Gene Immunotherapy

PROFILE

Cancer is a highly prevalent, difficult to treat and deadly disease. Moreover, classic therapies have devastating side effects for cancer patients. We investigate cancer immunotherapy, a novel approach to treat cancer that aims to induce cells of the patients’ own immune system, namely the cytotoxic T cells, to attack and specifically eliminate tumors. We study two different strategies to generate tumor-killer T cells. One strategy corresponds to vaccines that specifically stimulate and multiply tumor-killer T cells inside the patient’s body. The other strategy aims to manipulate cytotoxic T cells in the laboratory by genetic engineering with tumor-specific receptors that redirect the specificity of T cells against tumors. We have shown that both strategies are able to achieve strong antitumor effects in preclinical mouse models. Current work is focused on improving the efficacy of these strategies and translating these results to a clinical setting.

LAB MEMBERS

Research Head: Álvaro Lladser

Doctoral students: Felipe Gálvez • Evelyn Menares • Sofía Hidalgo

Undergraduate students: Ernesto López • Ornella Chovar • Pablo Cáceres

Research assistants: Eduardo Roa • Ximena Díaz

COLLABORATIONS

National Collaborations:
• Dr. Rodrigo Pacheco (Fundación Ciencia & Vida). We are studying how the dopaminergic regulation of cytotoxic T lymphocytes and dendritic cells affects the adaptive immune response against melanoma.
• Dr. Andrew Quest (Faculty of Medicine, Universidad de Chile). We are studying the signal transduction leading to metastasis, and the role of caveolin-1 in dendritic cell function.
• Dr. Flavio Salazar (Faculty of Medicine, Universidad de Chile). We are developing vaccines and immunotherapies that can be used in the clinic.
• Dr. Daniela Sauma (Faculty of Science, Universidad de Chile). We are studying the role of CD39 and CD73 in the stemness of CD8+ T-cells.
• Dr. Fabiola Osorio (Faculty of Medicine, Universidad de Chile). We collaborate on basic aspects of antigen cross-presentation in antitumor immune responses.

International Collaborations:
• Dr. Rolf Kiessling (Karolinska Institute, Sweden). We have a vast collaboration on developing novel T cell-based vaccines and therapies against cancer.
• Dr. Andreas Lundqvist (Karolinska Institute, Sweden). Development of T cell- and NK cell-based immunotherapies against cancer.
• Dr. Juliana Idoyaga (Stanford University, USA). We are studying the role of skin migratory dendritic cells in the generation of resident memory CD8 T cells.
• Dr. Anna Maria Lennon (Institut Curie, France). We are studying the role of caveolin-1 protein in dendritic cell migration.
• Dr. Pablo Vargas (Institut Curie, France). We are studying the role of caveolin-1 protein in the chemotaxis of dendritic cells.

