Journal Articles

Immunotherapy design

Novel approaches and designs of biologicals used for cancer immunotherapy as well as changes in the timing, combination sequence, adjuvant choice or route of immunization in immunotherapy regimens; biomarkers of response to therapy

T cell responses in the microenvironment of primary renal cell carcinoma - Implications for adoptive cell therapy

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In vitro expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC) are infiltrated with tumor-reactive T cells that could be efficiently employed for adoptive transfer immunotherapy. TILs and autologous tumor cell lines (TCLs) were successfully generated from 22 (92%) and 17 (77%) of 24 consecutive primary RCC specimens and compared to those generated from MM. Immune recognition of autologous TCLs or fresh tumor digests (FTD) was observed in CD8+ TILs from 82% of patients (18/22). Cytotoxicity assays confirmed the tumoricidal capacity of RCC-TILs. The overall expansion capacity of RCC-TILs was similar to MM-TILs. However, the magnitude, poly-functionality, and ability to expand in classical expansion protocols of CD8+ T-cell responses was lower compared to MM-TILs. The RCC-TILs that did react to the tumor were functional and antigen presentation and processing on RCC-tumors was similar to MM-TILs. Direct recognition of tumors with cytokine-induced overexpression of human leukocyte antigen (HLA) class II was observed from CD4+ T cells (6/12; 50%). Thus, TILs from primary RCC specimens could be isolated, expanded, and could recognize tumors. However, immune responses of expanded CD8+ RCC-TILs were typically weaker than MM-TILs and displayed a mono-/oligo- functional pattern. The ability to select, enrich, and expand tumor-reactive poly-functional T cells may be critical in developing effective ACT with TILs for RCC.

Author Info: (1) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital, University of Copenhagen. (2) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital

Author Info: (1) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital, University of Copenhagen. (2) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital, University of Copenhagen. (3) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital, University of Copenhagen. (4) Institute of Medical Immunology, Martin Luther University Halle-Wittenberg. (5) Division for Immunology and Vaccinology, Technical University of Denmark. (6) Division for Immunology and Vaccinology, Technical University of Denmark. (7) Department of Oncology, Herlev Hospital, University of Copenhagen. (8) Institute of Medical Immunology, Martin Luther University Halle-Wittenberg. (9) Department of Urology, Herlev Hospital, University of Copenhagen. (10) Department of Pathology, Herlev Hospital, University of Copenhagen. (11) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital, University of Copenhagen. (12) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital, University of Copenhagen inge.marie.svane@regionh.dk.

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Antigen-specific antitumor responses induced by OX40 agonist are enhanced by IDO inhibitor indoximod

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Although an immune response to tumors may be generated using vaccines, so far, this approach has only shown minimal clinical success. This is attributed to the tendency of cancer to escape immune surveillance via multiple immune suppressive mechanisms. Successful cancer immunotherapy requires targeting these inhibitory mechanisms along with enhancement of antigen-specific immune responses to promote sustained tumor-specific immunity. Here we evaluated the effect of indoximod, an inhibitor of the immunosuppressive indoleamine-(2,3)-dioxygenase (IDO) pathway, on antitumor efficacy of anti-OX40 agonist in the context of vaccine in the IDO- TC-1 tumor model. We demonstrate that although the addition of anti-OX40 to the vaccine moderately enhances therapeutic efficacy, incorporation of indoximod into this treatment leads to enhanced tumor regression and cure of established tumors in 60% of treated mice. We show that the mechanisms by which the IDO inhibitor leads to this therapeutic potency include (i) an increment of vaccine-induced tumor-infiltrating effector T cells that is facilitated by anti-OX40, and (ii) a decrease of IDO enzyme activity produced by non-tumor cells within the tumor microenvironment that results in enhancement of the specificity and the functionality of vaccine-induced effector T cells. Our findings suggest a translatable strategy to enhance the overall efficacy of cancer immunotherapy.

