Clinical landscape of LAG-3-targeted therapy

Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed.The OncoImmunology group is funded by the Spanish Association against Cancer ( AECC ) [grant number PROYE16001ESCO ]; Instituto de Salud Carlos III (ISCIII)-FEDER project grants [grant numbers FIS PI17/02119, FIS PI20/00010, COV20/00000, TRANSPOCART ICI19/00069]; a Biomedicine Project grant from the Department of Health of the Government of Navarre [grant number BMED 050-2019 ]; strategic projects from the Department of Industry, Government of Navarre (AGATA, Ref. 0011-1411-2020-000013; LINTERNA, Ref. 0011-1411-2020-000033; DESCARTHES, 0011-1411-2019-000058); European Project Horizon 2020 Improved Vaccination for Older Adults (ISOLDA; ID: 848166); Crescendo Biologics Ltd. supported the OncoImmunology group for the development and testing of PD-1 and LAG-3 bispecifics

Transcriptomic Correlates of Immunologic Activation in Head and Neck and Cervical Cancer

© 2021 Saiz-Ladera, Baliu-Piqué, Cimas, Manzano, García-Barberán, Camarero, Hinojal, Pandiella, Győrffy, Stewart, Cruz-Hernández, Pérez-Segura and Ocana.Targeting the immune system has emerged as an effective therapeutic strategy for the treatment of various tumor types, including Head and Neck Squamous Cell Carcinoma (HNSCC) and Non-small-Cell Lung Cancer (NSCLC), and checkpoint inhibitors have shown to improve patient survival in these tumor types. Unfortunately, not all cancers respond to these agents, making it necessary to identify responsive tumors. Several biomarkers of response have been described and clinically tested. As of yet what seems to be clear is that a pre-activation state of the immune system is necessary for these agents to be efficient. In this study, using established transcriptomic signatures, we identified a group of gene combination associated with favorable outcome in HNSCC linked to a higher presence of immune effector cells. CD2, CD3D, CD3E, and CXCR6 combined gene expression is associated with improved outcome of HNSCC patients and an increase of infiltrating immune effector cells. This new signature also identifies a subset of cervical squamous cell carcinoma (CSCC) patients with favorable prognosis, who show an increased presence of immune effector cells in the tumor, which outcome shows similarities with the HP-positive HNSCC cohort of patients. In addition, CD2, CD3D, CD3E, and CXCR6 signature is able to predict the best favorable prognosis in terms of overall survival of CSSC patients. Of note, these findings were not reproduced in other squamous cell carcinomas like esophageal SCC or lung SCC. Prospective confirmatory studies should be employed to validate these findings.This work has been supported by Instituto de Salud Carlos III (PI16/01121 and PI19/00808), ACEPAIN; Diputación de Albacete, CIBERONC and CRIS Cancer Foundation (to AO). Ministry of Economy and Competitiveness of Spain (BFU2015-71371-R), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and CIBERONC, the scientific foundation of the AECC and the CRIS Foundation (to AP). The work carried out in our laboratories receive support from the European Community through the regional development funding program (FEDER)

Genomic mapping of splicing-related genes identify amplifications in lsm1, clns1a, and ilf2 in luminal breast cancer

© 2021 by the authors.Alternative splicing is an essential biological process, which increases the diversity and complexity of the human transcriptome. In our study, 304 splicing pathway-related genes were evaluated in tumors from breast cancer patients (TCGA dataset). A high number of alterations were detected, including mutations and copy number alterations (CNAs), although mutations were less frequently present compared with CNAs. In the four molecular subtypes, 14 common splice genes showed high level amplification in >5% of patients. Certain genes were only amplified in specific breast cancer subtypes. Most altered genes in each molecular subtype clustered to a few chromosomal regions. In the Luminal subtype, amplifications of LSM1, CLNS1A, and ILF2 showed a strong significant association with prognosis. An even more robust association with OS and RFS was observed when expression of these three genes was combined. Inhibition of LSM1, CLNS1A, and ILF2, using siRNA in MCF7 and T47D cells, showed a decrease in cell proliferation. The mRNA expression of these genes was reduced by treatment with BET inhibitors, a family of epigenetic modulators. We map the presence of splicing-related genes in breast cancer, describing three novel genes, LSM1, CLNS1A, and ILF2, that have an oncogenic role and can be modulated with BET inhibitors.A.O.’s lab is supported by the Instituto de Salud Carlos III (ISCIII, PI19/00808); ACEPAIN; CRIS Cancer Foundation and Diputación de Albacete. This research is also supported by PI18/01020 from the Instituto de Salud Carlos III and co-financed by the European Development Regional Fund (FEDER) “A way to achieve Europe” (ERDF); N.L. MDM was supported by the Spanish Ministry of Education (FPU grant; Ref.: FPU18/01319). B.G. was financed by the 2018-2.1.17-TETKR-00001, 2020-1.1.6-JÖVO-2021-00013, and 2018-1.3.1-VKE-2018-00032 grants and by the Higher ˝ Education Institutional Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary

Prognostic capacity of peripheral blood-derived biomarkers in NSCLC patients treated with PD-1/PD-L1 blockade immunotherapy

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Prognostic capacity of peripheral blood-derived biomarkers in NSCLC patients treated with PD-1/PD-L1 blockade immunotherapy

El cáncer de pulmón genera una importante carga de morbimortalidad a nivel mundial. Durante la última década ha existido un importante desarrollo terapéutico por la aprobación de fármacos de inmunoterapia, especialmente en el bloqueo de PD-1 y PD-L1 en pacientes sin dianas terapéuticas. Pese a la propuesta de numerosos biomarcadores, resulta difícil identificar aquellos pacientes que se benefician del tratamiento y obtienen respuestas prolongadas. En este estudio observacional retrospectivo, se recogieron variables clínicas junto con la composición corporal medida por TC, así como extracción muestras de sangre periférica tras el inicio de tratamiento en una cohorte de pacientes con carcinoma no microcítico pulmonar avanzado en tratamiento con inmunoterapia. Se realizó una citometría de flujo multidimensional para la detección e inmunofenotipado de diferentes poblaciones mieloides. Además se analizó la concentración de 45 proteínas circulantes solubles en plasma, agrupados como puntos de control inmunes y quimiocinas mediante Luminex®. En contraste con bibliografía previa, no encontramos diferencias respecto a tasas de respuesta según la composición corporal. Respecto a variables clínicas, observamos un incremento de neutrófilos en sangre periférica en los pacientes no respondedores, así como una aceleración de este fenómeno previamente al deterioro clínico y fallecimiento del paciente, y un descenso paralelo de las cifras absolutas de linfocitos. No observamos diferencias respecto a las cifras de monocitos y plaquetas. Un inmunofenotipado preciso de estas poblaciones mediante citometría de flujo permitió detectar una predominancia de monocitos en respondedores y su correlación con la respuesta al tratamiento. Los niveles de expresión de PD-L1 en estas poblaciones mieloides se puede asociar con las respuestas al tratamiento de inmunoterapia. Las concentraciones de varias proteínas circulantes entre las que se encuentran TIM-3, HVEM, IFN-gamma y VEGF se asociaron con la actividad del tratamiento y el pronóstico de la enfermedad, con impacto en supervivencia global. Además, la histopatología del tumor primario fue un factor diferencial importante en el perfil de acti-vidad de estos tratamientos. Finalmente, se realizó un análisis multivariante de la cohorte. El número previo de líneas de tratamiento, un estatus funcional medido por ECOG > 2, el número de localizaciones metastásicas incluyendo las lesiones hepáticas, el incremento de neutrófilos circulantes medidos por citometría de flujo, y las concentraciones plasmáticas de MCP1 e IL-17alfa se establecieron como predictores independientes de supervivencia

DataSheet_2_Transcriptomic Mapping of Non-Small Cell Lung Cancer K-RAS p.G12C Mutated Tumors: Identification of Surfaceome Targets and Immunologic Correlates.pdf

Supplementary Table 1 | Investigational and approved drugs against K-RAS identified mutations. Specific K-RAS mutation, name of the drug, status (approved or investigational), identification code (NCT) and clinical studies with links and phases are included. Intervention is included if the drug is given in combination with others. Supplementary Table 2 | Gene functions of thirteen selected deregulated genes. Supplementary Table 3 | Upregulation details of cell surface-related genes analyzed. Name of the gene, mean of expression in mutant and wildtype K-RAS tumors, fold change (FC), direction and p-value are included. Supplementary Table 4 | Kaplan-Meier survival values of cell surface-related genes. Table includes the name of the gene, the hazard ratio (HR) (in blue, significant good prognosis, and in red, bad one), p-value and fold discovery rate (FDR) for FP and in LUAD patients.Targeting K-RAS-mutant non-small cell lung cancer (NSCLC) with novel inhibitors has shown promising results with the recent approval of sotorasib in this indication. However, progression to this agent is expected, as it has previously been observed with other inhibitors. Recently, new immune therapeutics, including vectorized compounds with antibodies or modulators of the host immune response, have demonstrated clinical activity. By interrogating massive datasets, including TCGA, we identified genes that code for surface membrane proteins that are selectively expressed in K-RAS mutated NSCLC and that could be used to vectorize novel therapies. Two genes, CLDN10 and TMPRSS6, were selected for their clear differentiation. In addition, we discovered immunologic correlates of outcome that were clearly de-regulated in this particular tumor type and we matched them with immune cell populations. In conclusion, our article describes membrane proteins and immunologic correlates that could be used to better select and optimize current therapies.Peer reviewe