scholarly journals Targeted Tumor Therapy Remixed—An Update on the Use of Small-Molecule Drugs in Combination Therapies

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 155 ◽  
Author(s):  
Martina Gatzka
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Small Molecule ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Therapy ◽  
Metabolic Reprogramming ◽  
Comprehensive Overview ◽  
Small Molecule Drugs ◽  
Mutational Status

Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.

scholarly journals Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints

2021 ◽  
Vol 11 ◽  
Author(s):  
Yaolin Xu ◽  
Lijie He ◽  
Qiang Fu ◽  
Junzhe Hu
Keyword(s):  
Clinical Trials ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Mitochondrial Biogenesis ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Tumor Therapy ◽  
Nucleotide Metabolism ◽  
Metabolic Reprogramming ◽  
Immune Checkpoints

Immune checkpoint inhibitors (ICIs), Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, have been applied in anti-tumor therapy and demonstrated exciting performance compared to conventional treatments. However, the unsatisfactory response rates, high recurrence and adaptive resistance limit their benefits. Metabolic reprogramming appears to be one of the crucial barriers to immunotherapy. The deprivation of required nutrients and altered metabolites not only promote tumor progression but also confer dysfunction on immune cells in the tumor microenvironment (TME). Glycolysis plays a central role in metabolic reprogramming and immunoregulation in the TME, and many therapies targeting glycolysis have been developed, and their combinations with ICIs are in preclinical and clinical trials. Additional attention has been paid to the role of amino acids, lipids, nucleotides and mitochondrial biogenesis in metabolic reprogramming and clinical anti-tumor therapy. This review attempts to describe reprogramming metabolisms within tumor cells and immune cells, from the aspects of glycolysis, amino acid metabolism, lipid metabolism, nucleotide metabolism and mitochondrial biogenesis and their impact on immunity in the TME, as well as the significance of targeting metabolism in anti-tumor therapy, especially in combination with ICIs. In particular, we highlight the expression mechanism of programmed cell death (ligand) 1 [PD-(L)1] in tumor cells and immune cells under reprogramming metabolism, and discuss in detail the potential of targeting key metabolic pathways to break resistance and improve the efficacy of ICIs based on results from current preclinical and clinical trials. Besides, we draw out biomarkers of potential predictive value in ICIs treatment from a metabolic perspective.

scholarly journals Metabolic Reprogramming by Reduced Calorie Intake or Pharmacological Caloric Restriction Mimetics for Improved Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1260
Author(s):  
Erwan Eriau ◽  
Juliette Paillet ◽  
Guido Kroemer ◽  
Jonathan G. Pol
Keyword(s):  
Clinical Trials ◽  
Caloric Restriction ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Therapeutic Interventions ◽  
Model Organisms ◽  
Calorie Intake ◽  
Multiple Model ◽  
Autophagy Induction

Caloric restriction and fasting have been known for a long time for their health- and life-span promoting effects, with coherent observations in multiple model organisms as well as epidemiological and clinical studies. This holds particularly true for cancer. The health-promoting effects of caloric restriction and fasting are mediated at least partly through their cellular effects—chiefly autophagy induction—rather than reduced calorie intake per se. Interestingly, caloric restriction has a differential impact on cancer and healthy cells, due to the atypical metabolic profile of malignant tumors. Caloric restriction mimetics are non-toxic compounds able to mimic the biochemical and physiological effects of caloric restriction including autophagy induction. Caloric restriction and its mimetics induce autophagy to improve the efficacy of some cancer treatments that induce immunogenic cell death (ICD), a type of cellular demise that eventually elicits adaptive antitumor immunity. Caloric restriction and its mimetics also enhance the therapeutic efficacy of chemo-immunotherapies combining ICD-inducing agents with immune checkpoint inhibitors targeting PD-1. Collectively, preclinical data encourage the application of caloric restriction and its mimetics as an adjuvant to immunotherapies. This recommendation is subject to confirmation in additional experimental settings and in clinical trials. In this work, we review the preclinical and clinical evidence in favor of such therapeutic interventions before listing ongoing clinical trials that will shed some light on this subject.

