CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma.

Genetically targeted T cells promise to solve the feasibility and efficacy hurdles of adoptive T-cell therapy for cancer. Selecting a target expressed in multiple-tumor types and that is required for tumor growth would widen disease indications and prevent immune escape caused by the emergence of antigen-loss variants. The adhesive receptor CD44 is broadly expressed in hematologic and epithelial tumors, where it contributes to the cancer stem/initiating phenotype. In this study, silencing of its isoform variant 6 (CD44v6) prevented engraftment of human acute myeloid leukemia (AML) and multiple myeloma (MM) cells in immunocompromised mice. Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and interleukin (IL)-7/IL-15 was required for antitumor efficacy in vivo. Finally, coexpressing a suicide gene enabled fast and efficient pharmacologic ablation of CD44v6-targeted T cells and complete rescue from hyperacute xenogeneic graft-versus-host disease modeling early and generalized toxicity. These results warrant the clinical investigation of suicidal CD44v6-targeted T cells in AML and MM.

[1]  Bernd Hauck,et al.  Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. , 2013, The New England journal of medicine.

[2]  Qing He,et al.  CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia , 2013, Science Translational Medicine.

[3]  Angel F. Lopez,et al.  Targeting of acute myeloid leukaemia by cytokine‐induced killer cells redirected with a novel CD123‐specific chimeric antigen receptor , 2013, British journal of haematology.

[4]  C. Eaves,et al.  Enhanced normal short-term human myelopoiesis in mice engineered to express human-specific myeloid growth factors. , 2013, Blood.

[5]  S. Bicciato,et al.  IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. , 2013, Blood.

[6]  H. Fine,et al.  Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. , 2012, Human gene therapy.

[7]  Kecheng Xu,et al.  Detection and Clinical Significance of CD44v6 and Integrin-β1 in Pancreatic Cancer Patients using a Triplex Real-Time RT-PCR Assay , 2012, Applied Biochemistry and Biotechnology.

[8]  Jinjuan Wang,et al.  CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. , 2012, Blood.

[9]  W. Wilson,et al.  B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. , 2012, Blood.

[10]  Steven A. Rosenberg,et al.  Adoptive immunotherapy for cancer: harnessing the T cell response , 2012, Nature Reviews Immunology.

[11]  Michel Sadelain,et al.  Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. , 2011, Blood.

[12]  Adrian P Gee,et al.  Inducible apoptosis as a safety switch for adoptive cell therapy. , 2011, The New England journal of medicine.

[13]  A. Bagg,et al.  Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. , 2011, The New England journal of medicine.

[14]  David L. Porter,et al.  T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia , 2011, Science Translational Medicine.

[15]  C. Bordignon,et al.  IL-7 receptor expression identifies suicide gene-modified allospecific CD8+ T cells capable of self-renewal and differentiation into antileukemia effectors. , 2011, Blood.

[16]  Hao Liu,et al.  CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. , 2011, The Journal of clinical investigation.

[17]  M. Zöller.  CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? , 2011, Nature Reviews Cancer.

[18]  Thomas M. Schmitt,et al.  The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. , 2010, Blood.

[19]  W. Wilson,et al.  Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. , 2010, Blood.

[20]  Alessandra Biffi,et al.  Identification of Hematopoietic Stem Cell–Specific miRNAs Enables Gene Therapy of Globoid Cell Leukodystrophy , 2010, Science Translational Medicine.

[21]  S. Rosenberg,et al.  Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice. , 2010, The Journal of clinical investigation.

[22]  T. Schumacher,et al.  Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy , 2010, Nature Medicine.

[23]  S. Rosenberg,et al.  Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[24]  M. Sadelain,et al.  Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[25]  R. Grossman,et al.  HER2-Specific T Cells Target Primary Glioblastoma Stem Cells and Induce Regression of Autologous Experimental Tumors , 2010, Clinical Cancer Research.

[26]  S. Rosenberg,et al.  A Herceptin-Based Chimeric Antigen Receptor with Modified Signaling Domains Leads to Enhanced Survival of Transduced T Lymphocytes and Antitumor Activity1 , 2009, The Journal of Immunology.

[27]  A. Ganser,et al.  Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study. , 2009, The Lancet. Oncology.

[28]  I. Pastan,et al.  Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains , 2009, Proceedings of the National Academy of Sciences.

[29]  T. Nagasawa,et al.  IL-7 and IL-15 allow the generation of suicide gene-modified alloreactive self-renewing central memory human T lymphocytes. , 2009, Blood.

[30]  Hao Liu,et al.  Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma , 2008, Nature Medicine.

[31]  H. Heslop,et al.  Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. , 2007, Blood.

[32]  R. Fanin,et al.  A comparison of allografting with autografting for newly diagnosed myeloma. , 2007, The New England journal of medicine.

[33]  R. A. Etten,et al.  Requirement for CD44 in homing and engraftment of BCR-ABL–expressing leukemic stem cells , 2006, Nature Medicine.

[34]  Gang Wang,et al.  A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer , 2006, Clinical Cancer Research.

[35]  Alexander Staab,et al.  A Phase I Dose Escalation Study with Anti-CD44v6 Bivatuzumab Mertansine in Patients with Incurable Squamous Cell Carcinoma of the Head and Neck or Esophagus , 2006, Clinical Cancer Research.

[36]  S. Rosenberg,et al.  Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes , 2006, Science.

[37]  J. Dick,et al.  Targeting of CD44 eradicates human acute myeloid leukemic stem cells , 2006, Nature Medicine.

[38]  P. Sharp,et al.  A positive feedback loop couples Ras activation and CD44 alternative splicing. , 2006, Genes & development.

[39]  C. Bordignon,et al.  Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes. , 2005, Blood.

[40]  H. Heslop,et al.  An inducible caspase 9 safety switch for T-cell therapy. , 2005, Blood.

[41]  L. Naldini,et al.  Coordinate dual-gene transgenesis by lentiviral vectors carrying synthetic bidirectional promoters , 2005, Nature Biotechnology.

[42]  E. Thiel,et al.  Bone marrow contains melanoma-reactive CD8+ effector T cells and, compared with peripheral blood, enriched numbers of melanoma-reactive CD8+ memory T cells. , 2003, Cancer research.

[43]  W. Oyen,et al.  Phase I therapy study with (186)Re-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with head and neck squamous cell carcinoma. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[44]  H. Kluin-Nelemans,et al.  A strong expression of CD44-6v correlates with shorter survival of patients with acute myeloid leukemia. , 1998, Blood.

[45]  R. Handgretinger,et al.  Expression of CD44 isoforms by highly enriched CD34-positive cells in cord blood, bone marrow and leukaphereses , 1997, Bone Marrow Transplantation.

[46]  C. Bordignon,et al.  HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. , 1997, Science.

[47]  Z. Eshhar,et al.  Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Martin Hofmann,et al.  A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells , 1991, Cell.

[49]  A. Rimm,et al.  Graft-versus-leukemia reactions after bone marrow transplantation. , 1990, Blood.

[50]  เอกรัฐ รัฐฤทธิ์ธำรง.  Loss of Mismatched HLA in Leukemia after Stem-Cell Transplantation , 2009 .

[51]  H. Döhner,et al.  CD44v6, a target for novel antibody treatment approaches, is frequently expressed in multiple myeloma and associated with deletion of chromosome arm 13q. , 2005, Haematologica.

[52]  P. Herrlich,et al.  CD44: From adhesion molecules to signalling regulators , 2003, Nature Reviews Molecular Cell Biology.