Mathilde Poussin - Academia.edu (original) (raw)

Papers by Mathilde Poussin

Research paper thumbnail of Supplementary Table from CD137 Accurately Identifies and Enriches for Naturally Occurring Tumor-Reactive T Cells in Tumor

Research paper thumbnail of Supplementary Figure 6 from Chimeric Antigen Receptor T Cells with Dissociated Signaling Domains Exhibit Focused Antitumor Activity with Reduced Potential for Toxicity In Vivo

PDF file - 583K, Figure S6. Trans-, but not cis-, signaling CART cells exhibit more limited in vi... more PDF file - 583K, Figure S6. Trans-, but not cis-, signaling CART cells exhibit more limited in vitro activity against cells bearing single antigen. IFN-γ secretion by trans M-z/F-28 CART cells was significantly reduced in response to A1847M+/F- cells compared with parental A1847M+/F+. M-z, M-z/F-28, or M-28z transduced T cells (1 x 105 T cells) were cultured alone (none) or stimulated overnight with an equal number of C30, A1847M+/F+ or A1847M+/F- cells. Cell-free supernatant was harvested after ~20 hours of incubation and the IFN- γ levels were measure with ELISA. Mean IFN- γ concentration plus-minus SEM (pg/ml) from triplicate cultures is shown. *P < 0.05 comparing the IFN- γ secretion produced by M-z/F-28 CART cells against A1847M+/F+ versus A1847M+/F- cells.

Research paper thumbnail of Supplementary Figure Legend from Follicle-Stimulating Hormone Receptor as a Target in the Redirected T-cell Therapy for Cancer

Supplementary Figure Legend from Follicle-Stimulating Hormone Receptor as a Target in the Redirec... more Supplementary Figure Legend from Follicle-Stimulating Hormone Receptor as a Target in the Redirected T-cell Therapy for Cancer

Research paper thumbnail of Supplementary Figure 3 from Chimeric Antigen Receptor T Cells with Dissociated Signaling Domains Exhibit Focused Antitumor Activity with Reduced Potential for Toxicity In Vivo

PDF file - 1935K, Figure S3. shRNA based silencing of FRa in A1847 ovarian cancer cells. The pare... more PDF file - 1935K, Figure S3. shRNA based silencing of FRa in A1847 ovarian cancer cells. The parental human ovarian cancer cell line A1847 which expresses surface mesothelin and FRa protein was transduced with lentiviral particles encoding for an shRNA specific for silencing FRa gene expression (A1847 sh4 M+/F-). To determine surface antigen expression, cells were stained with an anti-mesothelin biobody reagent (P4 Bb) and anti-FRa antibody or proper isotype antibody controls. FRa expression was unaltered after engineering cells with control shRNA (A1847 csh M+/F+).

Research paper thumbnail of Supplementary Figure 1 from Chimeric Antigen Receptor T Cells with Dissociated Signaling Domains Exhibit Focused Antitumor Activity with Reduced Potential for Toxicity In Vivo

PDF file - 1125K, Figure S1. Correlated scFv and GFP transgene expression following F-28 CAR tran... more PDF file - 1125K, Figure S1. Correlated scFv and GFP transgene expression following F-28 CAR transduction. T cells were lentivirally transduced to express the costimulatory F-28 CAR and 5 days later were stained for surface scFv using biotinylated protein-L followed by SA-APC. Transduction efficiency was also monitored using GFP transgene expression. Transduction efficiencies are indicated with the percentage of CAR expression of the transduced populations. Coordinate expression of surface scFv and GFP was observed in all experiments.

Research paper thumbnail of Supplementary Methods, Figure Legend from Chimeric Antigen Receptor T Cells with Dissociated Signaling Domains Exhibit Focused Antitumor Activity with Reduced Potential for Toxicity In Vivo

Research paper thumbnail of Supplementary Figure 2 from A Universal Strategy for Adoptive Immunotherapy of Cancer through Use of a Novel T-cell Antigen Receptor

PDF file - 21K, BBIR-z T cells loaded with biotinylated molecules and then washed do not produce ... more PDF file - 21K, BBIR-z T cells loaded with biotinylated molecules and then washed do not produce IFN�� in response to specific antigen stimulation. Following 45min incubation at 37oC with 1ug/ml of mesothelin specific biotinylated antybodies; P4 Biobody or K1 and control Bio-IgG1 antibody, BBIR-z T cells were washed with PBS and tested against plate-immobilized human mesothelin (105 cells/10ng mesothelin/well). After overnight incubation, culture supernatants were analyzed for human IFN�^ cytokine by ELISA. Concentration of IFN�� is expressed in pg/ml (means �� SEM; n = 3).

