revealed that cohort A was independently associated with a significant increase in OS [A vs. B: Hazard ratios (HR), 0.58; 95% CI, 0.47-0.72; P < 0.001]. Subgroup analysis adjusted using multivariate Cox model revealed a consistently better trend in most subgroups for cohort A compared with cohort B. Conclusions: Our study revealed prolonged survival in patients treated with REG and TFTD. Therefore, all active agents, including REG and TFTD, should be made available to mCRC patients.
RESUMEN
Single-cell level analysis is powerful tool to assess the heterogeneity of cellular components in tumor microenvironments (TME). In this study, we investigated immune-profiles using the single-cell analyses of endoscopically- or surgically-resected tumors, and peripheral blood mononuclear cells from gastric cancer patients. Furthermore, we technically characterized two distinct platforms of the single-cell analysis; RNA-seq-based analysis (scRNA-seq), and mass cytometry-based analysis (CyTOF), both of which are broadly embraced technologies. Our study revealed that the scRNA-seq analysis could cover a broader range of immune cells of TME in the biopsy-resected small samples of tumors, detecting even small subgroups of B cells or Treg cells in the tumors, although CyTOF could distinguish the specific populations in more depth. These findings demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of TME in small biopsy tumors, which would provide a novel strategies to overcome a therapeutic difficulties against cancer heterogeneity in TME.
Asunto(s)
Análisis de la Célula Individual , Neoplasias Gástricas/patología , Microambiente Tumoral , Adulto , Biopsia , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , RNA-Seq , Neoplasias Gástricas/genéticaRESUMEN
Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1+CD8+ T cells relative to that of PD-1+ regulatory T (Treg) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8+ T cells and Treg cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1+CD8+ T cells and enhanced PD-1+ Treg cell-mediated immunosuppression. A profound reactivation of effector PD-1+CD8+ T cells rather than PD-1+ Treg cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.