Author Info: (1) Georgia Cancer Center, Augusta University. (2) Georgia Cancer Center, Augusta University. (3) Georgia Cancer Center, Augusta University. (4) Georgia Cancer Center, Augusta University. (5)

Author Info: (1) Georgia Cancer Center, Augusta University. (2) Georgia Cancer Center, Augusta University. (3) Georgia Cancer Center, Augusta University. (4) Georgia Cancer Center, Augusta University. (5) Georgia Cancer Center, Augusta University. (6) Georgia Cancer Center, Augusta University. (7) Georgia Cancer Center, Augusta University. (8) Georgia Cancer Center, Augusta University. (9) The University of Aberdeen Dental School & Hospital, The Institute of Medicine, Medical Sciences & Nutrition, The University of Aberdeen. (10) Medimmune Inc. (11) Georgia Cancer Center, Augusta University. (12) Georgia Cancer Center, Augusta University skhleif@augusta.edu.

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Supramolecular Peptide Nanofibers Engage Mechanisms of Autophagy in Antigen-Presenting Cells

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Supramolecular peptide nanofibers are attractive for applications in vaccine development due to their ability to induce strong immune responses without added adjuvants or associated inflammation. Here, we report that self-assembling peptide nanofibers bearing CD4+ or CD8+ T cell epitopes are processed through mechanisms of autophagy in antigen-presenting cells (APCs). Using standard in vitro antigen presentation assays, we confirmed loss and gain of the adjuvant function using pharmacological modulators of autophagy and APCs deficient in multiple autophagy proteins. The incorporation of microtubule-associated protein 1A/1B-light chain-3 (LC3-II) into the autophagosomal membrane, a key biological marker for autophagy, was confirmed using microscopy. Our findings indicate that autophagy in APCs plays an essential role in the mechanism of adjuvant action of supramolecular peptide nanofibers.

Author Info: (1) Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd

Author Info: (1) Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. (2) Immunobiology and Transplant Science Center, Houston Methodist Research Institute, 6565 Fannin Street, Houston, Texas 77030, United States. (3) Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. (4) Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. (5) Division of Surgical Oncology, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, RM 3035, New Brunswick, New Jersey 08903, United States. (6) Immunobiology and Transplant Science Center, Houston Methodist Research Institute, 6565 Fannin Street, Houston, Texas 77030, United States. (7) Department of Pathology and Laboratory Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, P.O. Box 20708, Houston, Texas 77030, United States.

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Immunomodulatory effects of soluble CD5 on experimental tumor models

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Modulation of antitumor immune responses by targeting immune checkpoint regulators has been proven successful in the treatment of many different tumors. Recent evidence shows that the lymphocyte receptor CD5 -a negative regulator of TCR-mediated signaling- may play a role in the anti-tumor immune response. To explore such an issue, we developed transgenic C57BL/6 mice expressing a soluble form of human CD5 (shCD5EmuTg), putatively blocking CD5-mediated interactions ("decoy receptor" effect). Homozygous shCD5EmuTg mice showed reduced growth rates of tumor cells of melanoma (B16-F0) and thymoma (EG7-OVA) origin. Concomitantly, increased CD4(+) and CD8(+) T cell numbers, as well as reduced proportion of CD4(+)CD25(+)FoxP3(+) (Treg) cells were observed in tumor draining lymph nodes (TdLN). TdLN cell suspensions from tumor-bearing shCD5EmuTg mice showed increased both tumor specific and non-specific cytolitic activity. Moreover, subcutaneous peritumoral (p.t.) injection of recombinant shCD5 to wild-type (WT) mice slowed B16-F0 tumor growth, and reproduced the above mentioned TdLN cellular changes. Interestingly, lower intratumoral IL-6 levels -an inhibitor of Natural Killer (NK) cell cytotoxity- were observed in both transgenic and rshCD5-treated WT mice and the anti-tumor effect was abrogated by mAb-induced NK cell depletion. Taken together, the results further illustrate the putative regulatory role of CD5-mediated interactions in anti-tumor immune responses, which would be at least in part fostered by NK cells.