Molecular characterization of the Ras-MAPK pathway in metastatic breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1034-1034
Author(s):  
Justin Wayne Wong Tiu-lim ◽  
Jun Yin ◽  
Joanne Xiu ◽  
Wolfgang Michael Korn ◽  
Heinz-Josef Lenz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Mapk Pathway ◽  
Metastatic Breast ◽  
Molecular Alterations ◽  
Ras Genes ◽  
Mutational Status ◽  
Pathway Activation ◽  
Class 1

1034 Background: The Ras-MAPK pathway is a known driver of tumorigenesis and therapeutic target in a variety of cancers. Alterations in this pathway have been linked to decreased tumor immunogenicity. However, molecular alterations in the Ras-MAPK are rare in breast cancer (BC) and their clinical implications remain unclear. As mutational status does not accurately correlate with transcriptional activity, a MAPK pathway activity score (MPAS, Wagle et al., 2018, npj Precision Medicine) is indicative of MAPK activation and correlates with response to MEK (MEKi) or BRAF inhibition (BRAFi). Our goal was to determine the frequency of molecular alterations in the Ras-MAPK and correlate to MAPK pathway activation in MBC. Methods: A total of 6464 BC samples underwent comprehensive molecular profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq; whole exome sequencing, NovaSEQ), RNA (NovaSeq, whole transcriptome sequencing, WTS) and IHC. MPAS and immune cell fraction (ICF, Quantiseq) were assessed by mRNA analysis. Wilcoxon, Fisher’s exact, or Dunnett’s test was used. All results shown were statistically significant (p < 0.05). Results: The predominant alteration of RAS genes was mutation followed by amplification, no fusions were detected (Table). Only 0.17% of all tumors harbor KRAS G12c mutations. The highest MPAS scores were found in KRAS mutants (mut), HRAS mut (Q61, G1213), BRAF V600 (class 1) mut and NRAS Q61 mut (Table) and therefore used to define Genomic MAPK Activated Tumors (GMAT). GMAT compared to wild type (WT) had significantly higher PD-L1 expression, TMB and MSI/dMMR. GMAT had less B cells (3.4% vs 4.4%), more M1 Macrophages (4.4% vs 3.4%) and neutrophils (5.5% vs 2.7%) regardless of HR status but less NK cells (2.3% s 3.0%), MSDCs (0.9% vs 3.0%) only in HR- tumors with respect to WT. GMAT tumors showed more frequent mutation rate (mr) of PIK3CA (HR+: 57.3% vs 40%; HR-: 41.9% vs 17.9%). HR+ tumors had a higher mr of MSH3 (11.8% vs 0.6%) while HR- tumors had higher mr of PIK3R1 (9.6% vs 3.8%), RhoA (5.3% vs 0.5%), DNA repair genes (TERT, 18.2% vs 1.0%; ARID1A, 18.2% vs 5.9%; PRKDC, 3.9% vs 0) and lower TP53 mr (54.5% vs 85.8%) compared to WT. Conclusions: Our study demonstrates that RAS, BRAF and MEK1 mutations are associated with MAPK pathway activation indicative of benefit from MEKi or BRAFi. GMAT warrant further investigation for combinations targeting the RAS-MAPK pathway and immune checkpoint inhibitors.[Table: see text]

Efficacy of targeted therapy in alveolar soft part sarcoma: A systematic review and meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e23543-e23543
Author(s):  
Na Hyun Kim ◽  
Chenyu Sun ◽  
Apurwa Prasad ◽  
Humaed Mohammed Abdul ◽  
Saba Batool ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Disease Control ◽  
Randomized Clinical Trials ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Soft Part ◽  
Objective Response ◽  
Chromosome 17 ◽  
Alveolar Soft Part Sarcoma

