scholarly journals Adoptive cell therapy using tumor‐infiltrating lymphocytes for melanoma refractory to immune‐checkpoint inhibitors

2021 ◽  
Author(s):  
Ikuko Hirai ◽  
Takeru Funakoshi ◽  
Hajime Kamijuku ◽  
Keitaro Fukuda ◽  
Mariko Mori ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

scholarly journals 353 Safety and efficacy of tumor infiltrating lymphocytes (TIL, LN-145) in combination with pembrolizumab for advanced, recurrent or metastatic HNSCC

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A378-A378
Author(s):  
Antonio Jimeno ◽  
Sophie Papa ◽  
Missak Haigentz ◽  
Juan Rodríguez-Moreno ◽  
Julian Schardt ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Single Agent ◽  
Objective Response ◽  
Tumor Resection ◽  
Tumor Infiltrating Lymphocytes ◽  
Open Label ◽  
Safety And Efficacy ◽  
Infiltrating Lymphocytes

BackgroundSingle agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored.MethodsIOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naïve HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG <1, at least one resectable metastasis for LN-145 production, and at least another measurable lesion after tumor resection. Primary endpoints are ORR per RECIST v1.1 by investigator and safety as measured by the incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs). LN-145 production method uses central GMP manufacturing in a 22-day process yielding a cryopreserved TIL product (figure 1). Preconditioning chemotherapy consists of cyclophosphamide/fludarabine, followed by LN-145, and then < 6 doses of IL-2 over <3 days. Pembrolizumab is initiated post-tumor harvest but prior to LN-145 and continues after LN-145 infusion Q3W until toxicity or progression (figure 2).ResultsNine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached.Abstract 353 Figure 1Iovance LN-145 (autologous TIL cell therapy product) ManufacturingAbstract 353 Figure 2IOV-COM-202 Study SchemaConclusionsLN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented.Trial RegistrationNCT03645928Ethics ApprovalThe study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

Ανοσοθεραπεία ενάντια στον καρκίνο του παγκρέατος

2020 ◽  
Author(s):  
Παύλος Παπακοτούλας
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Ciclopirox Olamine ◽  
Ifn Γ ◽  
Infiltrating Lymphocytes

Το πιο συχνό είδος καρκίνου του παγκρέατος είναι το αδενοκαρκίνωμα του παγκρέατος. Το παγκρεατικό αδενοκαρκίνωμα είναι η 4η κύρια αιτία των θανάτων από καρκίνο παγκοσμίως. Περίπου 60-80% των ασθενών έχουν τη στιγμή της διάγνωσης προχωρημένη νόσο, επειδή ο καρκίνος εισβάλλει στους περιβάλλοντες ιστούς έξω από το πάγκρεας (τοπικά προχωρημένος), ή έχει δώσει μεταστάσεις έξω από το πάγκρεας (μεταστατικός). Καθώς η νόσος παρουσιάζει πολύ υψηλό ποσοστό θνητότητας, κρίνεται επιτακτική η ανάγκη ανεύρεσης νέων αποτελεσματικότερων θεραπειών. Με τη ανάπτυξη της μοριακής και βιολογικής κατανόησης της ογκογενετικής εξέλιξης, εφαρμόστηκαν νέες στρατηγικές στην αντιμετώπιση του καρκίνου και κατ’ επέκταση σε αυτόν της ανοσοθεραπείας του καρκίνου. Η κατανόηση των μοριακών μηχανισμών που διέπουν την ανοσοδιαφυγή των όγκων, αλλά και την αλληλεπίδραση των καρκινικών κυττάρων με τα κύτταρα του ανοσοποιητικού συστήματος, έχει δώσει τεράστια ώθηση στην ανοσοθεραπεία του καρκίνου την τελευταία δεκαετία. Τα κύτταρα του ανθρώπινου οργανισμού βρίσκονται υπό διαρκή ανοσιακή επιτήρηση και το ανοσοποιητικό σύστημα αποτελεί αποτρεπτικό μηχανισμό στον νεοπλασματικό μετασχηματισμό και τη δημιουργία νεοπλασιών. Κλινικό σημείο που επιβεβαιώνει τη θεωρία της ανοσοεπιτήρησης είναι η διαπίστωση της παρουσίας CD8+ T-λεμφοκυττάρων μέσα στους όγκους (Tumor Infiltrating Lymphocytes – TILs). Συνέπεια αυτού είναι και οι θεραπείες που βασίζονται στην καταστολή των σημείων ελέγχου του ανοσοποιητικού συστήματος (Immune Checkpoint Inhibitors). Είναι γνωστό ότι φάρμακα με αντιμυκητιακές ιδιότητες συμβάλλουν στην ενίσχυση του ανοσοποιητικού συστήματος. Ένα χαρακτηριστικό παράδειγμα είναι η κυκλοπιροξολαμίνη (Ciclopirox Olamine, CPX), που χορηγείται σε άτομα που ταλαιπωρούνται από μυκητιάσεις. Σύμφωνα με την παρούσα διατριβή η συγκεκριμένη θεραπεία μπορεί να μειώσει δραστικά την ταχύτητα εξέλιξης των καρκινικών όγκων, αλλά παράλληλα ενισχύει τη δράση των κυτταροστατικών που χορηγούνται στον ασθενή. Επίσης, η τινζαπαρίνη (Ηπαρίνη Χαμηλού Μοριακού Βάρους) χρησιμοποιείται για την πρόληψη και την αντιμετώπιση της φλεβικής θρομβοεμβολής, αλλά από τα αποτελέσματα της παρούσης διατριβής φαίνεται ότι μπορεί να διαδραματίζει ρόλο στην αντιμετώπιση του όγκου. Οι μηχανισμοί στους οποίους οφείλονται τα σημαντικά in vivο αποτελέσματα, είναι η αύξηση της IFN-γ, η αύξηση των CD8+ κυττάρων, η μείωση των Tregs κυττάρων, η μείωση της έκφρασης του VEGFR-2 και η αύξηση της απόπτωσης στα καρκινικά κύτταρα. Στην παρούσα διατριβή, προτείνεται πως η συνδυαστική θεραπεία με τη συμμετοχή της ανοσοθεραπείας, έχει προφανώς υψηλότερη αντινεοπλασματική επίδραση στη μείωση της ανάπτυξης του όγκου, υποδηλώνοντας μια συνεργική δράση. Αυτή η συνεργική στρατηγική μπορεί να ανοίξει νέους δρόμους για τη θεραπεία ασθενών με καρκίνο του παγκρέατος.

