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Improvement in the Neutrophil-Lymphocyte Ratio after Combined Fluorouracil, Leucovorina and Oxaliplatino based (FOLFOX) Chemotherapy for Stage III Colon Cancer is Associated with Improved Minimal Residual Disease and Outcome.
Murray, NP, Villalon, R, Hartmann, D, Rodriguez, PM, Aedo, S
Asian Pacific journal of cancer prevention : APJCP. 2022;(2):591-599
Abstract
INTRODUCTION Minimal residual disease (MRD) is the net result of the biological properties of disseminated tumour cells and the effect of the immune system and treatment to eliminate them. The aim of this study was to analyse the effect of combined chemotherapy on the immune function as determined by the neutrophil-lymphocyte ratio (NLR) and if it was associated with changes in the subtype of minimal residual disease and outcome in stage III colon cancer. METHODS AND PATIENTS A prospective, single centre observational study; the NLR was determined immediately prior to and one, two and three months after completing chemotherapy. Circulating tumour cells (CTCs) and bone marrow micro-metastasis (mM) using immunocytochemistry with anti-CEA were determined prior to and one month after chemotherapy. The association of changes in the NLR with MRD subtypes classified as Group I (negative for CTCs and mM), Group II (positive for mM) and Group III (positive for CTCs) as a result of chemotherapy and five-year disease free progression (DFS) analysed. RESULTS One hundred and eighty eight patients participated of whom 83 (44.9%) relapsed. In non-relapsing patients the NLR significantly increased and was higher after chemotherapy compared with relapsing patients. Significant increases in the NLR were associated with changes to a better MRD prognostic subtype and decreases with a worse MRD subtype. Neither baseline NLR nor MRD subtype predicted response to chemotherapy. DFS for MRD subgroups were 88%, 56% and 6% for Groups I to III respectively. CONCLUSIONS Immune function as measured by the NLR is associated with MRD prognostic subtypes, improvements in the NLR are associated with improvements in MRD post chemotherapy but neither baseline NLR or MRD predicted outcome.
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Ameliorative Potential of L-Alanyl L-Glutamine Dipeptide in Colon Cancer Patients Receiving Modified FOLFOX-6 Regarding the Incidence of Diarrhea, the Treatment Response, and Patients' Survival: A Randomized Controlled Trial.
Sabry, NM, Naguib, TM, Kabel, AM, Khafagy, ES, Arab, HH, Almorsy, WA
Medicina (Kaunas, Lithuania). 2022;(3)
Abstract
Background and Objectives: Diarrhea induced by chemotherapy may represent a life-threatening adverse effect in cancer patients receiving chemotherapy. FOLFOX, an effective treatment for colon cancer, has been associated with diarrhea with high severity, particularly with higher doses. Management of diarrhea is crucial to increase the survival of cancer patients and to improve the quality of life. Glutamine is an abundant protein peptide found in blood and has a crucial role in boosting immunity, increasing protein anabolism, and decreasing the inflammatory effects of chemotherapy on the mucosal membranes, including diarrhea. This study aimed to provide evidence that parenteral L-alanyl L-glutamine dipeptide may have a positive influence on the incidence of diarrhea, treatment response, and the overall survival in colon cancer patients treated with modified FOLFOX-6 (mFOLFOX-6). Materials and Methods: Forty-four stage II and III colon cancer patients were included in this study where they were treated with the standard colon cancer chemotherapy mFOLFOX-6 and were randomly allocated into glutamine group and placebo group, each of 22 patients. Results: L-alanyl L-glutamine dipeptide was found to be significantly effective in decreasing the frequency and severity of diarrhea when compared to the placebo group, particularly after four and six cycles of mFOLFOX-6. There was no significant difference between the studied groups regarding to the overall survival. Conclusion: L-alanyl L-glutamine dipeptide can be considered as an add-on with chemotherapy to improve the quality of life and the overall survival of colon cancer patients.