e23543 Background: Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma, characterized by a specific unbalanced translocation leading to the fusion of the TFE3 gene on chromosome-X to the ASPSCR1 gene on chromosome-17. Despite its indolent course, ASPS presents a challenge in treatment due to its resistance to conventional anthracycline-based chemotherapy and lack of large scale trial data for this rare sarcoma. This review aimed to assess the efficacy of tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) in metastatic alveolar soft part sarcoma. Methods: A systematic search was performed on Embase and Medline databases for studies that assessed best response of patients with unresectable or metastatic ASPS to TKI and ICI therapy, according to the Response Evaluation Criteria in Solid Tumors (RECIST) edition 1.0 or 1.1. This study followed the Preferred Reporting Items for Systematic Reviews (PRISMA) protocol. Four independent reviewers screened abstracts and extracted the data; any discrepancy was resolved by discussion among reviewers. Pooled objective response rate (ORR) and disease control rate (DCR) were obtained using the Freeman-Tukey double-arcsine transformation using random effects model on STATA software (version. 16.1, StataCorp). Results: 27 articles and abstracts published between 2011 and 2020 were included in the review, resulting in 2 randomized clinical trials (104 participants), 14 single arm prospective trials (214 participants), and 11 retrospective studies (120 patients). Among clinical trials, the pooled ORR and DCR were 18% (95% confidence interval [CI] 8 - 30%; I2 = 72.25%; p < 0.01) and 87% (95% CI 97 - 93%; I2 = 43.2%; p = 0.03) respectively. Conclusions: The response rate to targeted therapy in metastatic ASPS is not only clinically meaningful, but also comparable to that of first-line chemotherapy. The majority of patients receiving targeted therapy achieved disease control. Patients who had refractory or progressive disease to one targeted agent demonstrated response to other agents. More randomized trials are warranted to expand treatment options and compare to standard of care regimens.

STK11/TP53 co-mutated non-small cell lung cancer (NSCLC) to display a unique tumor microenvironment (TME) and metabolic profile.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9087-9087
Author(s):  
Abdul Rafeh Naqash ◽  
Charalampos S. Floudas ◽  
Asaf Maoz ◽  
Joanne Xiu ◽  
Yasmine Baca ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hierarchical Clustering ◽  
Immune Cell ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Cell Content

9087 Background: Recent data suggest inferior responses to immune checkpoint inhibitors (ICIs) in STK11-mt NSCLC. TP53 is a critical tumor suppressor gene regulating DNA repair by arresting cells in the G1 phase in response to critical double strand breaks. We hypothesized that accumulated DNA damage from mutations in the TP53 gene might increase immunogenicity and potentially enhance benefit of ICIs in STK11-mt NSCLC. Methods: A total of 16,896 NSCLC tumors submitted to Caris Life Sciences (Phoenix, AZ) for targeted NGS (DNA-Seq, 592 genes) were analyzed. A subset (N = 5034 tumors) had gene expression profiling (RNA-Seq, whole transcriptome). PD-L1 (TPS) was tested with 22c3 antibody (Dako). Exome-level neoantigen load for STK11-mt NSCLC was obtained from published TCGA Pan-immune analysis (Thorsson et al. 2018). Non-parametric tests were used for comparing differences in tumor mutational burden (TMB) and neoantigen load. Transcriptomic analysis included differential gene expression and hierarchical clustering. Tumor immune cell content was obtained from transcriptome using Microenvironment Cell Population-counter (MCP). Publicly available data from the POPLAR/OAK trials of atezolizumab in advanced NSCLC were used to model PFS and OS for STK11-mt with TP53-mt (n = 14) and without TP53-mt (n = 20). Results: Of 16,896 NSCLC samples, 12.6% had an STK11-mt with the proportions of TMB-high (≥10 Mut/Mb), PD-L1 ≥ 50% and MSI-high being 55.9%, 11.8%, and 0.72%, respectively. STK11-mt vs. STK11-wt NSCLC did not differ in median TMB (Caris:10 vs. 10 Mut/Mb; p > 0.1) or neoantigen load (TCGA: 154.5 vs. 165; p > 0.1). Median TMB (13 vs. 9 Mut/Mb; p < 0.001) and neoantigen load (263 vs. 134; p < 0.001) were higher in STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt. MCP analysis showed higher CD8, NK-cell and lower myeloid dendritic cell infiltration in STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt (p < 0.01). Expression of MYC and HIF-α were increased in the STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt (p < 0.01) along with higher expression (p < 0.01) of genes associated with both glycolysis ( HK2, LDHA, ALDOA) and glutamine metabolism ( GOT2, PPAT2). Hierarchical clustering of STK11-mt adenocarcinomas (n = 463) for STING pathway genes (CCL5, CXCL10, cGAS) identified a STING-high and a STING low cluster. The STING high cluster was significantly enriched in TP53-mt (48 vs. 32%; p < 0.01).In the OAK/POPLAR cohort, median OS (HR is 1.14, 95% CI 0.53 - 2.48); p > 0.1) and PFS (HR 1.88, 95% CI 0.89-3.97, p = 0.098) were not statistically different between STK11-mt/ TP53-mt vs. STK-mt/ TP53-wt. However, the 15-months PFS was 21% in the STK11-mt/ TP53-mt vs 0% in the STK11-mt/ TP53-wt. Conclusions: STK11-mt NSCLC with TP53-mt are associated with an immunologically active TME with metabolic reprogramming. These intrinsic properties could be exploited to improve outcomes to ICIs in combination with metabolically directed agents.