SELECTED PUBLICATIONS

  • Figueroa C., Gálvez-Cancino F., Oyarce C., Contreras F., Prado C., Valeria C., Cruz S., Lladser A., Pacheco R. Inhibition of dopamine receptor D3 signaling in dendritic cells increases antigen cross-presentation to CD8+ T-cells favoring anti-tumor immunity. J Neuroimmunol. 303:99-107. doi: 10.1016/j.jneuroim.2016.12.014 (2017). | | ABSTRACT
  • Ligtenberg M. A., Witt K., Gálvez-Cancino F., Sette A., Lladser A., Kiessling R. Cripto-1 vaccination elicits protective immunity against metastatic melanoma. Oncoimmunology 5(5):e1128613, DOI: 10.1080/2162402X.2015.1128613 (2016) | | ABSTRACT
  • Fernandez D., Flores-Santibañez F., Neira J., Osorio F., Tejón G., Nuñez S., Hidalgo Y., Fuenzalida M. J., Meza D., Ureta G., Lladser A., Pacheco R., Acuña-Castillo C., Guixé V., Quintana F. J., Bono M. R., Rosemblatt M., Sauma D. Purinergic signaling as a regulator of Th17 cell plasticity. Plos One 11(6):e0157889. DOI: 10.1371/journal.pone.0157889 (2016) | | ABSTRACT
  • Contreras F., Prado C., González H., Franz D., Osorio-Barrios F., Osorio F., Ugalde V., Lopez E., Elgueta D., Figueroa A., Lladser A., Pacheco R. Dopamine receptor D3 signaling on CD4+ T cells favors Th1- and Th17-mediated immunity. J. Immunol. 196(10):4143 (2016) | | ABSTRACT
  • Ligtenberg M. A., Mougiakakos D., Mukhopadhyay M., Witt K., Lladser A., Chmielewski M., Riet T., Abken H., Kiessling R. Coexpressed catalase protects chimeric antigen receptor-redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity. J. Immunol. 196(2):759 (2016) | | ABSTRACT
  • Lobos-González L., Aguilar L., Diaz J., Diaz N., Urra H., Torres V., Silva V., Fitzpatrick C., Lladser A., Hoek K. S., Leyton L., Quest A. E-cadherin determines Caveolin-1 tumor suppression or metastasis enhancing function in melanoma cells. Pigment Cell Melanoma Res. 26(4):555 (2013) | | ABSTRACT
  • Ligtenberg M., Rojas-Colonelli N., Kiessling R., Lladser A. NF-κB activation during intradermal DNA vaccination is essential for eliciting tumor protective antigen-specific CTL responses. Hum. Vaccin. Immunother. 9(10): 2189–2195 (2013) | PDF | ABSTRACT
  • Reyes D., Salazar L., Espinoza E., Pereda C., Castello E., Valdevenito R., Huidobro C., Inés Becker M., Lladser A., López M., Salazar-Onfray F. Tumour cell lysate-loaded dendritic cell vaccine induces biochemical and memory immune response in castration-resistant prostate cancer patients. Br. J. Cancer 109(6): 1488-1497 (2013) | PDF | ABSTRACT
  • Herrada A., Rojas-Colonelli N., González-Figueroa P., Roco J., Oyarce C., Ligtenberg M., Lladser A. Harnessing DNA-induced immune responses for improving cancer vaccines. Hum. Vaccin. Immunother. 8(11): 1682-1693 (2012) | PDF | ABSTRACT
  • Prado C., Contreras F., González H., Díaz P., Elgueta D., Barrientos M., Herrada A., Lladser A., Bernales S., Pacheco R. Stimulation of dopamine receptor D5 expressed on dendritic cells potentiates Th17-mediated immunity. J. Immunol., 88: 3062–3070 (2012) | PDF | ABSTRACT
  • Lladser Á., Mougiakakos D., Tufvesson H., Ligtenberg M. A., Quest A. F. G., Kiessling R. and Ljungberg K. DAI (DLM-1/ZBP1) as a genetic adjuvant for DNA vaccines that promotes effective antitumor CTL immunity. Mol. Ther. 19 (3): 594-601 (2011) | PDF | ABSTRACT
  • Mougiakakos D., Choudhury A., Lladser À., Kiessling R. and Johansson C. C. Regulatory T cells in Cancer. Advances in Cancer Res. 107, 57-117 (2010) | PDF | ABSTRACT
  • Lladser À., Ljungberg K., Tufvesson H., Tazzari M., Roos A-K., Quest A. F. G. and Kiessling R. Intradermal DNA electroporation induces survivin-specific CTLs, suppresses angiogenesis and confers protection against mouse melanoma. Cancer Immunol. Immunother. 59 (1): 81-92 (2010) | PDF | ABSTRACT
  • Torres V. A., Tapia J. C., Rodriguez D. A., Lladser À., Arredondo C., Leyton L. and Quest A. F. G. E-cadherin is required for caveolin-1-mediated down-regulation of the inhibitor of apoptosis protein survivin via reduced β-catenin-Tcf/Lef-dependent transcription. Mol. Cell. Biol. 27 (21): 7703-7717 (2007) | PDF | ABSTRACT
  • Lladser À., Párraga M., Quevedo L., Molina M. C., Silva S., Ferreira A., Billetta R. and Quest A. F. G. Naked DNA immunization as an approach to target the generic tumor antigen survivin induces humoral and cellular immune responses in mice. Immunobiology 211 (1-2): 11-27 (2006) | PDF | ABSTRACT
  • Moncada C., Fuentes N., Lladser Á., Encina G., Sapag A., Karahanian E. and Israel Y. Use of an “acetaldehyde clamp” in the determination of low-KM aldehyde dehydrogenase activity in H4-II-E-C3 rat hepatoma cells. Alcohol. 31 (1-2): 19-24 (2003) | | ABSTRACT
  • Lladser À., Sanhueza C., Kiessling R. and Quest A. F. G. Is survivin the potential Achilles’ heel of cancer?. Adv. Cancer Res. 111, 01-37 (2001) | PDF | ABSTRACT

PATENTS

  • Sorry, not patents related.