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Camrelizumab Combined with FOLFOX4 Regimen as First-Line Therapy for Advanced Hepatocellular Carcinomas: A Sub-Cohort of a Multicenter Phase Ib/II Study.
Li, H, Qin, S, Liu, Y, Chen, Z, Ren, Z, Xiong, J, Meng, Z, Zhang, X, Wang, L, Zhang, X, et al
Drug design, development and therapy. 2021;:1873-1882
Abstract
BACKGROUND Immune checkpoint inhibitors and chemotherapy can synergistically increase efficacy in a variety of malignancies. We conducted this phase Ib/II study to assess the safety and efficacy of anti-PD-1 antibody camrelizumab in combination with FOLFOX4 for treatment-naive advanced hepatocellular carcinoma (aHCC). METHODS This open-label, multicenter phase Ib/II study (NCT03092895) enrolled patients with aHCC and without prior systemic treatment for treatment with camrelizumab (3 mg/kg) and FOLFOX4 every two weeks. First, six patients were enrolled, followed by an additional 28 patients after dose-limiting toxicity cases were determined to be <33% of patients. The primary endpoint was tolerability and safety of treatment. RESULTS A total of 34 aHCC patients were enrolled and received study treatment. No dose-limiting toxicity were observed in the first six patients enrolled. Twenty-nine (85.3%) of the total 34 patients had grade ≥3 treatment-related adverse events (TRAEs), with the most common ones being decreased neutrophil count (55.9%) and decreased white blood cell count (38.2%). No TRAEs-related deaths occurred. The objective response and disease control rate were 29.4% (95% CI, 15.1-47.5) and 79.4% (95% CI, 62.1-91.3), respectively. The median duration of response, progression-free survival, and overall survival was 6.9 months (range, 3.3-11.5), 7.4 months (95% CI, 3.9-9.2), and 11.7 months (95% CI, 8.2-22.0), respectively. CONCLUSION Camrelizumab combined with FOLFOX4 for first-line treatment of patients with aHCC showed good safety and tolerability, with promising preliminary antitumor activity.
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A multi-center, single-arm, phase Ib study of pembrolizumab (MK-3475) in combination with chemotherapy for patients with advanced colorectal cancer: HCRN GI14-186.
Herting, CJ, Farren, MR, Tong, Y, Liu, Z, O'Neil, B, Bekaii-Saab, T, Noonan, A, McQuinn, C, Mace, TA, Shaib, W, et al
Cancer immunology, immunotherapy : CII. 2021;(11):3337-3348
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Modified FOLFOX6 is an established therapy for patients with metastatic colorectal cancer (mCRC). We conducted a single-arm phase Ib study to address the hypothesis that addition of pembrolizumab to this regimen could safely and effectively improve patient outcomes (NCT02375672). The relationship between immune biomarkers and clinical response were assessed in an exploratory manner. Patients with mCRC received concurrent pembrolizumab and modified FOLFOX6. The study included safety run-in for the first six patients. The primary objective was median progression-free survival (mPFS), with secondary objectives including median overall survival, safety, and exploratory assessment of immune changes. To assess immunological impact, peripheral blood was collected at baseline and during treatment. The levels of soluble factors were measured via bioplex, while a panel of checkpoint molecules and phenotypically defined cell populations were assessed with flow cytometry and correlated with RECIST and mPFS. Due to incidences of grade 3 and grade 4 neutropenia in the safety lead-in, the dose of mFOLFOX6 was reduced in the expansion cohort. Median PFS was 8.8 months and median OS was not reached at data cutoff. Best responses of stable disease, partial response, and complete response were observed in 43.3%, 50.0%, and 6.7% of patients, respectively. Several soluble and cellular immune biomarkers were associated with improved RECIST and mPFS. Immunosuppressive myeloid and T cell subsets that were analyzed were not associated with response. Primary endpoint was not superior to historic control. Biomarkers that were associated with improved response may be informative for future regimens combining chemotherapy with immune checkpoint inhibitors.
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Treatment strategy of adding transcatheter arterial chemoembolization to sorafenib for advanced stage hepatocellular carcinoma.
