Photo of Catherine J. Wu,  MD

Catherine J. Wu, MD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-5943
Fax: (617) 632-6380


cwu@partners.org

Catherine J. Wu, MD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Associate Professor, Medicine, Harvard Medical School
  • Associate Physician, Medical Oncology, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

Chronic lymphocytic leukemia (CLL), a disease of clonal CD19+CD5+CD23+ B cells, remains incurable by conventional chemotherapy, despite the use of increasingly efficacious combination chemotherapy regimens. Despite its immunophenotypic homogeneity, this disease is marked by high heterogeneity in the clinical course of patients; patients that are chemorefractory have particularly poor prognosis and early mortality. One promising approach for CLL treatment is through immunotherapy since CLL is highly immune-responsive, as demonstrated by its susceptibility to the graft-versus-leukemia (GvL) effect after hematopoietic stem cell transplantation (HSCT). A key question is whether we can develop simpler and safer tumor-specific immunotherapy that can enhance GvL or even replace HSCT.

Our previous studies have focused on dissecting mechanisms of effective tumor immunity in patients who have demonstrated long-lasting clinically evident immunity following HSCT. Together, those studies indicate that productive anti-tumor immune responses are long-lived, directed against multiple epitopes, elicit both B and T cell responses, and in general, are specific for an individual patient. We are now completing an analysis of the activation state of leukemia-infiltrating T cells before and after allotransplantation for CML and CLL, which appear to be predictive of clinical response. Altogether, these insights have led me to undertake three general approaches to devise immunotherapy for CLL patients that is personalized and directed against antigens that are truly specific to that individual tumor. (1) Whole tumor vaccines to augment the GvL effect: I am leading a high-priority clinical trial at DFCI to examine the safety and immunologic effects of vaccination with whole tumor cells (using irradiated autologous leukemia cells) and the cytokine adjuvant GM-CSF in post-transplant patients. Vaccinated subjects have developed CD8+ T cell responses to CLL-specific antigens, independent of allo-immunity, implying that personalized whole tumor cell vaccination can enhance anti-tumor immunity with minimal toxicity. Our completed and ongoing studies of this vaccine are laying the groundwork for using the post-transplant setting as a platform for developing tumor vaccines. (2) Expansion of tumor-reactive donor T cells as adoptive T cell immunotherapy. (3) Personal neoantigens at tumor-specific immune targets for vaccination: A high priority in cancer immunotherapy is the identification of tumor-specific antigens that would allow effective tumor targeting without collateral toxicity. We are pioneering the use of exome and transcriptome sequencing technologies to identify unique mutated CLL antigens that arise from individual-specific genetic alterations within a tumor, thus paving the way for developing personalized tumor vaccines. We have therefore undertaken large-scale genome analysis of CLL to systematically identify tumor-specific genetic alterations. Through integration of sequencing data of 91 CLL samples with clinical annotation, defining 9 key mutated genes and 6 pathways involved in CLL pathogenesis, we have discovered novel associations with prognostic factors. Our ongoing studies in this area focus on: (a) systematic analyses to couple tumor genotype with phenotype; (b) understanding CLL tumor heterogeneity; (c) mechanistic studies of specific tumors drivers, such as SF3B1.