scholarly journals Tumor-Infiltrating Lymphocytes and Breast Cancer: Are Immune Checkpoint Inhibitors Ready for Prime Time in Breast Cancer?

2016 ◽  
Vol 33 (4) ◽  
pp. 237-246 ◽  
Author(s):  
Ana Cvetanović ◽  
Slađana Filipović ◽  
Nikola Živković ◽  
Miloš Kostić ◽  
Svetislav Vrbić ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Breast Tumors ◽  
Prime Time ◽  
Infiltrating Lymphocytes

SummaryIn recent years, results obtained from different studies with large cohorts have revealed a bond between the presence of extensive lymphocytic infiltration and favourable prognostic associations in the early-stage of breast cancer (BC) and high response rates to neoadjuvant chemotherapy. Examiners used tumors from large cohorts of patients who took part in randomized neoadjuvant and adjuvant clinical trials. The importance of tumor infiltrating lymphocytes (TILs) appears to be subtype-specific and varies depending on the histological characteristics of the tumor. TILs have proven to be a good prognostic marker, but only in highly proliferative breast tumors such as triple negative breast tumors (TNBC) or HER 2 positive BC.In the era when standard, well-known, prognostic and predictive biomarkers are ever changing and the use of molecular profiling analyses are increasing, we are looking for techniques to improve our understanding of tumor biology and improve patient outcome. The relevance of TILs cannot be ignored but needs to be properly evaluated in larger prospective studies which must encompass the parameters set out in previous studies. The use of TILs as prognostic biomarkers in early breast cancer may represent a new dawn, and use of immunotherapy, especially immune checkpoint inhibitors, probably is the future for the breast cancer but it is not yet ready for prime time.

scholarly journals Application of Immunotherapy in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Lele Miao ◽  
Zhengchao Zhang ◽  
Zhijian Ren ◽  
Yumin Li
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Therapy ◽  
Immune Responses ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Research Progress ◽  
Tumor Vaccines ◽  
Immunosuppressive Microenvironment

Hepatocellular carcinoma is one of the most common malignancies globally. It not only has a hidden onset but also progresses rapidly. Most HCC patients are already in the advanced stage of cancer when they are diagnosed, and have even lost the opportunity for surgical treatment. As an inflammation-related tumor, the immunosuppressive microenvironment of HCC can promote immune tolerance through a variety of mechanisms. Immunotherapy can activate tumor-specific immune responses, which brings a new hope for the treatment of HCC. At the present time, main immunotherapy strategies of HCC include immune checkpoint inhibitors, tumor vaccines, adoptive cell therapy, and so on. This article reviews the application and research progress of immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapy in the treatment of HCC.