Lee, WC, Hung, HC, Lee, JC, Wang, YC, Cheng, CH, Wu, TH, Lee, CF, Wu, TJ, Chou, HS, Chan, KM
Cancer reports (Hoboken, N.J.). 2021;(1):e1294
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BACKGROUND Therapeutic effect and immunosuppressor cell alteration in adding transcatheter arterial chemoembolization (TACE) to sorafenib for advanced stage hepatocellular carcinoma (HCC) remain unclear. AIMS To examine the therapeutic effect and immunosuppressor cell alteration in adding TACE to sorafenib. METHODS Forty-four advanced stage HCC patients were divided into group A (n = 17) treated by sorafenib (400-600 mg/day) alone and group B patients (n = 27) treated by sorafenib and TACE. The frequency of regulatory T-cells and myeloid-derived suppressor cells (MDSC), and patients' outcomes were examined. Advanced HCC patients' survival was improved by adding TACE to sorafenib if N/L was reduced from ≥2.5 to <2.5 by TACE. RESULTS The median (interquartile) follow-up for all patients was 8.5 (3.5 to 15.5) with a range from 1 to 71 months. The median (interquartile) survival was 5.0 (2.3-11.3) months for group A and 11.0 (5.0-19.0) months for group B patients (P = .024). In group A, the patients (n = 8) with neutrophil-to-lymphocytes ratio (N/L) < 2.5 had better survival than the patients (n = 9) with N/L ≥ 2.5 (P = .006). In group B, 6 of 13 patients with N/L ≥ 2.5 had N/L reduction to <2.5 after combination therapy of sorafenib and TACE, and their 6-month, 1-year and 2-year survival were improved (P = .013). For immune cell examination, the frequency of CD4+ and CD8+ T-lymphocytes, regulatory T-cell and MDSC were not altered by sorafenib treatment. However, actual number of lymphocytes had a tendency to increase (from 978.5 ± 319.4/mm3 prior to treatment to 1378.0 ± 403.3/mm3 , P = .086) for the patients with N/L reduction. CONCLUSION Immunosuppressor cells were not altered by sorafeinb. Patients' survival was improved if N/L ≥ 2.5 was reduced to <2.5 by TACE.
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Oxaliplatin-induced Immune Thrombocytopenia: A Case Report and Literature Review.
Stack, A, Khanal, R, Denlinger, CS
Clinical colorectal cancer. 2021;(1):e1-e4
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Oxaliplatin-induced immune thrombocytopenia is a rare manifestation of oxaliplatin hypersensitivity, presenting as an acute onset of severe thrombocytopenia after oxaliplatin administration. No standard therapeutic approach outside of permanent discontinuation of oxaliplatin exists. Here, we present a case of oxaliplatin-induced immune thrombocytopenia occurring after oxaliplatin retreatment for metastatic colon cancer. Possible mechanisms of disease and approach to treatment are discussed.
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Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer.
Keenan, TE, Guerriero, JL, Barroso-Sousa, R, Li, T, O'Meara, T, Giobbie-Hurder, A, Tayob, N, Hu, J, Severgnini, M, Agudo, J, et al
Nature communications. 2021;(1):5563
Abstract
Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.
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Current strategies for intratumoural immunotherapy - Beyond immune checkpoint inhibition.