Research paper thumbnail of Supplementary Figure 3 from A Universal Strategy for Adoptive Immunotherapy of Cancer through Use of a Novel T-cell Antigen Receptor

PDF file - 113K, Flow Cytometry analysis of an antigen surface expression on mouse AE17 cell line... more PDF file - 113K, Flow Cytometry analysis of an antigen surface expression on mouse AE17 cell lines transduced to express human FR�� or mesothelin and human ovarian cancer cell line, A1847. FR��-specific mAb Mov18, EpCAM-specific and mesothelin-specific K1 antibody and P4 Biobody were used to measure antigen expression on tumor cell lines (open empty histogram), compared to a matched isotype Ab control (filled gray histogram). Numbers within plots refer to specific mean fluorescent intensity (MFI).

Research paper thumbnail of Supplementary Figures Legends 1-5 from In Vivo Persistence, Tumor Localization, and Antitumor Activity of CAR-Engineered T Cells Is Enhanced by Costimulatory Signaling through CD137 (4-1BB)

Supplementary Figures Legends 1-5 from In Vivo Persistence, Tumor Localization, and Antitumor Act... more Supplementary Figures Legends 1-5 from In Vivo Persistence, Tumor Localization, and Antitumor Activity of CAR-Engineered T Cells Is Enhanced by Costimulatory Signaling through CD137 (4-1BB)

Research paper thumbnail of Supplementary Figure 1 from In Vivo Persistence, Tumor Localization, and Antitumor Activity of CAR-Engineered T Cells Is Enhanced by Costimulatory Signaling through CD137 (4-1BB)

Supplementary Figure 1 from In Vivo Persistence, Tumor Localization, and Antitumor Activity of CA... more Supplementary Figure 1 from In Vivo Persistence, Tumor Localization, and Antitumor Activity of CAR-Engineered T Cells Is Enhanced by Costimulatory Signaling through CD137 (4-1BB)

Research paper thumbnail of Supplementary Figure Legend from CD137 Accurately Identifies and Enriches for Naturally Occurring Tumor-Reactive T Cells in Tumor

Supplementary Figure Legend - PDF file 61K, Supplementary figure legend

Research paper thumbnail of TCRvβ-CART therapy mediates high-precision targeting of malignant T-cell clones

Blood Advances

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid malignancies associated... more Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid malignancies associated with poor prognosis due to ineffective treatment options and high rates of relapse. The success of chimeric antigen receptor T-cell (CART) therapy for certain hematologic malignancies makes it an attractive treatment option for PTCLs. However, shared expression of potential target antigens by both malignant and healthy T cells poses a challenge. Current prospective CART approaches cause a high degree of on-target, off-tumor activity, resulting in fratricide during CART expansion, depletion of healthy T cells in vivo, and immune compromise in the patient. To limit off-tumor targeting, we sought to develop a CART platform specific for a given T-cell receptor vβ (TCRvβ) family that would endow CAR-modified T cells with the ability to mediate lysis of the clonal malignant population while preserving the majority of healthy T cells. Here, CAR constructs specific for multiple TCRvβ family mem...

Research paper thumbnail of Data from CD137 Accurately Identifies and Enriches for Naturally Occurring Tumor-Reactive T Cells in Tumor

Purpose: Upregulation of CD137 (4-1BB) on recently activated CD8+ T cells has been used to identi... more Purpose: Upregulation of CD137 (4-1BB) on recently activated CD8+ T cells has been used to identify rare viral or tumor antigen-specific T cells from peripheral blood. Here, we evaluated the immunobiology of CD137 in human cancer and the utility of a CD137-positive separation methodology for the identification and enrichment of fresh tumor-reactive tumor-infiltrating lymphocytes (TIL) or tumor-associated lymphocytes (TAL) from ascites for use in adoptive immunotherapy.Experimental Design: TILs from resected ovarian cancer or melanoma were measured for surface CD137 expression directly or after overnight incubation in the presence of tumor cells and homeostatic cytokines. CD137pos TILs were sorted and evaluated for antitumor activity in vitro and in vivo.Results: Fresh ovarian TILs and TALs naturally expressed higher levels of CD137 than circulating T cells. An HLA-dependent increase in CD137 expression was observed following incubation of fresh enzyme-digested tumor or ascites in IL...