Author Info: (1) Immunoreceptors of the Innate and Adaptive System, Institut d'Investigacions Biomediques August Pi i Sunyer, 08036, Barcelona, Spain. (2) Immunoreceptors of the Innate and Adaptive

Author Info: (1) Immunoreceptors of the Innate and Adaptive System, Institut d'Investigacions Biomediques August Pi i Sunyer, 08036, Barcelona, Spain. (2) Immunoreceptors of the Innate and Adaptive System, Institut d'Investigacions Biomediques August Pi i Sunyer, 08036, Barcelona, Spain. (3) Immunoreceptors of the Innate and Adaptive System, Institut d'Investigacions Biomediques August Pi i Sunyer, 08036, Barcelona, Spain. (4) Immunoreceptors of the Innate and Adaptive System, Institut d'Investigacions Biomediques August Pi i Sunyer, 08036, Barcelona, Spain. (5) Immunoreceptors of the Innate and Adaptive System, Institut d'Investigacions Biomediques August Pi i Sunyer, 08036, Barcelona, Spain. (6) Immunoreceptors of the Innate and Adaptive System, Institut d'Investigacions Biomediques August Pi i Sunyer, 08036, Barcelona, Spain. (7) Immunoreceptors of the Innate and Adaptive System, Institut d'Investigacions Biomediques August Pi i Sunyer, 08036, Barcelona, Spain. Servei d'Immunologia, Centre de Diagnostic Biomedic, Hospital Clinic de Barcelona, 08036, Barcelona, Spain. Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, 08036, Barcelona, Spain.

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Blockade of TNFR2 signaling enhances the immunotherapeutic effect of CpG ODN in a mouse model of colon cancer

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Through the tumor necrosis factor (TNF) receptor type II (TNFR2), TNF preferentially activates, expands, and promotes the phenotypic stability of CD4(+)Foxp3(+) regulatory T (Treg) cells. Those Treg cells that have a high abundance of TNFR2 have the maximal immunosuppressive capacity. We investigated whether targeting TNFR2 could effectively suppress the activity of Treg cells and consequently enhance the efficacy of cancer immunotherapy. We found that, relative to a suboptimal dose of the immunostimulatory Toll-like receptor 9 ligand CpG oligodeoxynucleotide (ODN), the combination of the suboptimal dose of CpG ODN with the TNFR2-blocking antibody M861 more markedly inhibited the growth of subcutaneously grafted mouse CT26 colon tumor cells. This resulted in markedly fewer TNFR2(+) Treg cells and more interferon-gamma-positive (IFN-gamma(+)) CD8(+) cytotoxic T lymphocytes infiltrating the tumor and improved long-term tumor-free survival in the mouse cohort. Tumor-free mice were resistant to rechallenge by the same but not unrelated (4T1 breast cancer) cells. Treatment with the combination of TNFR2-blocking antibody and a CD25-targeted antibody also resulted in enhanced inhibition of tumor growth in a syngeneic 4T1 mouse model of breast cancer. Thus, the combination of a TNFR2 inhibitor and an immunotherapeutic stimulant may represent a more effective treatment strategy for various cancers.

Author Info: (1) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Department of Research, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002

Author Info: (1) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Department of Research, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China. (2) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China. (3) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. (4) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. (5) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. (6) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. (7) Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. xchen@umac.mo oppenhej@mail.nih.gov. (8) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China. xchen@umac.mo oppenhej@mail.nih.gov. Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.

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Development of novel vaccine vectors: chimpanzee adenoviral vectors

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Adenoviral vector has been employed as one of the most efficient means against infectious diseases and cancer. It can be genetically modified and armed with foreign antigens to elicit specific antibody responses and T cell responses in hosts as well as engineered to induce apoptosis in cancer cells. The chimpanzee adenovirus-based vector is one kind of novel vaccine carriers whose unique features and non-reactivity to pre-existing human adenovirus neutralizing antibodies makes it an outstanding candidate for vaccine research and development. Here, we review the different strategies for constructing chimpanzee adenoviral vectors and their applications in recent clinical trials and also discuss the oncolytic virotherapy and immunotherapy based on chimpanzee adenoviral vectors.

Author Info: (1) a Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences , Shanghai 200031 , China

Author Info: (1) a Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences , Shanghai 200031 , China. (2) a Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences , Shanghai 200031 , China. b Guangzhou Women and Children's Medical Center , Guangzhou , 510623 , China. (3) a Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences , Shanghai 200031 , China.