Analysis of real-world data (RWD) on treatment (tx) sequencing in patients with advanced non-small cell lung cancer (aNSCLC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20642-e20642
Author(s):  
Meng Ma ◽  
Xiang Zhou ◽  
Howard Goldsweig ◽  
Nicholas Hahner ◽  
Dianwei Han ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Rank Test ◽  
Real World Data ◽  
Therapeutic Modalities ◽  
Platinum Based Chemotherapy ◽  
Line Of Therapy ◽  
Line Setting

e20642 Background: While optimal sequencing of systemic therapy in aNSCLC is critical to achieve maximal clinical benefit, it is practically challenging to study tx sequencing through clinical trials. RWD allow retrospective, observational studies to examine tx patterns and associated clinical outcomes. Methods: 1,609 aNSCLC patients who received systemic therapies at Mount Sinai hospitals were analyzed for the number of line of therapy (LOT), therapeutic modalities (chemotherapy, targeted therapy and immunotherapy), and the sequence in which treatments were given when LOT > 1. Time to tx discontinuation (TTD) was used as a surrogate clinical endpoint for outcomes. Results: 578 of the 1,609 (36%) patients received more than one LOT. 356 (22%) received tyrosine kinase inhibitors (TKIs), and 297 (16%) received immune checkpoint inhibitors (CPIs). Kaplan-Meier analysis revealed that among 297 patients who received CPIs, median TTD was longer in the 1st line setting (295 days, 95% CI 169 to 523; n=132) than when LOT > 1 (169 days, 95% CI 113 to 269; n=165), although the difference was not statistically significant (P=0.092, log-rank test). No difference of TTD on TKIs was observed between LOT = 1 and LOT > 1 (P=0.51). With respect to tx sequencing, when patients (n=94) received TKIs as the 1st LOT, 60%, 35%, and 5% of them received another TKI, chemotherapy, or a CPI-containing regimen, respectively, as the 2nd LOT. Among patients (n=370) who progressed on 1st line platinum-based chemotherapy, 52%, 32%, and 16% received another chemo regimen, a CPI-containing regimen, or a targeted therapy, respectively, as the 2nd LOT; these percentages shifted significantly toward more CPIs (24%, 66%, 10% for chemo, CPI, targeted, respectively) when only 2016-2018 data were examined. In the 2nd line setting after platinum therapy, TTD was significantly longer in the CPI group (332 days, 95% CI 169-484) compared to the chemo group (88 days, 95% CI 65-100; P<0.0001), consistent with results from pivotal clinical trials. Conclusions: As the tx algorithm of aNSCLC has been evolving rapidly, we observed diverse tx patterns in RWD. Various tx sequences may impact patient outcomes, and therefore warrant further investigation.

scholarly journals Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer

2022 ◽  
Vol 12 ◽  
Author(s):  
An-Ping Shi ◽  
Xi-Yang Tang ◽  
Yan-Lu Xiong ◽  
Kai-Fu Zheng ◽  
Yu-Jian Liu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Cell ◽  
Biological Effects ◽  
Tumor Therapy ◽  
Interaction Mechanism ◽  
Therapy Resistance ◽  
Comprehensive Overview ◽  
Intracellular Signals ◽  
Interaction Domains ◽  
Therapy Strategies