Publications

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  • Bachireddy P, Burkhardt UE, Rajasagi M, Wu CJ. Haematological malignancies: at the forefront of immunotherapeutic innovation. Nat Rev Cancer 2015; 15:201-15. PubMed
  • Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 2015; 160:48-61. PubMed
  • Wang L, Shalek AK, Lawrence M, Ding R, Gaublomme JT, Pochet N, Stojanov P, Sougnez C, Shukla SA, Stevenson KE, Zhang W, Wong J, Sievers QL, MacDonald BT, Vartanov AR, Goldstein NR, Neuberg D, He X, Lander E, Hacohen N, Regev A, Getz G, Brown JR, Park H, Wu CJ. Somatic mutation as a mechanism of Wnt/硫-catenin pathway activation in CLL. Blood 2014. PubMed
  • Rajasagi M, Shukla SA, Fritsch EF, Keskin DB, DeLuca D, Carmona E, Zhang W, Sougnez C, Cibulskis K, Sidney J, Stevenson K, Ritz J, Neuberg D, Brusic V, Gabriel S, Lander ES, Getz G, Hacohen N, Wu CJ. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood 2014. PubMed
  • Fritsch EF, Rajasagi M, Ott PA, Brusic V, Hacohen N, Wu CJ. HLA-Binding Properties of Tumor Neoepitopes in Humans. Cancer Immunol Res 2014; 2:522-9. PubMed
  • Ott PA, Fritsch EF, Wu CJ, Dranoff G. Vaccines and Melanoma. Hematol Oncol Clin North Am 2014; 28:559-569. PubMed
  • Bachireddy P, Hainz U, Rooney M, Pozdnyakova O, Aldridge J, Zhang W, Liao X, Hodi FS, O'Connell K, Haining WN, Goldstein NR, Canning CM, Soiffer RJ, Ritz J, Hacohen N, Alyea EP, Kim HT, Wu CJ. Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion. Blood 2014; 123:1412-21. PubMed
  • Landau DA, Carter SL, Getz G, Wu CJ. Clonal evolution in hematological malignancies and therapeutic implications. Leukemia 2014; 28:34-43. PubMed
  • Burkhardt UE, Wu CJ. Boosting leukemia-specific T cell responses in patients following stem cell transplantation. Oncoimmunology 2014; 2:e26587. PubMed
  • Gress RE, Miller JS, Battiwalla M, Bishop MR, Giralt SA, Hardy NM, Kröger N, Wayne AS, Landau DA, Wu CJ. Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part I. Biology of relapse after transplantation. Biol Blood Marrow Transplant 2013; 19:1537-45. PubMed
  • Burkhardt UE, Hainz U, Stevenson K, Goldstein NR, Pasek M, Naito M, Wu D, Ho VT, Alonso A, Hammond NN, Wong J, Sievers QL, Brusic A, McDonough SM, Zeng W, Perrin A, Brown JR, Canning CM, Koreth J, Cutler C, Armand P, Neuberg D, Lee JS, Antin JH, Mulligan RC, Sasada T, Ritz J, Soiffer RJ, Dranoff G, Alyea EP, Wu CJ. Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells. J Clin Invest 2013; 123:3756-65. PubMed
  • Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortés ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Lee RS, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CW, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013; 499:214-8. PubMed
  • Hacohen N, Fritsch EF, Carter TA, Lander ES, Wu CJ. Getting personal with neoantigen-based therapeutic cancer vaccines. Cancer Immunol Res 2014; 1:11-5. PubMed
  • Wan Y, Wu CJ. SF3B1 mutations in chronic lymphocytic leukemia. Blood 2013; 121:4627-34. PubMed
  • Reardon DA, Wucherpfennig KW, Freeman G, Wu CJ, Chiocca EA, Wen PY, Curry WT, Mitchell DA, Fecci PE, Sampson JH, Dranoff G. An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma. 2013; 12:597-615. PubMed
  • Landau DA, Wu CJ. Chronic lymphocytic leukemia: molecular heterogeneity revealed by high-throughput genomics. Genome Med 2013; 5:47. PubMed
  • Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, Sougnez C, Stewart C, Sivachenko A, Wang L, Wan Y, Zhang W, Shukla SA, Vartanov A, Fernandes SM, Saksena G, Cibulskis K, Tesar B, Gabriel S, Hacohen N, Meyerson M, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 2013; 152:714-26. PubMed
