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Marco L. Davila
My research is dedicated to developing gene-engineered cell therapies that target cancer cells in animal models of cancer. The goal of this research is to identify optimal cell therapies that can then be evaluated in cancer patients. As a former Principal Investigator of a clinical trial using genetically engineered T cells targeted against malignant B cells, I witnessed the potential for this as a cancer immunotherapy. Its my hope that our innovative laboratory and clinical research here at the Moffitt Cancer Center will lead to similar therapeutic options for patients with other cancers.
- Blood and Marrow Transplant and Cellular Immunotherapy
Education & Training
- Duke University, MD
- Duke University, PhD - Immunology
- New York Presbyterian Weill Cornell Medical Center, Resident - Medicine
- Memorial Sloan Kettering Cancer Center, Clinical Fellow - Medical Oncology
The Davila laboratory is interested in the development of T cell therapies for cancer. One such therapy involves chimeric antigen receptors (CAR) that can target hematologic and solid tumor malignancies. Recent clinical trials have demonstrated the potential of targeting the CD19 antigen for B cell malignancies with CAR T cells. These trials have demonstrated that an acute B cell malignancy, B cell acute lymphoblastic leukemia (B-ALL), is tremendously responsive. These early Phase trials, while exciting, leave many questions to be answered, which oftentimes is best done in pre-clinical animal models. There are three major research projects in the laboratory. 1. We have created a syngeneic mouse model of B-ALL using the Eμ-ALL cell line (Davila et al PLOS ONE 2013), which was derived from the Eμ-myc transgenic mouse prone to B cell malignancies. Our Eμ-ALL mouse model allows the evaluation of important mechanisms involving the targeting of B cell malignancies with mouse CAR T cells in fully immunocompetent animals. Using this model we are a) evaluating the biology behind activation and costimulation of CAR T cells. 2. We recognize that targeting CD19, and thereby B cell malignancies, is just the beginning of this new field and we are developing new CARs against other hematologic and solid tumor malignancies. Our initial focus is to develop CARs against Acute Myeloid Leukemia (AML), which has well-defined antigens that have been previously targeted with therapeutic monoclonal antibodies. However, responses to these antibodies, as well as pre-clinical studies involving CARs targeting these same antigens, demonstrate safety concerns due to the shared expression of the antigens on hematopoietic stem cells and/or granulocytes. Therefore we are engineering safety mechanisms to avoid this dangerous off-target toxicity. 3. We also recognize that some cancer may not be suitable for targeting with a CAR. Therefore, in collaboration with other investigators at Moffitt we are refining and optimizing the production of tumor-infiltrating lymphocytes (TILs) from solid tumor metastases. Our goal is to rapidly develop and re-infuse these TILs back into patients.
- Betts BC, Pidala J, Kim J, Mishra A, Nishihori T, Perez L, Ochoa-Bayona JL, Khimani F, Walton K, Bookout R, Nieder M, Khaira DK, Davila M, Alsina M, Field T, Ayala E, Locke FL, Riches M, Kharfan-Dabaja M, Fernandez H, Anasetti C. IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation. Haematologica. 2017 May;102(5):948-957. Pubmedid: 28104702. Pmcid: PMC5477614.
- Locke FL, Davila ML. Regulatory challenges and considerations for the clinical application of CAR-T cell anti-cancer therapy. Expert Opin Biol Ther. 2017 Jun;17(6):659-661. Pubmedid: 28454503.
- Sallman DA, Davila ML. Is Disease-Specific Immunotherapy a Potential Reality for MDS?. Clin Lymphoma Myeloma Leuk. 2017 Jul;17S:S26-S30. Pubmedid: 28760299.
- Ghosh A, Smith M, James SE, Davila ML, Velardi E, Argyropoulos KV, Gunset G, Perna F, Kreines FM, Levy ER, Lieberman S, Jay HV, Tuckett AZ, Zakrzewski JL, Tan L, Young LF, Takvorian K, Dudakov JA, Jenq RR, Hanash AM, Motta AC, Murphy GF, Liu C, Schietinger A, Sadelain M, van den Brink MR. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat Med. 2017 Feb;23(2):242-249. Pubmedid: 28067900. Pmcid: PMC5528161.
- Li G, Park K, Davila ML. Gammaretroviral Production and T Cell Transduction to Genetically Retarget Primary T Cells Against Cancer. Methods Mol Biol. 2017 Feb;1514:111-118. Pubmedid: 27787796.
- Davila ML, Brentjens RJ. CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Clin Adv Hematol Oncol. 2016 Oct;14(10):802-808. Pubmedid: 27930631. Pmcid: PMC5536094.
- Abate-Daga D, Davila ML. CAR models: next-generation CAR modifications for enhanced T-cell function. Mol Ther Oncolytics. 2016 May;3:16014. Pubmedid: 27231717. Pmcid: PMC4871190.
- Davila ML, Sadelain M. Biology and clinical application of CAR T cells for B cell malignancies. Int J Hematol. 2016 Jul;104(1):6-17. Pubmedid: 27262700. Pmcid: PMC5512169.
