João Lacerda Lab

Hematology and Transplantation Immunology

The main research focus of our laboratory is the study of immune reconstitution after hematopoietic stem cell transplantation (HSCT) in humans and the development of strategies that modulate immune responses and tolerance post-transplant. Donor immunity emerging post-transplant plays a pivotal role in the protection against pathogens, such as Aspergillus, CMV and EBV, as well as in the development of graft-versus-host disease (GVHD) and graft-versus-leukemia effect.

Our laboratory aims to identify immunological risk factors and the mechanisms by which these complications emerge post-transplant. We are particularly interested in developing strategies that may be translated into the clinical setting, such as the use of pathogen-specific T cells, donor regulatory T cells for GVHD and disease-specific T cells, with the aim of improving patient survival.

We continue to develop several lines of research in the field of genetic susceptibility for viral and fungal infections after hematopoietic stem cell transplantation.

More recently, we engaged in developing several novel strategies for CAR T cell therapies of hematologic malignancies and solid tumors.

Research Team

Research Areas

• Immune reconstitution after hematopoietic stem cell transplantation (HSCT)
• Homeostasis of regulatory T cells (Treg) in patients submitted to HSCT
• Adoptive transfer of donor Treg in patients with chronic graft-versus-host disease (GvHD) – ongoing clinical trial
• Recruitment and expansion of antigen-specific Treg cells
• Pathogen-specific T cell therapy following HSCT
• Genetic susceptibility to invasive fungal infections
• CAR T cell therapies targeting cancer-specific proteoglycans

Ongoing Research Projects

2021/2024 Generation and in-depth characterization of antigen-specific regulatory T cells to be applied in allogeneic hematopoietic stem transplantation. Coordinator: João F. Lacerda. Funding Agency: Fundação para a Ciência e a Tecnologia.

2020/2023 Development of Chimeric Antigen Receptor T cell therapy targeting oncological-associated chondroitin sulfate as cancer treatment.

2020/2022 CMV infection and CMV-specific T-cell reconstitution in unrelated donor allo-HSCT after in vivo T-cell depletion with ATG: a comparative study of prophlylaxis with letermovir versus standard of care preemptive. Coordinator: João F. Lacerda. Funding Agency: Merck and Co, NJ, USA.

2020/2021 Development of a novel chimeric antigen receptor T cell therapy using B-cell activating factor, for triple targeting of B-cell specific receptors for multiple myeloma and other mature B cell neoplasms. Coordinator: João F. Lacerda. Funding Agency: Fellowship Building the future knowledge in mature B cell malignancies attributed by SPH, APCL and Gilead Sciences.

2015/2021 Repair of tissue and organ damage in refractory chronic graft versus host disease after hematopoietic stem cell transplantation by the infusion of purified allogeneic donor regulatory T lymphocytes. Coordinator: João F. Lacerda. Funding Agency: European Commission HORIZON 2020.

Previous Research Projects

2019/2020 Apoio Educacional. Coordinator: João Lacerda. Funding Agency: Janssen.

2019/2020 Apoio Doutoral INPhINIT Incoming. Coordinator: Carolina Pacini. Funding Agency: “la Caixa” Foundation.

2013/2016 Induction of Immune Tolerance in Human Allogeneic Hematopoietic Stem Cell Transplantation. Coordinator: João F. Lacerda. Funding Agency: HMSP - Harvard Medical School Portugal Program Collaborative Research Grant.

2013/2015 Phase I Clinical Trial of donor regulatory T cells for steroid-refractory chronic graft-versus-host disease. Coordinator: João F. Lacerda. Funding Agency: Miltenyi Biotec.

2012/2014 Impact of cellular therapy with CMV-specific CD4+ and CD8+ T cells following unrelated hematopoietic stem cell transplantation. Coordinator: João F. Lacerda. Funding Agency: Terry Fox Grant 2012

2009/2012 Clinical implications of activation of PI3K/Akt signaling pathway in primary adult acute lymphoblastic leukemia. Coordinator: João F. Lacerda. Funding Agency: Fundação para a Ciência e a Tecnologia.

2005/2008 Naive and regulatory T cells in patients submitted to unrelated or full haplotype mismatched related stem cell transplantation. Correlation with immune reconstitution and clinical course. Coordinator: Maria Soares. Co-Coordinator: João F. Lacerda. Funding Agency: Fundação para a Ciência e a Tecnologia.