Research paper thumbnail of Expression of inducible factors reprograms CAR-T cells for enhanced function and safety

Research paper thumbnail of Additional file 2: Figure S2. of Effective adoptive immunotherapy of triple-negative breast cancer by folate receptor-alpha redirected CAR T cells is influenced by surface antigen expression level

MDA-231 tumors retained a stable FRα expression profile after UNT, CD19 CAR, or FRα CAR T cell tr... more MDA-231 tumors retained a stable FRα expression profile after UNT, CD19 CAR, or FRα CAR T cell treatment. On day 73, mice bearing MDA-231 tumors were sacrificed and tumors were collected and cut up in RPMI 1640, washed, and centrifuged at room temperature at 800 rpm for 5 min and then resuspended in enzymatic digestion buffer (collagenase [0.2 mg/mL] and DNase [30 units/mL] in RPMI 1640) for overnight digestion at room temperature. FRα-specific mAb MOv18 was used to measure FRα expression on MDA-231 tumors treated with different T cells. (TIF 51 kb)

Research paper thumbnail of A Novel Approach for the Treatment of T Cell Malignancies: Targeting T Cell Receptor Vβ Families

Vaccines, 2020

Peripheral T cell lymphomas (PTCLs) are generally chemotherapy resistant and have a poor prognosi... more Peripheral T cell lymphomas (PTCLs) are generally chemotherapy resistant and have a poor prognosis. The lack of targeted immunotherapeutic approaches for T cell malignancies results in part from potential risks associated with targeting broadly expressed T cell markers, namely T cell depletion and clinically significant immune compromise. The knowledge that the T cell receptor (TCR) β chain in human α/β TCRs are grouped into Vβ families that can each be targeted by a monoclonal antibody can therefore be exploited for therapeutic purposes. Here, we develop a flexible approach for targeting TCR Vβ families by engineering T cells to express a chimeric CD64 protein that acts as a high affinity immune receptor (IR). We found that CD64 IR-modified T cells can be redirected with precision to T cell targets expressing selected Vβ families by combining CD64 IR-modified T cells with a monoclonal antibody directed toward a specific TCR Vβ family in vitro and in vivo. These findings provide pro...

Research paper thumbnail of Additional file 4: Figure S4. of Effective adoptive immunotherapy of triple-negative breast cancer by folate receptor-alpha redirected CAR T cells is influenced by surface antigen expression level

Tumor volume fold changes after CAR T cell treatment on days 60 and 74. NSG mice were inoculated ... more Tumor volume fold changes after CAR T cell treatment on days 60 and 74. NSG mice were inoculated with MDA-231 or MDA-231. FRα tumor cells. Mice bearing established MDA-231.FRα or MDA-231 tumors received tail vein injections of 1 × 107 CAR+ T cells on days 40 and 46, and tumor growth was monitored by caliper measurements. (TIF 37 kb)

Research paper thumbnail of Évaluation d'une technique d'immunocapture destinée à la mise en évidence des IgM anti-Chlamydia

La Revue de Médecine Interne, 1995

Research paper thumbnail of Modèle expérimental d'immunoprotection induite vis-à-vis de Chlamydia psittaci

La Revue de Médecine Interne, 1995

Research paper thumbnail of Abstract POSTER-THER-1433: Overcoming resistance to antibody targeted therapy in ovarian cancer

