scholarly journals Targeting Tumor-Induced Immunosuppression Using Conventional Cancer Therapeutics

2021 ◽  
Vol 9 (12) ◽  
Author(s):  
Emma Eriksson ◽  
Tanja Lövgren ◽  
Angelica Loskog
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Suppressor Cells ◽  
Cancer Therapeutics ◽  
Phase Iii ◽  
Current View ◽  
T Cell Therapy ◽  
Combination Treatments

Immunosuppression remains a challenge in the immunotherapy field and needs to be combated to increase survival of patients suffering from cancer. There have been no phase III trials that have in an organized, statistically reliable setting compared immunotherapy outcome with or without so called preconditioning, or metronomic conditioning, in randomized settings. The current view on preconditioning is that it may be used both to reduce tumor load and to reduce suppressive immune cells prior to immunotherapy. For combination treatments, immunotherapy such as checkpoint blockade has shown benefit in combination with chemotherapy even if the major goals of those studies may not have been to condition the patient for a better immune response due to reduced immunosuppression. Nevertheless, there is a need to further enhance the promising effect of cancer immunotherapy. We argue herein that there are several interesting conventional cancer therapeutics to explore for combinational use with immunotherapy to enhance response rates and achieve a longer overall survival of patients. This review will discuss mechanisms of conventional cancer therapeutics of interest for combination therapy. For example, gemcitabine and several tyrosine kinase inhibitors have profound effect on myeloid-derived suppressor cells while tyrosine kinase inhibitors can enhance T cell infiltration into tumors likely due to increased chemokine signaling. Further, cyclophosphamide is well known for its capacity to reduce Tregs and is used to precondition patients prior T cell therapy. How to combine these agents with immunotherapy to further increase patient survival is an important next step in the immunotherapeutic field.

scholarly journals BCR-ABL–specific T-cell therapy in Ph+ ALL patients on tyrosine-kinase inhibitors

Blood ◽  
2017 ◽  
Vol 129 (5) ◽  
pp. 582-586 ◽  
Author(s):  
Patrizia Comoli ◽  
Sabrina Basso ◽  
Giovanni Riva ◽  
Patrizia Barozzi ◽  
Ilaria Guido ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
T Cell ◽  
Cell Therapy ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
T Cell Therapy ◽  
Specific Ctls ◽  
Healthy Donors ◽  
Key Points

Key Points BCR-ABL–specific CTLs may be obtained by stimulation with peptides derived from BCR-ABL junctional region and alternative splicing. T-cell therapy with BCR-ABL–specific CTLs from healthy donors or patients mediates molecular or hematologic CR in patients with Ph+ ALL.

scholarly journals Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

2021 ◽  
Vol 22 (2) ◽  
pp. 493
Author(s):  
Christos Vallilas ◽  
Panagiotis Sarantis ◽  
Anastasios Kyriazoglou ◽  
Evangelos Koustas ◽  
Stamatios Theocharis ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Cancer Therapeutics ◽  
Gastrointestinal Neoplasms ◽  
Mesenchymal Tumors ◽  
Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

scholarly journals Canadian perspectives: update on inhibition of ALK-positive tumours in advanced non-small-cell lung cancer

2018 ◽  
Vol 25 (5) ◽  
Author(s):  
B. Melosky ◽  
P. Cheema ◽  
J. Agulnik ◽  
R. Albadine ◽  
D. G. Bebb ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Alk Inhibitor ◽  
Alk Positive