Awards

Selected Publications

Azevedo RI, Minskaia E, Fernandes-Platzgummer A, Vieira AIS, da Silva CL, Cabral JMS, Lacerda JF (2020). Mesenchymal stromal cells induce regulatory T cells via epigenetic conversion of human conventional CD4 T cells in vitro. Stem Cells 38:1007–1019. doi.org/10.1002/stem.3185

Soares MV, Azevedo RI, Ferreira IA, Bucar S, Ribeiro AC, Vieira A, Pereira PNG, Ribeiro RM, Ligeiro D, Alho AC, Soares AS, Camacho N, Martins C, Lourenço F, Moreno R, Ritz J, Lacerda JF (2019). Naive and stem cell memory T cell subset recovery reveals opposing reconstitution patterns in CD4 and CD8 T cells in chronic graft vs. host disease. Frontiers of Immunology 10:334. doi: 10.3389/fimmu.2019.00334

Minskaia E, Saraiva BC, Soares MV, Azevedo RI, Ribeiro RM, Kumar SD, Vieira AIS, Lacerda JF (2018). Molecular Markers Distinguishing T Cell Subtypes with TSDR Strand-Bias Methylation. Frontiers of Immunology 9:2540. doi.org/10.3389/fimmu.2018.02540

Stappers MHT, Clark AE, Aimanianda V, Bidula S, Reid DM, Asamaphan P, Hardison SE, Dambuza IM, Valsecchi I, Kerscher B, Plato A, Wallace CA, Yuecel R, Hebecker B, da Glória Teixeira Sousa M, Cunha C, Liu Y, Feizi T, Brakhage AA, Kwon-Chung KJ, Gow NAR, Zanda M, Piras M, Zanato C, Jaeger M, Netea MG, van de Veerdonk FL, Lacerda JF, Campos A, Carvalho A, Willment JA, Latgé JP, Brown GD (2018). Recognition of DHN-melanin by a C-type lectin receptor is required for immunity to Aspergillus. Nature 555:382–386. doi.org/10.1038/nature25974

Gresnigt MS, Cunha C, Jaeger M, Gonçalves SM, Malireddi RK, Ammerdorffer A, Lubbers R, Oosting M, Rasid O, Jouvion G, Fitting C, Jong DJ, Lacerda JF, Campos A Jr, Melchers WJG, Lagrou K, Maertens J, Kanneganti TD, Carvalho A, Ibrahim-Granet O, van de Veerdonk FL (2018). Genetic deficiency of NOD2 confers resistance to invasive aspergillosis. Nature Communications 9:2636. doi.org/10.1038/s41467-018-04912-3

Alho AC, Kim HT, Chammas MJ, Reynolds CG, Matos TR, Forcade E, Whangbo J, Nikiforow S, Cutler CS, Koreth J, Ho VT, Armand P, Antin JH, Alyea EP, Lacerda JF, Soiffer RJ, Ritz J (2016). Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood 127(5):646-657. doi.org/10.1182/blood-2015-10-672345

Hirakawa M, Matos T, Liu H, Koreth J, Kim HT, Paul NE, Murase K, Whangbo J, Alho AC, Nikiforow S, Cutler C, Ho VT, Armand P, Alyea EP, Antin JH, Blazar BR, Lacerda JF, Soiffer RJ, Ritz J (2016). Low-dose interleukin-2 selectively activates discrete subsets of CD4 regulatory T cells and natural killer cells. JCI Insight 1(18):e89278. doi: 10.1172/jci.insight.89278

Gomes AM, Soares MV, Ribeiro P, Caldas J, Póvoa V, Martins LR, Melão A, Serra-Caetano A, de Sousa AB, Lacerda JF, Barata JT (2014). Adult B-cell acute lymphoblastic leukemia cells display decreased PTEN activity and constitutive hyperactivation of PI3K/Akt pathway despite high PTEN protein levels. Haematologica PMID: 24561792. doi.org/10.3324/haematol.2013.096438

Cunha C, Aversa F, Lacerda JF, Busca A, Kurzai O, Grube M, Löffler J, Maertens JA, Bell AS, Inforzato A, Barbati E, Almeida B, Santos e Sousa P, Barbui A, Potenza L, Caira M, Rodrigues F, Salvatori G, Pagano L, Luppi M, Mantovani A, Velardi A, Romani L, Carvalho A (2014). Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. The New England Journal of Medicine 370:421-432. DOI: 10.1056/NEJMoa1211161

Azevedo RI, Soares MV, Albuquerque AS, Tendeiro R, Soares RS, Martins M, Ligeiro D, Victorino RM, Lacerda JF, Sousa AE (2013). Long-term immune reconstitution of naive and memory t cell pools after haploidentical hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation 19(5):703-12. DOI: 10.1016/j.bbmt.2013.01.017

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