Clinical Cancer Research, 2015

Targeted therapies utilizing monoclonal antibodies (mAbs) are now the major class of successful t... more Targeted therapies utilizing monoclonal antibodies (mAbs) are now the major class of successful therapeutics for treating a variety of malignancies. Mechanistically, mAbs can have direct antitumoral activity but often their effectiveness relies upon antibody-dependent cellular cytotoxicity (ADCC). For instance, Trastuzumab is a therapeutic monoclonal antibody directed against HER2 that is well-tolerated and useful in the treatment of HER2-positive breast cancer, where efficacy is mediated in part by ADCC. In contrast, Trastuzumab is relatively ineffective in the treatment of epithelial ovarian cancer (EOC) where virtually all cancer cells express detectable levels of HER2. Poor response to mAb therapy in EOC and other types of cancers may be explained in part by diminished numbers and cytotoxic potential of NK cells in cancer patients, compared to healthy individuals. Therefore, reports of poor antitumor effect of Ab-therapy in cancer led us to hypothesize that the development of potent effector cells with the capacity to bind tumor-bound mAb and mediate strong antibody-directed cellular cytotoxicity would markedly improve the efficacy of mAb-targeted therapy for EOC. In order to expand applications for T cell-based immunotherapy and to enhance ADCC, we developed novel effector T cells engineered to express Fc binding immune receptors (FcIR) containing human Fc receptor of low FcγRIIIA (CD16), intermediate FcγRIIA (CD32) or high affinity FcγRI (CD64) molecules fused to intracellular TCR and co-stimulatory signaling domains in order to enable cytotoxic T cells to mediate strong mAb-directed cytotoxicity against antigen-expressing tumor cells. Following FcIR gene transduction, all forms of FcγRs were efficiently expressed on the surface of primary human T cells which allowed these cells to be armed with mAb. Trastuzumab-armed FcIR T cells specifically recognized HER2+ cancer cells, as did unarmed FcIRs but only when the cancer cells were first pre-bound with Trastuzumab. Addition of a CD28 cytoplasmic domain juxtaposed to the TCR CD3z signaling moiety increased IFN-g secretion by FcIR-28z transduced T cells following encounter with antigen-bound mAb on the cancer cell surface. Notably, T cells expressing a high affinity FcIRI (CD64) demonstrated the greatest specific anti-tumor reactivity in comparison to cells expressing FcγRIIA (CD32) or FcγRIIIA (CD16) FcIRs. In addition, FcIRI (CD64) T cells exhibited stronger specific lytic activity than NK cells, even at low antibody concentrations. Further, co-administration of FcIRI (CD64) FcIR-28z T cells with immunotherapeutic mAb, Trastuzumab, exerted strong antitumor activity in vivo, completely eliminating HER2+ tumor. In summary, our results show that ADCC can be enhanced by human T cells engineered to express an FcIR and that this novel approach may overcome issues of resistance to mAb-targeted therapies including those utilizing Trastuzumab. Citation Format: Katarzyna Urbanska, Mathilde Poussin, Caitlin Stashwick, Jenessa B. Smith, Daniel J. Powell Jr. Overcoming resistance to antibody targeted therapy in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1433.

Research paper thumbnail of Supplementary Table from CD137 Accurately Identifies and Enriches for Naturally Occurring Tumor-Reactive T Cells in Tumor

Research paper thumbnail of Supplementary Figure 6 from Chimeric Antigen Receptor T Cells with Dissociated Signaling Domains Exhibit Focused Antitumor Activity with Reduced Potential for Toxicity In Vivo

PDF file - 583K, Figure S6. Trans-, but not cis-, signaling CART cells exhibit more limited in vi... more PDF file - 583K, Figure S6. Trans-, but not cis-, signaling CART cells exhibit more limited in vitro activity against cells bearing single antigen. IFN-γ secretion by trans M-z/F-28 CART cells was significantly reduced in response to A1847M+/F- cells compared with parental A1847M+/F+. M-z, M-z/F-28, or M-28z transduced T cells (1 x 105 T cells) were cultured alone (none) or stimulated overnight with an equal number of C30, A1847M+/F+ or A1847M+/F- cells. Cell-free supernatant was harvested after ~20 hours of incubation and the IFN- γ levels were measure with ELISA. Mean IFN- γ concentration plus-minus SEM (pg/ml) from triplicate cultures is shown. *P < 0.05 comparing the IFN- γ secretion produced by M-z/F-28 CART cells against A1847M+/F+ versus A1847M+/F- cells.