BackgroundInhibition of the anaplastic lymphoma kinase (alk) oncogenic driver in advanced non-small-cell lung carcinoma (nsclc) improves survival. In 2015, Canadian thoracic oncology specialists published a consensus guideline about the identification and treatment of ALK-positive patients, recommending use of the alk inhibitor crizotinib in the first line. New scientific literature warrants a consensus update.MethodsClinical trials of alk inhibitor were reviewed to assess benefits, risks, and implications relative to current Canadian guidance in patients with ALK-positive nsclc.ResultsRandomized phase iii trials have demonstrated clinical benefit for single-agent alectinib and ceritinib used in treatment-naïve patients and as second-line therapy after crizotinib. Phase ii trials have demonstrated activity for single-agent brigatinib and lorlatinib in further lines of therapy. Improved responses in brain metastases were observed for all second- and next/third-generation alk tyrosine kinase inhibitors in patients progressing on crizotinib. Canadian recommendations are therefore revised as follows:Patients with advanced nonsquamous nsclc have to be tested for the presence of an ALKrearrangement.Treatment-naïve patients with ALK-positive disease should initially be offered single-agent alectinib or ceritinib, or both sequentially.Crizotinib-refractory patients should be treated with single-agent alectinib or ceritinib, or both sequentially.Further treatments could include single-agent brigatinib or lorlatinib, or both sequentially.Patients progressing on alk tyrosine kinase inhibitors should be considered for pemetrexed-based chemotherapy.Other systemic therapies should be exhausted before immunotherapy is considered.SummaryMultiple lines of alk inhibition are now recommended for patients with advanced nsclc with an ALKrearrangement.

Targeted Therapy in Combination with Chemotherapy in Recurrent and/or Metastatic Head and Neck Cancer

2010 ◽  
Vol 06 (01) ◽  
pp. 43
Author(s):  
Pol Specenier ◽  
Jan B Vermorken ◽  
◽  
Keyword(s):  
Monoclonal Antibodies ◽  
Tyrosine Kinase ◽  
Head And Neck ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Cell Cancer ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Platinum Based Chemotherapy ◽  
Pathway Inhibition

Two epidermal growth factor receptor (EGFR)-targeting strategies are used in recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN): monoclonal antibodies and small-molecule tyrosine kinase inhibitors. Thus far, the monoclonal antibody cetuximab has been studied in most detail. Based on the results of two randomised phase III trials, cetuximab in combination with platinum-based chemotherapy should be considered the new standard first-line regimen for patients with recurrent and/or metastatic disease for whom a platinum-based regimen regimen is considered the best treatment option. Other EGFR-directed monoclonal antibodies are under investigation. The role of EGFR tyrosine kinase inhibitors (TKIs) in SCCHN is less well established and early data on other targeted agents have also been disappointing thus far. Dual pathway inhibition may overcome resistance to single pathway inhibition.

scholarly journals Tyrosine kinases in etiopathogenesis and therapy of malignant diseases: c-kit activating mutations

2010 ◽  
Vol 63 (5-6) ◽  
pp. 380-386
Author(s):  
Karmen Stankov ◽  
Gordana Bogdanovic ◽  
Stevan Popovic
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Malignant Disease ◽  
Therapeutic Response ◽  
Kinase Inhibitors ◽  
New Technologies ◽  
Cancer Therapeutics ◽  
Activating Mutations ◽  
Gene Expression Levels

Introduction. In the last 15 years, the introduction of molecular biology methods and techniques for identifying mutations and measuring gene expression levels of mutated genes since recently, have enabled precise molecular diagnostics, classification and assessment of prognosis and therapeutic response of malignant disease to specific therapies. The increased knowledge of the cancer genome and the introduction of multiple new technologies in cancer research have significantly improved the drug discovery process, leading to key success in targeted cancer therapeutics, including tyrosine kinase inhibitors. Tyrosine kinase inhibitors are the molecular targeted neoadjuvant and adjuvant therapy of various malignancies. Many more results which are expected from ongoing trials are necessary to specify the appropriate dosages, stages at which to start the treatment, and which therapeutic combinations to apply.

scholarly journals FLT3 Mutations in Early T-Cell Precursor ALL Characterize a Stem Cell Like Leukemia and Imply the Clinical Use of Tyrosine Kinase Inhibitors

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e53190 ◽  
Author(s):  
Martin Neumann ◽  
Ebru Coskun ◽  
Lars Fransecky ◽  
Liliana H. Mochmann ◽  
Isabelle Bartram ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Clinical Use ◽  
Cell Precursor ◽  
Flt3 Mutations

