TRANSPOCART: ENSAYO CLINICO MULTICENTRICO DE FASE I/II CON CELULAS CART ESPECIFICAS DE CD19 BASADAS EN TRASPOSONES EN PACIENTES CON R/R LLA CD19+

ICI19/00069

Nombre agencia financiadora Instituto de Salud Carlos III
Acrónimo agencia financiadora ISCIII
Programa Programa Estatal de Generación de Conocimiento y Fortalecimiento del Sistema Español de I+D+I
Subprograma Subprograma Estatal de Generación de Conocimiento
Convocatoria Proyectos de Investigación Clínica Independiente
Año convocatoria 2019
Unidad de gestión Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)
Centro beneficiario FUNDACION INSTITUTO DE ESTUDIOS DE CIENCIAS DE LA SALUD DE CASTILLA Y LEON
Centro realización INSTITUTO DE INVESTIGACION BIOMEDICA DE SALAMANCA (IBSAL)
Identificador persistente https://doi.org/10.13039/501100004587

Publicaciones

Found(s) 7 result(s)
Found(s) 1 page(s)

Systemic CD4 immunity and PD-L1/PD-1 blockade immunotherapy

Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
  • Escors Murugarren, David
  • Bocanegra Gondán, Ana Isabel
  • Chocarro de Erauso, Luisa
  • Blanco, Ester
  • Piñeiro Hermida, Sergio
  • Garnica, Maider
  • Fernández Rubio, Leticia
  • Vera García, Ruth
  • Arasanz Esteban, Hugo
  • Kochan, Grazyna
PD-L1/PD-1 blockade immunotherapy has changed the therapeutic approaches for the treatment of many cancers. Nevertheless, the mechanisms underlying its efficacy or treatment failure are still unclear. Proficient systemic immunity seems to be a prerequisite for efficacy, as recently shown in patients and in mouse models. It is widely accepted that expansion of anti-tumor CD8 T cell populations is principally responsible for anti-tumor responses. In contrast, the role of CD4 T cells has been less studied. Here we review and discuss the evidence supporting the contribution of CD4 T cells to anti-tumor immunity, especially recent advances linking CD4 T cell subsets to efficacious PD-L1/PD-1 blockade immunotherapy. We also discuss the role of CD4 T cell memory subsets present in peripheral blood before the start of immunotherapies, and their utility as predictors of response., The OncoImmunology group is funded by the Spanish Association against Cancer (AECC, PROYE16001ESCO); Instituto de Salud Carlos III (ISCIII)-FEDER project grants (FIS PI17/02119, FIS PI20/00010, COV20/00000, and TRANSPOCART ICI19/00069); a Biomedicine Project grant from the Department of Health of the Government of Navarre (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); This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 848166.




Leading edge: intratumor delivery of monoclonal antibodies for the treatment of solid tumors

Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
  • Blanco, Ester
  • Chocarro de Erauso, Luisa
  • Fernández Rubio, Leticia
  • Bocanegra Gondán, Ana Isabel
  • Arasanz Esteban, Hugo
  • Echaide Górriz, Míriam
  • Garnica, Maider
  • Piñeiro Hermida, Sergio
  • Kochan, Grazyna
  • Escors Murugarren, David
Immunotherapies based on immune checkpoint blockade have shown remarkable clinical outcomes and durable responses in patients with many tumor types. Nevertheless, these therapies lack efficacy in most cancer patients, even causing severe adverse events in a small subset of patients, such as inflammatory disorders and hyper-progressive disease. To diminish the risk of developing serious toxicities, intratumor delivery of monoclonal antibodies could be a solution. Encouraging results have been shown in both preclinical and clinical studies. Thus, intratumor immunotherapy as a new strategy may retain efficacy while increasing safety. This approach is still an exploratory frontier in cancer research and opens up new possibilities for next-generation personalized medicine. Local intratumor delivery can be achieved through many means, but an attractive approach is the use of gene therapy vectors expressing mAbs inside the tumor mass. Here, we summarize basic, translational, and clinical results of intratumor mAb delivery, together with descriptions of non-viral and viral strategies for mAb delivery in preclinical and clinical development. Currently, this is an expanding research subject that will surely play a key role in the future of oncology., 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 bispecific antibodies.