  • Shalek AK, Gaublomme JT, Wang L, Yosef N, Chevrier N, Andersen MS, Robinson JT, Pochet N, Neuberg D, Gertner RS, Amit I, Brown JR, Hacohen N, Regev A, Wu CJ, Park H. Nanowire-mediated delivery enables functional interrogation of primary immune cells: application to the analysis of chronic lymphocytic leukemia. Nano Lett 2012; 12:6498-504. PubMed
  • Wu CJ. CLL clonal heterogeneity: an ecology of competing subpopulations. Blood 2012; 120:4117-8. PubMed
  • Davids MS, Deng J, Wiestner A, Lannutti BJ, Wang L, Wu CJ, Wilson WH, Brown JR, Letai A. Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia. Blood 2012; 120:3501-9. PubMed
  • Cai A, Keskin DB, Deluca DS, Alonso A, Zhang W, Zhang GL, Hammond NN, Nardi V, Stone RM, Neuberg D, Sidney J, Brusic V, Wu CJ. Mutated BCR-ABL Generates Immunogenic T-cell Epitopes in CML Patients. Clin Cancer Res 2012; 18:5761-72. PubMed
  • Brusic A, Hainz U, Wadleigh M, Neuberg D, Su M, Canning CM, Deangelo DJ, Stone RM, Lee JS, Mulligan RC, Ritz J, Dranoff G, Sasada T, Wu CJ. Detecting T-cell reactivity to whole cell vaccines: Proof of concept analysis of T-cell response to K562 cell antigens in CML patients. Oncoimmunology 2012; 1:1095-1103. PubMed
  • Naito M, Hainz U, Burkhardt UE, Fu B, Ahove D, Stevenson KE, Rajasagi M, Zhu B, Alonso A, Witten E, Matsuoka KI, Neuberg D, Duke-Cohan JS, Wu CJ, Freeman GJ. CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells. Cancer Immunol Immunother 2012. PubMed
  • Brown JR, Hanna M, Tesar B, Werner L, Pochet N, Asara JM, Wang YE, Dal Cin P, Fernandes SM, Thompson C, Macconaill L, Wu CJ, Van de Peer Y, Correll M, Regev A, Neuberg D, Freedman AS. Integrative genomic analysis implicates gain of PIK3CA at 3q26 and MYC at 8q24 in chronic lymphocytic leukemia. Clin Cancer Res 2012; 18:3791-802. PubMed
  • Biernacki MA, Tai YT, Zhang GL, Alonso A, Zhang W, Prabhala R, Zhang L, Munshi N, Neuberg D, Soiffer RJ, Ritz J, Alyea EP, Brusic V, Anderson KC, Wu CJ. Novel myeloma-associated antigens revealed in the context of syngeneic hematopoietic stem cell transplantation. Blood 2012; 119:3142-50. PubMed
  • Brusic A, Wu CJ. Enhancing graft-versus-leukemia after transplant: the rise of anti-cancer vaccines. Front Biosci 2011; 17:635-55. PubMed
  • Chapman M, Warren EH, Wu CJ. Applications of next-generation sequencing to blood and marrow transplantation. Biol Blood Marrow Transplant 2012; 18:S151-60. PubMed
  • Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, Werner L, Sivachenko A, DeLuca DS, Zhang L, Zhang W, Vartanov AR, Fernandes SM, Goldstein NR, Folco EG, Cibulskis K, Tesar B, Sievers QL, Shefler E, Gabriel S, Hacohen N, Reed R, Meyerson M, Golub TR, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 2011; 365:2497-506. PubMed
  • Lin Y, Zhang L, Cai AX, Lee M, Zhang W, Neuberg D, Canning CM, Soiffer RJ, Alyea EP, Ritz J, Hacohen N, Means TK, Wu CJ. Effective posttransplant antitumor immunity is associated with TLR-stimulating nucleic acid-immunoglobulin complexes in humans. J Clin Invest 2011. PubMed
  • Anderson KS, Zeng W, Sasada T, Choi J, Riemer AB, Su M, Drakoulakos D, Kang YJ, Brusic V, Wu C, Reinherz EL. Impaired tumor antigen processing by immunoproteasome-expressing CD40-activated B: cells and dendritic cells. Cancer Immunol Immunother 2011. PubMed
  • Hsieh MM, Wu CJ, Tisdale JF. In mixed hematopoietic chimerism, the donor red cells win. Haematologica 2011; 96:13-5. PubMed
  • Marina O, Duke-Cohan JS, Wu CJ. A coprecipitation-based validation methodology for interactions identified using protein microarrays. Methods Mol Biol 2011; 723:239-54. PubMed
  • Deluca DS, Marina O, Ray S, Zhang GL, Wu CJ, Brusic V. Data processing and analysis for protein microarrays. Methods Mol Biol 2011; 723:337-47. PubMed