Immunotherapy for cholangiocarcinoma: a 2021 update

Immunotherapy ◽  
2021 ◽  
Author(s):  
Nikolaos Charalampakis ◽  
Georgios Papageorgiou ◽  
Sergios Tsakatikas ◽  
Rodanthi Fioretzaki ◽  
Christo Kole ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Cancer Vaccines ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Oncolytic Viruses ◽  
Dismal Prognosis ◽  
Rare Malignancy

Cholangiocarcinoma (CCA) is a rare malignancy with generally dismal prognosis. Immunotherapy has revolutionized the management of cancer patients during the last decade, offering durable responses with an acceptable safety profile, but there are still no significant advances regarding CCA. Novel immunotherapeutic methods, such as cancer vaccines, oncolytic viruses, adoptive cell therapy and combinations of immune checkpoint inhibitors with other agents are currently under investigation and may improve prognosis. Efforts to find robust biomarkers for response are also ongoing. In this review, we discuss the rationale for the use of immunotherapy in CCA and available clinical data. Ongoing trials will also be presented, as well as key findings from each study.

scholarly journals Immune Checkpoint Blockade to Improve Tumor Infiltrating Lymphocytes for Adoptive Cell Therapy

PLoS ONE ◽  
2016 ◽  
Vol 11 (4) ◽  
pp. e0153053 ◽  
Author(s):  
Krithika N. Kodumudi ◽  
Jessica Siegel ◽  
Amy M. Weber ◽  
Ellen Scott ◽  
Amod A. Sarnaik ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Immune Checkpoint ◽  
Adoptive Cell Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Infiltrating Lymphocytes

Immune Checkpoint Inhibitors in Brain Metastases: From Biology to Treatment

2016 ◽  
pp. e116-e122 ◽  
Author(s):  
Anna S. Berghoff ◽  
Vyshak A. Venur ◽  
Matthias Preusser ◽  
Manmeet S. Ahluwalia
Keyword(s):  
Immune Response ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Scientific Evidence ◽  
Tumor Infiltrating Lymphocytes ◽  
Treatment Target ◽  
Infiltrating Lymphocytes ◽  
Extracranial Metastases

Cancer immunotherapy has been a subject of intense research over the last several years, leading to new approaches for modulation of the immune system to treat malignancies. Immune checkpoint inhibitors (anti–CLTA-4 antibodies and anti–PD-1/PD-L1 antibodies) potentiate the host’s own antitumor immune response. These immune checkpoint inhibitors have shown impressive clinical efficacy in advanced melanoma, metastatic kidney cancer, and metastatic non–small cell lung cancer (NSCLC)—all malignancies that frequently cause brain metastases. The immune response in the brain is highly regulated, challenging the treatment of brain metastases with immune-modulatory therapies. The immune microenvironment in brain metastases is active with a high density of tumor-infiltrating lymphocytes in certain patients and, therefore, may serve as a potential treatment target. However, clinical data of the efficacy of immune checkpoint inhibitors in brain metastases compared with extracranial metastases are limited, as most clinical trials with these new agents excluded patients with active brain metastases. In this article, we review the current scientific evidence of brain metastases biology with specific emphasis on inflammatory tumor microenvironment and the evolving state of clinical application of immune checkpoint inhibitors for patients with brain metastases.

scholarly journals Integrating Immunotherapy with Chemotherapy: A New Approach to Drug Repurposing

2021 ◽  
Author(s):  
Hina Qayoom ◽  
Umar Mehraj ◽  
Shariqa Aisha ◽  
Shazia Sofi ◽  
Manzoor Ahmad Mir
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Breast Cancer Subtype ◽  
Drug Repurposing ◽  
Tumor Infiltrating Lymphocytes ◽  
Her2 Receptor ◽  
Infiltrating Lymphocytes

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking the three hormonal receptors namely estrogen receptor, progesterone receptor and HER2 receptor, and the only treatment option available for TNBC is chemotherapy. Chemotherapy lacks specificity since it acts on normal healthy cells as well resulting into secondary diseases in TNBC patients. In addition chemotherapy poses recurrence and relapse issues due to the development of chemoresistance among TNBC patients. Immunotherapy remarkably immune checkpoint inhibitors show a great therapeutic potential in TNBC. As TNBC contain an increased TILs (tumor infiltrating lymphocytes) infiltration making it more suitable as a therapeutic target anti-tumor immune strategy. Moreover, evidences have indicated that chemotherapy upregulates the anti-tumor immune response in TNBC. As a result, a combination of immunotherapy with chemotherapy may increase the overall relapse and recurrence free survival of TNBC patients. Therefore, in this chapter we will focus on how the immunotherapy works in TNBC, their effects and consequences. We will further be discussing the clinical studies and the importance of immune checkpoint inhibitors (ICIs) in combination with various therapeutic agents and target. Further, we will explore the processes involved.

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