- Oluwole OO, Davila ML. At The Bedside: Clinical review of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies. J Leukoc Biol. 2016 Dec;100(6):1265-1272. Pubmedid: 27354412.
- Bouhassira DC, Thompson JJ, Davila ML. Using gene therapy to manipulate the immune system in the fight against B-cell leukemias. Expert Opin Biol Ther. 2015 Mar;15(3):403-416. Pubmedid: 25666545. Pmcid: PMC4586131.
- Davila ML, Papapetrou EP. CARs Move To the Fast Lane. Mol Ther. 2014 Mar;22(3):477-478. Pubmedid: 28141992. Pmcid: PMC3944338.
- Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, Chung SS, Stefanski J, Borquez-Ojeda O, Olszewska M, Qu J, Wasielewska T, He Q, Fink M, Shinglot H, Youssif M, Satter M, Wang Y, Hosey J, Quintanilla H, Halton E, Bernal Y, Bouhassira DC, Arcila ME, Gonen M, Roboz GJ, Maslak P, Douer D, Frattini MG, Giralt S, Sadelain M, Brentjens R. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014 Feb;6(224):224ra25. Pubmedid: 24553386. Pmcid: PMC4684949.
- Davila ML, Bouhassira DC, Park JH, Curran KJ, Smith EL, Pegram HJ, Brentjens R. Chimeric antigen receptors for the adoptive T cell therapy of hematologic malignancies. Int J Hematol. 2014 Apr;99(4):361-371. Pubmedid: 24311149. Pmcid: PMC4684946.
- Davila ML, Kloss CC, Gunset G, Sadelain M. CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia. PLoS One. 2013 Oct;8(4):e61338. Pubmedid: 23585892. Pmcid: PMC3621858.
- Davila ML, Hofstetter WL. Endoscopic management of Barrett's esophagus with high-grade dysplasia and early-stage esophageal adenocarcinoma. Thorac Surg Clin. 2013 Nov;23(4):479-489. Pubmedid: 24199698.
- Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, Borquez-Ojeda O, Qu J, Wasielewska T, He Q, Bernal Y, Rijo IV, Hedvat C, Kobos R, Curran K, Steinherz P, Jurcic J, Rosenblat T, Maslak P, Frattini M, Sadelain M. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013 Mar;5(177):177ra38. Pubmedid: 23515080. Pmcid: PMC3742551.
- Davila ML, Brentjens R. Chimeric antigen receptor therapy for chronic lymphocytic leukemia: what are the challenges?. Hematol Oncol Clin North Am. 2013 Apr;27(2):341-353. Pubmedid: 23561477. Pmcid: PMC3615434.
- Davila ML, Brentjens R, Wang X, Rivière I, Sadelain M. How do CARs work?: Early insights from recent clinical studies targeting CD19. Oncoimmunology. 2012 Dec;1(9):1577-1583. Pubmedid: 23264903. Pmcid: PMC3525612.
- Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O, Olszewska M, Bernal Y, Pegram H, Przybylowski M, Hollyman D, Usachenko Y, Pirraglia D, Hosey J, Santos E, Halton E, Maslak P, Scheinberg D, Jurcic J, Heaney M, Heller G, Frattini M, Sadelain M. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011 Nov;118(18):4817-4828. Pubmedid: 21849486. Pmcid: PMC3208293.
- Lieberman AE, Kuraoka M, Davila M, Kelsoe G, Cowell LG. Conserved cryptic recombination signals in Vkappa gene segments are cleaved in small pre-B cells. BMC Immunol. 2009 Jun;10:37. Pubmedid: 19555491. Pmcid: PMC2711918.
- Davila M, Liu F, Cowell LG, Lieberman AE, Heikamp E, Patel A, Kelsoe G. Multiple, conserved cryptic recombination signals in VH gene segments: detection of cleavage products only in pro B cells. J Exp Med. 2007 Dec;204(13):3195-3208. Pubmedid: 18056287. Pmcid: PMC2150985.
- Cowell LG, Davila M, Ramsden D, Kelsoe G. Computational tools for understanding sequence variability in recombination signals. Immunol Rev. 2004 Aug;200:57-69. Pubmedid: 15242396.
- Cowell LG, Davila M, Kepler TB, Kelsoe G. Identification and utilization of arbitrary correlations in models of recombination signal sequences. Genome Biol. 2003 Jun;3(12). Pubmedid: 12537561. Pmcid: PMC151174.
- Cowell LG, Davila M, Yang K, Kepler TB, Kelsoe G. Prospective estimation of recombination signal efficiency and identification of functional cryptic signals in the genome by statistical modeling. J Exp Med. 2003 Jan;197(2):207-220. Pubmedid: 12538660. Pmcid: PMC2193808.
- Davila ML, Sauter C, Brentjens R. CD19-Targeted T Cells for Hematologic Malignancies: Clinical Experience to Date. Cancer J. 21(6):470-474. Pubmedid: 26588678. Pmcid: PMC4656120.