  • Huynh H, Zheng J, Umikawa M, Silvany R, Xie XJ, Wu CJ, Holzenberger M, Wang Q, Zhang CC. Components of the hematopoietic compartments in tumor stroma and tumor-bearing mice. PLoS ONE 2011; 6:e18054. PubMed
  • Koreth J, Biernacki M, Aldridge J, Kim HT, Alyea EP, Armand P, Cutler C, Ho VT, Wu CJ, Antin JH, Soiffer RJ. Syngeneic Donor Hematopoietic Stem Cell Transplantation is Associated with High Rates of Engraftment Syndrome. Biol Blood Marrow Transplant 2010. PubMed
  • Zhang W, Choi J, Zeng W, Rogers SA, Alyea EP, Rheinwald JG, Canning CM, Brusic V, Sasada T, Reinherz EL, Ritz J, Soiffer RJ, Wu CJ. Graft-versus-leukemia antigen CML66 elicits coordinated B-cell and T-cell immunity after donor lymphocyte infusion. Clin Cancer Res 2010; 16:2729-39. PubMed
  • Ofran Y, Kim HT, Brusic V, Blake L, Mandrell M, Wu CJ, Sarantopoulos S, Bellucci R, Keskin DB, Soiffer RJ, Antin JH, Ritz J. Diverse patterns of T-cell response against multiple newly identified human Y chromosome-encoded minor histocompatibility epitopes. Clin Cancer Res 2010; 16:1642-51. PubMed
  • Marina O, Hainz U, Biernacki MA, Zhang W, Cai A, Duke-Cohan JS, Liu F, Brusic V, Neuberg D, Kutok JL, Alyea EP, Canning CM, Soiffer RJ, Ritz J, Wu CJ. Serologic markers of effective tumor immunity against chronic lymphocytic leukemia include nonmutated B-cell antigens. Cancer Res 2010; 70:1344-55. PubMed
  • Biernacki MA, Marina O, Zhang W, Liu F, Bruns I, Cai A, Neuberg D, Canning CM, Alyea EP, Soiffer RJ, Brusic V, Ritz J, Wu CJ. Efficacious immune therapy in chronic myelogenous leukemia (CML) recognizes antigens that are expressed on CML progenitor cells. Cancer Res 2010; 70:906-15. PubMed
  • Wu CJ, Ritz J. Revealing tumor immunity after hematopoietic stem cell transplantation. Clin Cancer Res 2009; 15:4515-7. PubMed
  • Krishnamurti L,Kharbanda S,Biernacki MA,Zhang W,Baker KS,Wagner JE,Wu CJ. Stable long-term donor engraftment following reduced-intensity hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant 2008; 14:1270-8. PubMed
  • Armistead PM,Mohseni M,Gerwin R,Walsh EC,Iravani M,Chahardouli B,Rostami S,Zhang W,Neuberg D,Rioux J,Ghavamzadeh A,Ritz J,Antin JH,Wu CJ. Erythroid-lineage-specific engraftment in patients with severe hemoglobinopathy following allogeneic hematopoietic stem cell transplantation. Exp Hematol 2008; 36:1205-15. PubMed
  • Marina O, Biernacki MA, Brusic V, Wu CJ. A concentration-dependent analysis method for high density protein microarrays. J Proteome Res 2008; 7:2059-68. PubMed
  • Lin CJ, Pan CF, Wu CJ, Chen HH, Kao CR, Lee CC. A giant gastric ulcer mimicking carcinoma in a renal transplant recipient with CMV infection. South Med J 2008; 101:327. PubMed
  • Volarevic M, Smolic R, Wu CH, Wu GY. Potential role of RNAi in the treatment of HCV infection. Expert Rev Anti Infect Ther 2007; 5:823-31. PubMed
  • Wu CJ, Ritz J. Induction of tumor immunity following allogeneic stem cell transplantation. Adv Immunol 2006; 90:133-73. PubMed
  • Wu CJ, Krishnamurti L, Kutok JL, Biernacki M, Rogers S, Zhang W, Antin JH, Ritz J. Evidence for ineffective erythropoiesis in severe sickle cell disease. Blood 2005; 106:3639-45. PubMed
  • Wu CJ, Biernacki M, Kutok JL, Rogers S, Chen L, Yang XF, Soiffer RJ, Ritz J. Graft-versus-leukemia target antigens in chronic myelogenous leukemia are expressed on myeloid progenitor cells. Clin Cancer Res 2005; 11:4504-11. PubMed
  • Bellucci R, Alyea EP, Chiaretti S, Wu CJ, Zorn E, Weller E, Wu B, Canning C, Schlossman R, Munshi NC, Anderson KC, Ritz J. Graft-versus-tumor response in patients with multiple myeloma is associated with antibody response to BCMA, a plasma-cell membrane receptor. Blood 2005; 105:3945-50. PubMed