Research paper thumbnail of Supplementary Figure Legend from Follicle-Stimulating Hormone Receptor as a Target in the Redirected T-cell Therapy for Cancer

Supplementary Figure Legend from Follicle-Stimulating Hormone Receptor as a Target in the Redirec... more Supplementary Figure Legend from Follicle-Stimulating Hormone Receptor as a Target in the Redirected T-cell Therapy for Cancer

Research paper thumbnail of Supplementary Figure 3 from Chimeric Antigen Receptor T Cells with Dissociated Signaling Domains Exhibit Focused Antitumor Activity with Reduced Potential for Toxicity In Vivo

PDF file - 1935K, Figure S3. shRNA based silencing of FRa in A1847 ovarian cancer cells. The pare... more PDF file - 1935K, Figure S3. shRNA based silencing of FRa in A1847 ovarian cancer cells. The parental human ovarian cancer cell line A1847 which expresses surface mesothelin and FRa protein was transduced with lentiviral particles encoding for an shRNA specific for silencing FRa gene expression (A1847 sh4 M+/F-). To determine surface antigen expression, cells were stained with an anti-mesothelin biobody reagent (P4 Bb) and anti-FRa antibody or proper isotype antibody controls. FRa expression was unaltered after engineering cells with control shRNA (A1847 csh M+/F+).

Research paper thumbnail of Supplementary Figure 1 from Chimeric Antigen Receptor T Cells with Dissociated Signaling Domains Exhibit Focused Antitumor Activity with Reduced Potential for Toxicity In Vivo

PDF file - 1125K, Figure S1. Correlated scFv and GFP transgene expression following F-28 CAR tran... more PDF file - 1125K, Figure S1. Correlated scFv and GFP transgene expression following F-28 CAR transduction. T cells were lentivirally transduced to express the costimulatory F-28 CAR and 5 days later were stained for surface scFv using biotinylated protein-L followed by SA-APC. Transduction efficiency was also monitored using GFP transgene expression. Transduction efficiencies are indicated with the percentage of CAR expression of the transduced populations. Coordinate expression of surface scFv and GFP was observed in all experiments.

Research paper thumbnail of Supplementary Methods, Figure Legend from Chimeric Antigen Receptor T Cells with Dissociated Signaling Domains Exhibit Focused Antitumor Activity with Reduced Potential for Toxicity In Vivo

Research paper thumbnail of Supplementary Figure 2 from A Universal Strategy for Adoptive Immunotherapy of Cancer through Use of a Novel T-cell Antigen Receptor

PDF file - 21K, BBIR-z T cells loaded with biotinylated molecules and then washed do not produce ... more PDF file - 21K, BBIR-z T cells loaded with biotinylated molecules and then washed do not produce IFN�� in response to specific antigen stimulation. Following 45min incubation at 37oC with 1ug/ml of mesothelin specific biotinylated antybodies; P4 Biobody or K1 and control Bio-IgG1 antibody, BBIR-z T cells were washed with PBS and tested against plate-immobilized human mesothelin (105 cells/10ng mesothelin/well). After overnight incubation, culture supernatants were analyzed for human IFN�^ cytokine by ELISA. Concentration of IFN�� is expressed in pg/ml (means �� SEM; n = 3).

Research paper thumbnail of Supplementary Figure 3 from A Universal Strategy for Adoptive Immunotherapy of Cancer through Use of a Novel T-cell Antigen Receptor

PDF file - 113K, Flow Cytometry analysis of an antigen surface expression on mouse AE17 cell line... more PDF file - 113K, Flow Cytometry analysis of an antigen surface expression on mouse AE17 cell lines transduced to express human FR�� or mesothelin and human ovarian cancer cell line, A1847. FR��-specific mAb Mov18, EpCAM-specific and mesothelin-specific K1 antibody and P4 Biobody were used to measure antigen expression on tumor cell lines (open empty histogram), compared to a matched isotype Ab control (filled gray histogram). Numbers within plots refer to specific mean fluorescent intensity (MFI).