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A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vgamma9Vdelta2-T cells

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Though Vgamma9Vdelta2-T cells constitute only a small fraction of the total T cell population in human peripheral blood, they play a vital role in tumor defense and are therefore of major interest to explore for cancer immunotherapy. Vgamma9Vdelta2-T cell-based cancer immunotherapeutic approaches developed so far have been generally well tolerated and were able to induce significant clinical responses. However, overall results were inconsistent, possibly due to the fact that these strategies induced systemic activation of Vgamma9Vdelta2-T cells without preferential accumulation and targeted activation in the tumor. Here we show that a novel bispecific nanobody-based construct targeting both Vgamma9Vdelta2-T cells and EGFR induced potent Vgamma9Vdelta2-T cell activation and subsequent tumor cell lysis both in vitro and in an in vivo mouse xenograft model. Tumor cell lysis was independent of KRAS and BRAF tumor mutation status and common Vgamma9Vdelta2-T cell receptor sequence variations. In combination with the conserved monomorphic nature of the Vgamma9Vdelta2-TCR and the facile replacement of the tumor-specific nanobody, this immunotherapeutic approach can be applied to a large group of cancer patients.

Author Info: (1) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (2) Department of Medical Oncology, VU University Medical

Author Info: (1) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (2) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (3) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (4) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (5) Innate Immunity Unit, Institut Pasteur, Paris, France. Institut National de la Sante et de la Recherche Medicale (INSERM) U1223, Paris, France. Universite Paris-Sud, Universite Paris-Saclay, Gif-sur-Yvette, France. (6) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (7) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (8) Department of Hematology and Laboratory of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. (9) Department of Hematology and Laboratory of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. (10) Department of Radiology and Nuclear Medicine, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (11) Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (12) Department of Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. (13) Innate Immunity Unit, Institut Pasteur, Paris, France. Institut National de la Sante et de la Recherche Medicale (INSERM) U1223, Paris, France. (14) Department of Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. (15) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (16) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (17) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

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Toll-like receptor 2 ligand and interferon-gamma suppress anti-tumor T cell responses by enhancing the immunosuppressive activity of monocytic myeloid-derived suppressor cells

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CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs) suppress activation/proliferation of cytotoxic T cells, thereby hindering cancer immunotherapy. MDSCs are increased after adjuvant therapy with toll-like receptor (TLR) 2 ligands, such as Pam2CSK4, in tumor-bearing mice. However, it remains unknown if the activation of TLR2 in MDSCs affects their function and the therapeutic efficacy of TLR2 ligand. Here, we show that TLR2 signaling in CD11b(+)Ly6G(-)Ly6C(high) monocytic MDSCs (M-MDSCs), but not CD11b(+)Ly6G(+)Ly6C(low) granulocytic MDSCs (G-MDSCs), enhances their immunosuppressive activity, thereby limiting anti-tumor T cell responses induced by TLR2-activated dendritic cells (DCs). iNOS induction was critical for Pam2CSK4-enhanced T cell suppression by M-MDSCs. iNOS was expressed in M-MDSC-derived macrophages, but not undifferentiated M-MDSCs, in cocultures with CD8(+) T cells, CD11c(+) DCs, antigen peptide and Pam2CSK4. Pam2CSK4 increased the differentiation frequency of M-MDSCs to macrophages, and iNOS expression required interferon-gamma (IFN-gamma) production by CD8(+) T cells that had been transiently stimulated by M-MDSC-derived macrophages in an antigen/TLR2-dependent manner. Although Pam2CSK4 triggered DC maturation and tumor regression via induction of tumor antigen-specific cytotoxic T lymphocyte (CTL) responses in tumor-bearing mice, Pam2CSK4 plus antigen increased the frequency of iNOS(+) macrophages in the tumor. Treatment with iNOS inhibitor enhanced the therapeutic efficacy of Pam2CSK4. Hence, the results suggest that TLR2 ligand and T cell-derived IFN-gamma enhance M-MDSC-mediated immunosuppression, which may negatively regulate anti-tumor CTL response.