Cutting-edge CAR engineering: beyond T cells

Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
  • Chocarro de Erauso, Luisa
  • Blanco, Ester
  • Fernández Rubio, Leticia
  • Arasanz Esteban, Hugo
  • Bocanegra Gondán, Ana Isabel
  • Echaide Górriz, Míriam
  • Garnica, Maider
  • Ramos, Pablo
  • Piñeiro Hermida, Sergio
  • Vera García, Ruth
  • Kochan, Grazyna
  • Escors Murugarren, David
Chimeric antigen receptor (CAR)-T adoptive cell therapy is one of the most promising advanced therapies for the treatment of cancer, with unprecedented outcomes in haematological malignancies. However, it still lacks efficacy in solid tumours, possibly because engineered T cells become inactive within the immunosuppressive tumour microenvironment (TME). In the TME, cells of the myeloid lineage (M) are among the immunosuppressive cell types with the highest tumour infiltration rate. These cells interact with other immune cells, mediating immunosuppression and promoting angiogenesis. Recently, the development of CAR-M cell therapies has been put forward as a new candidate immunotherapy with good efficacy potential. This alternative CAR strategy may increase the efficacy, survival, persistence, and safety of CAR treatments in solid tumours. This remains a critical frontier in cancer research and opens up a new possibility for next-generation personalised medicine to overcome TME resistance. However, the exact mechanisms of action of CAR-M and their effect on the TME remain poorly understood. Here, we summarise the basic, translational, and clinical results of CAR-innate immune cells and CAR-M cell immunotherapies, from their engineering and mechanistic studies to preclinical and clinical development., 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.




Mrna vaccines against sars-cov-2: advantages and caveats

Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
  • Echaide Górriz, Míriam
  • Chocarro de Erauso, Luisa
  • Bocanegra Gondán, Ana Isabel
  • Blanco, Ester
  • Kochan, Grazyna
  • Escors Murugarren, David
The application of BNT162b2 and mRNA-1273 vaccines against SARS-CoV-2 infection
has constituted a determinant resource to control the COVID-19 pandemic. Since the beginning of
2021, millions of doses have been administered in several countries of North and South America
and Europe. Many studies have confirmed the efficacy of these vaccines in a wide range of ages
and in vulnerable groups of people against COVID-19. Nevertheless, the emergence and selection
of new variants have led to a progressive decay in vaccine efficacy. Pfizer–BioNTech and Moderna
developed updated bivalent vaccines—Comirnaty and Spikevax—to improve responses against the
SARS-CoV-2 Omicron variants. Frequent booster doses with monovalent or bivalent mRNA vaccines,
the emergence of some rare but serious adverse events and the activation of T-helper 17 responses
suggest the need for improved mRNA vaccine formulations or the use of other types of vaccines.
In this review, we discuss the advantages and limitations of mRNA vaccines targeting SARS-CoV-2
focusing on the most recent, related publications., The OncoImmunology group is funded by the Spanish Association against Cancer (AECC, PROYE16001ESCO); Instituto de Salud Carlos III (ISCIII)-FEDER project grants (FIS PI17/02119, FIS PI20/00010, COV20/00000, and TRANSPOCART ICI19/00069); a Biomedicine Project grant from the Department of Health of the Government of Navarre (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); This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 848166.




Clinical landscape of LAG-3-targeted therapy

Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
  • Chocarro de Erauso, Luisa
  • Blanco, Ester
  • Arasanz Esteban, Hugo
  • Fernández Rubio, Leticia
  • Bocanegra Gondán, Ana Isabel
  • Echaide Górriz, Míriam
  • Garnica, Maider
  • Ramos, Pablo
  • Fernández Hinojal, Gonzalo
  • Vera García, Ruth
  • Kochan, Grazyna
  • Escors Murugarren, David
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.




Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics

Dadun. Depósito Académico Digital de la Universidad de Navarra
  • Arasanz, H. (Hugo)
  • Zuazo, M. (Miren)
  • Bocanegra, A. (Ana)
  • Gato-Cañas, M. (María)
  • Martinez-Aguillo, M. (M.)
  • Morilla, I. (Idoia)
  • Fernández-Hinojal, G. (Gonzalo)
  • Hernández, B. (Berta)
  • López, P. (Paúl)
  • Alberdi, N. (Nerea)
  • Hernández, C. (Carlos)
  • Chocarro, L. (Luisa)
  • Teijeira, L. (Lucía)
  • Vera, R. (Ruth)
  • Kochan, G. (Grazyna)
  • Escors, D. (David)
Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an
acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on
radiological evaluation present important technical limitations. No biomarkers have been identified
yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy
after progression to platinum-based therapy were prospectively studied. Samples from peripheral
blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood
mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified
by flow cytometry and correlated with HPD as identified with radiological criteria. A strong
expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and
second cycle of therapy was observed in HPD patients. After normalizing, the proportion of
posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the
rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD
progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cut-off value of 1.3
identified HPD with 82% specificity and 70% sensitivity. An increase of CD28− CD4 T lymphocytes ≥
1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR)
was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients
(median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03,
p = 0.0126). A strong expansion of CD28− CD4 lymphocytes in peripheral blood within the first
cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in
clinical practice and complements radiological evaluation.




Plasma fractalkine contributes to systemic myeloid diversity and PD-L1/PD-1 blockade in lung cancer

Dadun. Depósito Académico Digital de la Universidad de Navarra
  • Bocanegra, A. (Ana)
  • Fernández-Hinojal, G. (Gonzalo)
  • Ajona-Martínez-Polo, D. (Daniel)
  • Blanco, E. (Ester)
  • Zuazo, M. (Miren)
  • Garnica, M. (Maider)
  • Chocarro, L. (Luisa)
  • Alfaro-Arnedo, E. (Elvira)
  • Piñeiro-Hermida, S. (Sergio)
  • Morente, P. (Pilar)
  • Fernández, L. (Leticia)
  • Remirez, A. (Ana)
  • Echaide, M. (Miriam)
  • Martinez-Aguillo, M. (M.)
  • Morilla, I. (Idoia)
  • Tavira, B. (Beatriz)
  • Roncero, A. (Alejandra)
  • Gotera-Rivera, C. (Carolina)
  • Ventura, A. (Alfonso)
  • Recalde, N. (Nerea)
  • Pichel, J.G. (José G.)
  • Lasarte, J.J. (Juan José)
  • Montuenga-Badia, L.M. (Luis M.)
  • Vera, R. (Ruth)
  • Pio, R. (Rubén)
  • Escors, D. (David)
  • Kochan, G. (Grazyna)
Recent studies highlight the importance of baseline functional immunity for immune checkpoint blockade therapies. High-dimensional systemic immune profiling is performed in a cohort of non-small-cell lung cancer patients undergoing PD-L1/PD-1 blockade immunotherapy. Responders show high baseline myeloid phenotypic diversity in peripheral blood. To quantify it, we define a diversity index as a potential biomarker of response. This parameter correlates with elevated activated monocytic cells and decreased granulocytic phenotypes. High-throughput profiling of soluble factors in plasma identifies fractalkine (FKN), a chemokine involved in immune chemotaxis and adhesion, as a biomarker of response to immunotherapy that also correlates with myeloid cell diversity in human patients and murine models. Secreted FKN inhibits lung adenocarcinoma growth in vivo through a prominent contribution of systemic effector NK cells and increased tumor immune infiltration. FKN sensitizes murine lung cancer models refractory to anti-PD-1 treatment to immune checkpoint blockade immunotherapy. Importantly, recombinant FKN and tumor-expressed FKN are efficacious in delaying tumor growth in vivo locally and systemically, indicating a potential therapeutic use of FKN in combination with immunotherapy.