Research paper thumbnail of Supplementary Figures Legends 1-5 from In Vivo Persistence, Tumor Localization, and Antitumor Activity of CAR-Engineered T Cells Is Enhanced by Costimulatory Signaling through CD137 (4-1BB)

Supplementary Figures Legends 1-5 from In Vivo Persistence, Tumor Localization, and Antitumor Act... more Supplementary Figures Legends 1-5 from In Vivo Persistence, Tumor Localization, and Antitumor Activity of CAR-Engineered T Cells Is Enhanced by Costimulatory Signaling through CD137 (4-1BB)

Research paper thumbnail of Supplementary Figure 1 from In Vivo Persistence, Tumor Localization, and Antitumor Activity of CAR-Engineered T Cells Is Enhanced by Costimulatory Signaling through CD137 (4-1BB)

Supplementary Figure 1 from In Vivo Persistence, Tumor Localization, and Antitumor Activity of CA... more Supplementary Figure 1 from In Vivo Persistence, Tumor Localization, and Antitumor Activity of CAR-Engineered T Cells Is Enhanced by Costimulatory Signaling through CD137 (4-1BB)

Research paper thumbnail of Supplementary Figure Legend from CD137 Accurately Identifies and Enriches for Naturally Occurring Tumor-Reactive T Cells in Tumor

Supplementary Figure Legend - PDF file 61K, Supplementary figure legend

Research paper thumbnail of TCRvβ-CART therapy mediates high-precision targeting of malignant T-cell clones

Blood Advances

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid malignancies associated... more Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid malignancies associated with poor prognosis due to ineffective treatment options and high rates of relapse. The success of chimeric antigen receptor T-cell (CART) therapy for certain hematologic malignancies makes it an attractive treatment option for PTCLs. However, shared expression of potential target antigens by both malignant and healthy T cells poses a challenge. Current prospective CART approaches cause a high degree of on-target, off-tumor activity, resulting in fratricide during CART expansion, depletion of healthy T cells in vivo, and immune compromise in the patient. To limit off-tumor targeting, we sought to develop a CART platform specific for a given T-cell receptor vβ (TCRvβ) family that would endow CAR-modified T cells with the ability to mediate lysis of the clonal malignant population while preserving the majority of healthy T cells. Here, CAR constructs specific for multiple TCRvβ family mem...

Research paper thumbnail of Data from CD137 Accurately Identifies and Enriches for Naturally Occurring Tumor-Reactive T Cells in Tumor

Purpose: Upregulation of CD137 (4-1BB) on recently activated CD8+ T cells has been used to identi... more Purpose: Upregulation of CD137 (4-1BB) on recently activated CD8+ T cells has been used to identify rare viral or tumor antigen-specific T cells from peripheral blood. Here, we evaluated the immunobiology of CD137 in human cancer and the utility of a CD137-positive separation methodology for the identification and enrichment of fresh tumor-reactive tumor-infiltrating lymphocytes (TIL) or tumor-associated lymphocytes (TAL) from ascites for use in adoptive immunotherapy.Experimental Design: TILs from resected ovarian cancer or melanoma were measured for surface CD137 expression directly or after overnight incubation in the presence of tumor cells and homeostatic cytokines. CD137pos TILs were sorted and evaluated for antitumor activity in vitro and in vivo.Results: Fresh ovarian TILs and TALs naturally expressed higher levels of CD137 than circulating T cells. An HLA-dependent increase in CD137 expression was observed following incubation of fresh enzyme-digested tumor or ascites in IL...

Research paper thumbnail of Expression of inducible factors reprograms CAR-T cells for enhanced function and safety

Research paper thumbnail of Additional file 2: Figure S2. of Effective adoptive immunotherapy of triple-negative breast cancer by folate receptor-alpha redirected CAR T cells is influenced by surface antigen expression level

MDA-231 tumors retained a stable FRα expression profile after UNT, CD19 CAR, or FRα CAR T cell tr... more MDA-231 tumors retained a stable FRα expression profile after UNT, CD19 CAR, or FRα CAR T cell treatment. On day 73, mice bearing MDA-231 tumors were sacrificed and tumors were collected and cut up in RPMI 1640, washed, and centrifuged at room temperature at 800 rpm for 5 min and then resuspended in enzymatic digestion buffer (collagenase [0.2 mg/mL] and DNase [30 units/mL] in RPMI 1640) for overnight digestion at room temperature. FRα-specific mAb MOv18 was used to measure FRα expression on MDA-231 tumors treated with different T cells. (TIF 51 kb)