Identifying resistance biomarkers against five clinically approved tyrosine kinase inhibitors in 45 cell lines.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21005-e21005
Author(s):  
Zsófia Pénzváltó ◽  
Bálint Tegze ◽  
Attila Marcell Szasz ◽  
Reinhold Schäfer ◽  
Balazs Gyorffy
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Resistance Index ◽  
Cancer Therapeutics ◽  
Immunohistochemical Analysis ◽  
Clinical Samples

e21005 Background: Clinical studies show low overall response rates of 10-47% to targeted cancer therapeutics. Our aim was to identify new biomarkers for predicting sensitivity against five already approved tyrosine kinase inhibitors. Methods: Sensitivity to sunitinib, erlotinib, lapatinib, sorafenib and gefitinib were tested in 45 cancer cell lines, and a resistance index was calculated for each cell line. The gene expression profiles (data were obtained by interrogating the raw microarray data of the caArray database) in the subset of resistant vs. sensitive cell lines were compared for each drug. Feature selection was carried out using significance analysis of microarrays and rank products. The results were validated by qPCR in the cell lines and - in case of four sunitinib resistance associated genes - in clinical samples by immunohistochemistry. Results: A set of 63 genes was identified as associated with resistance against the examined drugs. Overall classification accuracy of the prediction was 92.8% in a leave-one-out cross validation using prediction analysis of microarrays. The expression of the genes was validated by qPCR in the cell lines. The results confirmed 45/63 of the microarray-based resistance associated genes and 7/32 of literature based genes. All together 48 sunitinib-treated metastatic renal cell carcinomas were collected. The immunohistochemical analysis in these confirmed the correlation of the expression of RAB17, LGALS8, and EPCAM with overall survival. Conclusions: We identified new predictive biomarker candidates for five tyrosine kinase inhibitors, and validated a set of sunitinib resistance associated genes in an independent patient cohort.

Is there a benefit on survival of tyrosine-kinase inhibitors versus chemotherapy in first line in mutated EGFR patients with advanced non-small cell cancer (NSCLC)? A meta-analysis.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18020-e18020
Author(s):  
Gaetan Des Guetz ◽  
Bernard Uzzan ◽  
Kader Chouahnia ◽  
Patrick Nicolas ◽  
Jean F. Morere
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Cell Cancer ◽  
Random Effect Model ◽  
Lung Neoplasm ◽  
Phase Iii ◽  
Wild Type ◽  
Effect Model

e18020 Background: Tyrosine-Kinase Inhibitors (TKIs) markedly improve Progression Free Survival (PFS) of advanced NSCLC patients mutated for Epidermal Growth Factor Receptor (EGFR). Results on Overall Survival (OS) are more questionable. Therefore, we performed a publication-based meta-analysis to further assess this issue. Methods: We did a PubMed query using keywords simultaneously (lung neoplasm, TKI, EGFR mutation, survival). We also searched for relevant abstracts in proceedings of ASCO, ESMO, WCLC annual meetings. We cross-checked all references from all articles. Only phase III randomized controlled trials comparing TKI and chemotherapy were included. We used EasyMA software. Results: The 6 eligible studies included 2223 patients (516 males, 1688 females, mostly Asian, median age 60 years, 2155 adenocarcinomas (97 %), 996 mutated tumors, 389 stage IIIB, 1572 Stage IV (71 %), 1989 never smokers (89.5 %). Four studies assessed gefitinib, 2 erlotinib. Chemotherapies were doublets including a platinum salt. Four studies included only mutated patients. Compared to chemotherapy, EGFR TKIs significantly improved PFS (HR=0.39, 95 % CI 0.28-0.53, random effect model). Conversely, OS was similar among patients who first received TKI or chemotherapy (HR=1.00, CI 0.83-1.22, fixed effect model). PFS was significantly worse among non mutated patients in the 2 studies including both mutated and wild-type EGFR patients, whereas OS was unchanged. Concerning side-effects, rash, diarrhoea and interstitial lung disease were significantly more frequent after TKI (RRs 5.00; 2.40 and 6.07). As expected, fatigue (RR 0.41), nausea/vomiting (0.19) and haematological disorders were all significantly more frequent after chemotherapy (RRs for neutropenia, thrombocytopenia and anaemia 0.08; 0.18 and 0.26). Conclusions: The major discrepancy between a markedly improved PFS and a similar OS after TKI compared with chemotherapy could be related to the high level of crossing-over between the 2 groups. We found no detrimental effect on OS of TKIs among wild-type patients.

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