  • Miklos DB, Kim HT, Miller KH, Guo L, Zorn E, Lee SJ, Hochberg EP, Wu CJ, Alyea EP, Cutler C, Ho V, Soiffer RJ, Antin JH, Ritz J. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood 2004; 105:2973-8. PubMed
  • Bellucci R, Wu CJ, Chiaretti S, Weller E, Davies FE, Alyea EP, Dranoff G, Anderson KC, Munshi NC, Ritz J. Complete response to donor lymphocyte infusion in multiple myeloma is associated with antibody responses to highly expressed antigens. Blood 2003; 103:656-63. PubMed
  • Yan Y, Phan L, Yang F, Talpaz M, Yang Y, Xiong Z, Ng B, Timchenko NA, Wu CJ, Ritz J, Wang H, Yang XF. A novel mechanism of alternative promoter and splicing regulates the epitope generation of tumor antigen CML66-L. J Immunol 2003; 172:651-60. PubMed
  • Wu CJ, Hochberg EP, Rogers SA, Kutok JL, Biernacki M, Nascimento AF, Marks P, Bridges K, Ritz J. Molecular assessment of erythroid lineage chimerism following nonmyeloablative allogeneic stem cell transplantation. Exp Hematol 2003; 31:924-33. PubMed
  • Antin JH, Kim HT, Cutler C, Ho VT, Lee SJ, Miklos DB, Hochberg EP, Wu CJ, Alyea EP, Soiffer RJ. Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood 2003; 102:1601-5. PubMed
  • Wu CJ, Neuberg D, Chillemi A, McLaughlin S, Hochberg EP, Galinsky I, DeAngelo D, Soiffer RJ, Alyea EP, Capdeville R, Stone RM, Ritz J. Quantitative monitoring of BCR/ABL transcript during STI-571 therapy. Leuk Lymphoma 2003; 43:2281-9. PubMed
  • Yang XF, Wu CJ, Chen L, Alyea EP, Canning C, Kantoff P, Soiffer RJ, Dranoff G, Ritz J. CML28 is a broadly immunogenic antigen, which is overexpressed in tumor cells. Cancer Res 2002; 62:5517-22. PubMed
  • Bellucci R, Alyea EP, Weller E, Chillemi A, Hochberg E, Wu CJ, Canning C, Schlossman R, Soiffer RJ, Anderson KC, Ritz J. Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma. Blood 2002; 99:4610-7. PubMed
  • Hochberg EP, Chillemi AC, Wu CJ, Neuberg D, Canning C, Hartman K, Alyea EP, Soiffer RJ, Kalams SA, Ritz J. Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults. Blood 2001; 98:1116-21. PubMed
  • Yang XF, Wu CJ, McLaughlin S, Chillemi A, Wang KS, Canning C, Alyea EP, Kantoff P, Soiffer RJ, Dranoff G, Ritz J. CML66, a broadly immunogenic tumor antigen, elicits a humoral immune response associated with remission of chronic myelogenous leukemia. Proc Natl Acad Sci U S A 2001; 98:7492-7. PubMed
  • Zorn E, Orsini E, Wu CJ, Stein B, Chillemi A, Canning C, Alyea EP, Soiffer RJ, Ritz J. A CD4+ T cell clone selected from a CML patient after donor lymphocyte infusion recognizes BCR-ABL breakpoint peptides but not tumor cells. Transplantation 2001; 71:1131-7. PubMed
  • Wu CJ, Yang XF, McLaughlin S, Neuberg D, Canning C, Stein B, Alyea EP, Soiffer RJ, Dranoff G, Ritz J. Detection of a potent humoral response associated with immune-induced remission of chronic myelogenous leukemia. J Clin Invest 2000; 106:705-14. PubMed
  • Bachireddy P, Hainz U, Rooney M, Pozdnyakova O, Aldridge J, Zhang W, Liao X, Hodi FS, O'Connell K, Haining WN, Goldstein NR, Canning CM, Soiffer RJ, Ritz J, Hacohen N, Alyea EP, Kim HT, Wu CJ. Reversal of in situ T cell exhaustion during effective human anti-leukemia responses to donor lymphocyte infusion Blood 2014.
  • Wu CJ, Chillemi A, Alyea EP, Orsini E, Neuberg D, Soiffer RJ, Ritz J. Reconstitution of T-cell receptor repertoire diversity following T-cell depleted allogeneic bone marrow transplantation is related to hematopoietic chimerism. Blood 1999; 95:352-9. PubMed
  • Wu CJ, Scadden DT. Posttransplant Kaposi's sarcoma treated with paclitaxel. J Clin Oncol 1998; 16:3478-9. PubMed
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