Yuan, J, Khilnani, A, Brody, J, Andtbacka, RHI, Hu-Lieskovan, S, Luke, JJ, Diab, A, Marabelle, A, Snyder, A, Cao, ZA, et al
European journal of cancer (Oxford, England : 1990). 2021;:493-510
Abstract
Immunotherapy has revolutionised cancer treatment through restoration of host antitumour immune response. Immune checkpoint inhibitors (ICIs) confer durable responses in only a subset of patients. Mechanisms of ICI resistance to improve durable response rates and overall survival are an area of intense clinical research. Robust clinical development is ongoing to evaluate novel combination therapies to overcome ICI resistance, including targeting immunoregulatory pathways in the tumour microenvironment. Intratumoural (IT) immunotherapies such as toll-like receptor agonists, stimulator of interferon-induced gene agonists, retinoic-inducible gene I-like receptor agonists and oncolytic viruses may represent potential combination treatment options to overcome ICI resistance. Use of IT immunotherapies in combination with ICIs may alter the tumour microenvironment to address resistance mechanisms and improve antitumour response. Optimisation of IT immunotherapy clinical trials will elucidate resistance mechanisms, facilitate clinical trial design, define pharmacodynamic predictors that identify patients who may most benefit and inform clinical development of combination immunotherapy regimens. Here we provide an overview of IT immunotherapy principles, mechanisms of action, categories of IT immunotherapeutics, emerging data, clinical development strategies, response assessment, dose and schedule determination, clinical trial design and translational study design.
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Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel.
Sams, L, Kruger, S, Heinemann, V, Bararia, D, Haebe, S, Alig, S, Haas, M, Zhang, D, Westphalen, CB, Ormanns, S, et al
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2021;(11):2394-2401
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PURPOSE This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. RESULTS Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. CONCLUSIONS Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.
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AtezoTRIBE: a randomised phase II study of FOLFOXIRI plus bevacizumab alone or in combination with atezolizumab as initial therapy for patients with unresectable metastatic colorectal cancer.
Antoniotti, C, Borelli, B, Rossini, D, Pietrantonio, F, Morano, F, Salvatore, L, Lonardi, S, Marmorino, F, Tamberi, S, Corallo, S, et al
BMC cancer. 2020;(1):683
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) reported remarkable achievements in several solid tumours. However, in metastatic colorectal cancer (mCRC) promising results are limited to patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-high) tumours due to their immune-enriched microenvironment. Combining cytotoxic agents and bevacizumab in mCRC with proficient mismatch repair/microsatellite stability (pMMR/MSS) could make ICIs efficacious by increasing the exposure of neoantigens, especially with highly active chemotherapy regimens, inducing immunogenic cell death, increasing the tumoral infiltration of CD8+ T-cells and reducing tumour-associated myeloid-derived suppressor cells. VEGF-blockade also plays an immunomodulatory role by inhibiting the expansion of T regulatory lymphocytes. Consistently with this rationale, a phase Ib study combined the anti-PDL-1 atezolizumab with FOLFOX/bevacizumab as first-line treatment of mCRC, irrespective of microsatellite status, and reported interesting activity and efficacy results, without safety concerns. Phase III trials led to identify FOLFOXIRI plus bevacizumab as an upfront therapeutic option in selected mCRC patients. Drawing from these considerations, the combination of atezolizumab with an intensified upfront treatment (FOLFOXIRI) and bevacizumab could be worthy of investigation. METHODS AtezoTRIBE is a prospective, open label, phase II, comparative trial in which initially unresectable and previously untreated mCRC patients, irrespective of microsatellite status, are randomized in a 1:2 ratio to receive up to 8 cycles of FOLFOXIRI/bevacizumab alone or in combination with atezolizumab, followed by maintenance with bevacizumab plus 5-fluoruracil/leucovorin with or without atezolizumab according to treatment arm until disease progression. The primary endpoint is PFS. Assuming a median PFS of 12 months for standard arm, 201 patients should be randomized in a 1:2 ratio to detect a hazard ratio of 0.66 in favour of the experimental arm. A safety run-in phase including the first 6 patients enrolled in the FOLFOXIRI/bevacizumab/atezolizumab arm was planned, and no unexpected adverse events or severe toxicities were highlighted by the Safety Monitoring Committee. DISCUSSION The AtezoTRIBE study aims at assessing whether the addition of atezolizumab to an intensified chemotherapy plus bevacizumab might be an efficacious upfront strategy for the treatment of mCRC, irrespective of the microsatellite status. TRIAL REGISTRATION AtezoTRIBE is registered at Clinicaltrials.gov ( NCT03721653 ), October 26th, 2018 and at EUDRACT (2017-000977-35), Februray 28th, 2017.