LAG3 is the most promising immune checkpoint next to PD-1 and CTLA-4. High LAG3 and FGL1 expression boosts tumor growth by inhibiting the immune microenvironment. This review comprises four sections presenting the structure/expression, interaction, biological effects, and clinical application of LAG3/FGL1. D1 and D2 of LAG3 and FD of FGL1 are the LAG3-FGL1 interaction domains. LAG3 accumulates on the surface of lymphocytes in various tumors, but is also found in the cytoplasm in non-small cell lung cancer (NSCLC) cells. FGL1 is found in the cytoplasm in NSCLC cells and on the surface of breast cancer cells. The LAG3-FGL1 interaction mechanism remains unclear, and the intracellular signals require elucidation. LAG3/FGL1 activity is associated with immune cell infiltration, proliferation, and secretion. Cytokine production is enhanced when LAG3/FGL1 are co-expressed with PD-1. IMP321 and relatlimab are promising monoclonal antibodies targeting LAG3 in melanoma. The clinical use of anti-FGL1 antibodies has not been reported. Finally, high FGL1 and LAG3 expression induces EGFR-TKI and gefitinib resistance, and anti-PD-1 therapy resistance, respectively. We present a comprehensive overview of the role of LAG3/FGL1 in cancer, suggesting novel anti-tumor therapy strategies.

scholarly journals Nucleic Acid-Based Approaches for Tumor Therapy

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2061
Author(s):  
Simone Hager ◽  
Frederic Julien Fittler ◽  
Ernst Wagner ◽  
Matthias Bros
Keyword(s):  
Nucleic Acid ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Tumor Therapy ◽  
Comprehensive Overview ◽  
Tumor Immune Evasion ◽  
Combination Treatments ◽  
Current State ◽  
Antigen Presenting ◽  
Molecular Adjuvants

Within the last decade, the introduction of checkpoint inhibitors proposed to boost the patients’ anti-tumor immune response has proven the efficacy of immunotherapeutic approaches for tumor therapy. Furthermore, especially in the context of the development of biocompatible, cell type targeting nano-carriers, nucleic acid-based drugs aimed to initiate and to enhance anti-tumor responses have come of age. This review intends to provide a comprehensive overview of the current state of the therapeutic use of nucleic acids for cancer treatment on various levels, comprising (i) mRNA and DNA-based vaccines to be expressed by antigen presenting cells evoking sustained anti-tumor T cell responses, (ii) molecular adjuvants, (iii) strategies to inhibit/reprogram tumor-induced regulatory immune cells e.g., by RNA interference (RNAi), (iv) genetically tailored T cells and natural killer cells to directly recognize tumor antigens, and (v) killing of tumor cells, and reprograming of constituents of the tumor microenvironment by gene transfer and RNAi. Aside from further improvements of individual nucleic acid-based drugs, the major perspective for successful cancer therapy will be combination treatments employing conventional regimens as well as immunotherapeutics like checkpoint inhibitors and nucleic acid-based drugs, each acting on several levels to adequately counter-act tumor immune evasion.

scholarly journals Monitoring T Cells Responses Mounted by Therapeutic Cancer Vaccines

2021 ◽  
Vol 8 ◽  
Author(s):  
Kue Peng Lim ◽  
Nur Syafinaz Zainal
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
Cancer Vaccine ◽  
Cancer Vaccines ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Rapid Development ◽  
Activated T Cells ◽  
Specific Cytotoxicity

With the regulatory approval of Provenge and Talimogene laherparepvec (T-VEC) for the treatment of metastatic prostate cancer and advanced melanoma respectively, and other promising clinical trials outcomes, cancer vaccine is gaining prominence as a cancer therapeutic agent. Cancer vaccine works to induce T cell priming, expansion, and infiltration resulting in antigen-specific cytotoxicity. Such an approach that can drive cytotoxicity within the tumor could complement the success of checkpoint inhibitors as tumors shown to have high immune cell infiltration are those that would respond well to these antibodies. With the advancements in cancer vaccine, methods to monitor and understand how cancer vaccines modify the immune milieu is under rapid development. This includes using ELISpot and intracellular staining to detect cytokine secretion by activated T cells; tetramer and CyTOF to quantitate the level of antigen specific T cells; proliferation and cell killing assay to detect the expansion of T cell and specific killing activity. More recently, T cell profiling has provided unprecedented detail on immune cell subsets and providing clues to the mechanism involved in immune activation. Here, we reviewed cancer vaccines currently in clinical trials and highlight available techniques in monitoring the clinical response in patients.

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