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1.
Drugs ; 79(4): 401-415, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30796733

ABSTRACT

While impressive clinical responses have been observed using chimeric antigen receptor (CAR) T cells targeting CD19+ hematologic malignancies, limited clinical benefit has been observed using CAR T cells for a variety of solid tumors. Results of clinical studies have highlighted several obstacles which CAR T cells face in the context of solid tumors, including insufficient homing to tumor sites, lack of expansion and persistence, encountering a highly immunosuppressive tumor microenvironment, and heterogeneous antigen expression. In this review, we review clinical outcomes and discuss strategies to improve the antitumor activity of CAR T cells for solid tumors.


Subject(s)
Antineoplastic Agents/therapeutic use , Immunotherapy, Adoptive/methods , Neoplasms/drug therapy , Receptors, Chimeric Antigen/therapeutic use , T-Lymphocytes/immunology , Antigens, CD19 , Genes, Transgenic, Suicide , Genetic Therapy , Hematologic Neoplasms/drug therapy , Humans , Immunosuppressive Agents/therapeutic use , Treatment Outcome , Tumor Microenvironment
2.
Cancer Discov ; 7(11): 1306-1319, 2017 11.
Article in English | MEDLINE | ID: mdl-28801306

ABSTRACT

Adoptive immunotherapy with T cells expressing chimeric antigen receptors (CAR) has had limited success for solid tumors in early-phase clinical studies. We reasoned that introducing into CAR T cells an inducible costimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)-binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T-cell activation. In the presence of CID, T cells expressing HER2-CARζ and a MyD88/CD40-based iCO molecule (HER2ζ.iCO T cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2ζ.iCO T cells without CID and T cells expressing HER2-CAR.CD28ζ. HER2ζ.iCO T cells with CID also significantly improved survival in vivo in two xenograft models. Repeat injections of CID were able to further increase the antitumor activity of HER2ζ.iCO T cells in vivo Thus, expressing MyD88/CD40-based iCO molecules in CAR T cells has the potential to improve the efficacy of CAR T-cell therapy approaches for solid tumors.Significance: Inducible activation of MyD88 and CD40 in CAR T cells with a small-molecule drug not only enhances their effector function, resulting in potent antitumor activity in preclinical solid tumors, but also enables their remote control post infusion. Cancer Discov; 7(11); 1306-19. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1201.


Subject(s)
CD40 Antigens/genetics , Immunotherapy, Adoptive/methods , Myeloid Differentiation Factor 88/genetics , Neoplasms/therapy , Receptors, Antigen, T-Cell/therapeutic use , Animals , CD40 Antigens/immunology , CD40 Antigens/therapeutic use , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic/immunology , Humans , Mice , Myeloid Differentiation Factor 88/immunology , Myeloid Differentiation Factor 88/therapeutic use , Neoplasms/genetics , Neoplasms/immunology , Receptor, ErbB-2/genetics , Receptor, ErbB-2/immunology , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology , Xenograft Model Antitumor Assays
4.
Immunotherapy ; 7(1): 21-35, 2015.
Article in English | MEDLINE | ID: mdl-25572477

ABSTRACT

Current therapy for sarcomas, though effective in treating local disease, is often ineffective for patients with recurrent or metastatic disease. To improve outcomes, novel approaches are needed and cell therapy has the potential to meet this need since it does not rely on the cytotoxic mechanisms of conventional therapies. The recent successes of T-cell therapies for hematological malignancies have led to renewed interest in exploring cell therapies for solid tumors such as sarcomas. In this review, we will discuss current cell therapies for sarcoma with special emphasis on genetic approaches to improve the effector function of adoptively transferred cells.


Subject(s)
Adoptive Transfer , Immunity, Cellular , Sarcoma , T-Lymphocytes , Animals , Humans , Sarcoma/immunology , Sarcoma/pathology , Sarcoma/therapy , T-Lymphocytes/immunology , T-Lymphocytes/pathology , T-Lymphocytes/transplantation
5.
J Immunother ; 37(8): 407-15, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25198528

ABSTRACT

Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has shown promising antitumor activity in early phase clinical studies, especially for hematological malignancies. However, most preclinical models do not reliably mimic human disease. We reasoned that developing an adoptive T-cell therapy approach for spontaneous osteosarcoma (OS) occurring in dogs would more closely reproduce the condition in human cancer. To generate CAR-expressing canine T cells, we developed expansion and transduction protocols that allow for the generation of sufficient numbers of CAR-expressing canine T cells for future clinical studies in dogs within 2 weeks of ex vivo culture. To evaluate the functionality of CAR-expressing canine T cells, we targeted HER2(+) OS. We demonstrate that canine OS is positive for HER2, and that canine T cells expressing a HER2-specific CAR with human-derived transmembrane and CD28.ζ signaling domains recognize and kill HER2(+) canine OS cell lines in an antigen-dependent manner. To reduce the potential immunogenicity of the CAR, we evaluated a CAR with canine-derived transmembrane and signaling domains, and found no functional difference between human and canine CARs. Hence, we have successfully developed a strategy to generate CAR-expressing canine T cells for future preclinical studies in dogs. Testing T-cell therapies in an immunocompetent, outbred animal model may improve our ability to predict their safety and efficacy before conducting studies in humans.


Subject(s)
Immunotherapy, Adoptive/methods , Osteosarcoma/therapy , Receptor, ErbB-2/immunology , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/immunology , Animals , CD28 Antigens/genetics , CD28 Antigens/metabolism , Cytotoxicity, Immunologic , Disease Models, Animal , Dogs , Humans , K562 Cells , Lymphocyte Activation , Receptors, Antigen, T-Cell/genetics , T-Cell Antigen Receptor Specificity , T-Lymphocytes/transplantation , Transgenes/genetics
6.
Mol Ther ; 21(8): 1611-20, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23732988

ABSTRACT

Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.


Subject(s)
Fibroblasts/immunology , Gelatinases/immunology , Membrane Proteins/immunology , Neoplasms/immunology , Receptors, Antigen/immunology , Serine Endopeptidases/immunology , T-Lymphocytes/immunology , Animals , Cell Line, Tumor , Cytokines/biosynthesis , Cytotoxicity, Immunologic , Disease Models, Animal , Endopeptidases , Fibroblasts/metabolism , Gelatinases/genetics , Gelatinases/metabolism , Gene Expression , Gene Order , Genetic Vectors , Humans , Immunotherapy , Inflammation Mediators/metabolism , Lung/immunology , Lung/metabolism , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Neoplasms/metabolism , Neoplasms/mortality , Neoplasms/pathology , Receptors, Antigen/genetics , Receptors, Antigen/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , Recombinant Fusion Proteins/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , T-Lymphocytes/metabolism
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