Author Info: (1) Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, Japan. Department of Immunology, Graduate School of

Author Info: (1) Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, Japan. Department of Immunology, Graduate School of Medical Sciences, Nagoya City University, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan. (2) Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, Japan. (3) Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, Japan. (4) Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, Japan. (5) Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, Japan. (6) Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, Japan.

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mSA2 affinity-enhanced biotin-binding CAR T cells for universal tumor targeting

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Chimeric antigen receptor T cells (CAR-Ts) are promising cancer therapeutics. However, since cancer cells can lose the CAR-targeted antigen and avoid destruction, targeting multiple antigens with multiple CARs has been proposed. We illustrate here a less cumbersome alternative, anti-tag CARs (AT-CARs) that bind to tags on tumor-targeting antibodies. We have created novel AT-CARs, using the affinity-enhanced monomeric streptavidin 2 (mSA2) biotin-binding domain that when expressed on T cells can target cancer cells coated with biotinylated antibodies. Human T cells expressing mSA2 CARs with CD28-CD3zeta and 4-1BB-CD3zeta signaling domains were activated by plate-immobilized biotin and by tumor cells coated with biotinylated antibodies against the tumor-associated antigens CD19 and CD20. Furthermore, mSA2 CAR T cells were capable of mediating cancer cell lysis and IFNgamma production in an antibody dose-dependent manner. The mSA2 CAR is a universal AT-CAR that can be combined with biotinylated tumor-specific antibodies to potentially target many different tumor types.

Author Info: (1) University of Pittsburgh School of Medicine, Department of Immunology, Pittsburgh, PA USA. (2) University of Pittsburgh School of Medicine, Department of Immunology, Pittsburgh, PA

Author Info: (1) University of Pittsburgh School of Medicine, Department of Immunology, Pittsburgh, PA USA. (2) University of Pittsburgh School of Medicine, Department of Immunology, Pittsburgh, PA USA. Carnegie Mellon University, Department of Biomedical Engineering, Pittsburgh, PA USA. (3) University of Pittsburgh School of Medicine, Department of Immunology, Pittsburgh, PA USA. (4) University of Pittsburgh School of Medicine, Department of Immunology, Pittsburgh, PA USA.

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Substrate-bound CCL21 and ICAM1 combined with soluble IL-6 collectively augment the expansion of antigen-specific murine CD4(+) T cells

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Immune processes within the complex microenvironment of the lymph node involve multiple intercellular, cell-matrix, and paracrine interactions, resulting in the expansion of antigen-specific T cells. Inspired by the lymph node microenvironment, we aimed to develop an ex vivo "synthetic immune niche" (SIN), which could effectively stimulate the proliferation of antigen-activated CD4(+) T cells. This engineered SIN consisted of surfaces coated with the chemokine C-C motif ligand 21 (CCL21) and with the intercellular adhesion molecule 1 (ICAM1), coupled with the soluble cytokine interleukin 6 (IL-6) added to the culture medium. When activated by ovalbumin-loaded dendritic cells, OT-II T cells growing on regular uncoated culture plates form nonadherent, dynamic clusters around the dendritic cells. We found that functionalization of the plate surface with CCL21 and ICAM1 and the addition of IL-6 to the medium dramatically increases T-cell proliferation and transforms the culture topology from that of suspended 3-dimensional cell clusters into a firm, substrate-attached monolayer of cells. Our findings demonstrate that the components of this SIN collectively modulate T-cell interactions and augment both the proliferation and survival of T cells in an antigen-specific manner, potentially serving as a powerful approach for expanding immunotherapeutic T cells.

Author Info: (1) Department of Molecular Cell Biology. (2) Department of Immunology. (3) Electron Microscopy Unit, and. (4) Electron Microscopy Unit, and. (5) Life Sciences Core Facilities

Author Info: (1) Department of Molecular Cell Biology. (2) Department of Immunology. (3) Electron Microscopy Unit, and. (4) Electron Microscopy Unit, and. (5) Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel. (6) Department of Molecular Cell Biology. (7) Department of Immunology.

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