Research paper thumbnail of A Novel Approach for the Treatment of T Cell Malignancies: Targeting T Cell Receptor Vβ Families

Vaccines, 2020

Peripheral T cell lymphomas (PTCLs) are generally chemotherapy resistant and have a poor prognosi... more Peripheral T cell lymphomas (PTCLs) are generally chemotherapy resistant and have a poor prognosis. The lack of targeted immunotherapeutic approaches for T cell malignancies results in part from potential risks associated with targeting broadly expressed T cell markers, namely T cell depletion and clinically significant immune compromise. The knowledge that the T cell receptor (TCR) β chain in human α/β TCRs are grouped into Vβ families that can each be targeted by a monoclonal antibody can therefore be exploited for therapeutic purposes. Here, we develop a flexible approach for targeting TCR Vβ families by engineering T cells to express a chimeric CD64 protein that acts as a high affinity immune receptor (IR). We found that CD64 IR-modified T cells can be redirected with precision to T cell targets expressing selected Vβ families by combining CD64 IR-modified T cells with a monoclonal antibody directed toward a specific TCR Vβ family in vitro and in vivo. These findings provide pro...

Research paper thumbnail of Additional file 4: Figure S4. of Effective adoptive immunotherapy of triple-negative breast cancer by folate receptor-alpha redirected CAR T cells is influenced by surface antigen expression level

Tumor volume fold changes after CAR T cell treatment on days 60 and 74. NSG mice were inoculated ... more Tumor volume fold changes after CAR T cell treatment on days 60 and 74. NSG mice were inoculated with MDA-231 or MDA-231. FRα tumor cells. Mice bearing established MDA-231.FRα or MDA-231 tumors received tail vein injections of 1 × 107 CAR+ T cells on days 40 and 46, and tumor growth was monitored by caliper measurements. (TIF 37 kb)

Research paper thumbnail of Évaluation d'une technique d'immunocapture destinée à la mise en évidence des IgM anti-Chlamydia

La Revue de Médecine Interne, 1995

Research paper thumbnail of Modèle expérimental d'immunoprotection induite vis-à-vis de Chlamydia psittaci

La Revue de Médecine Interne, 1995

Research paper thumbnail of Abstract POSTER-THER-1433: Overcoming resistance to antibody targeted therapy in ovarian cancer

Clinical Cancer Research, 2015

Targeted therapies utilizing monoclonal antibodies (mAbs) are now the major class of successful t... more Targeted therapies utilizing monoclonal antibodies (mAbs) are now the major class of successful therapeutics for treating a variety of malignancies. Mechanistically, mAbs can have direct antitumoral activity but often their effectiveness relies upon antibody-dependent cellular cytotoxicity (ADCC). For instance, Trastuzumab is a therapeutic monoclonal antibody directed against HER2 that is well-tolerated and useful in the treatment of HER2-positive breast cancer, where efficacy is mediated in part by ADCC. In contrast, Trastuzumab is relatively ineffective in the treatment of epithelial ovarian cancer (EOC) where virtually all cancer cells express detectable levels of HER2. Poor response to mAb therapy in EOC and other types of cancers may be explained in part by diminished numbers and cytotoxic potential of NK cells in cancer patients, compared to healthy individuals. Therefore, reports of poor antitumor effect of Ab-therapy in cancer led us to hypothesize that the development of potent effector cells with the capacity to bind tumor-bound mAb and mediate strong antibody-directed cellular cytotoxicity would markedly improve the efficacy of mAb-targeted therapy for EOC. In order to expand applications for T cell-based immunotherapy and to enhance ADCC, we developed novel effector T cells engineered to express Fc binding immune receptors (FcIR) containing human Fc receptor of low FcγRIIIA (CD16), intermediate FcγRIIA (CD32) or high affinity FcγRI (CD64) molecules fused to intracellular TCR and co-stimulatory signaling domains in order to enable cytotoxic T cells to mediate strong mAb-directed cytotoxicity against antigen-expressing tumor cells. Following FcIR gene transduction, all forms of FcγRs were efficiently expressed on the surface of primary human T cells which allowed these cells to be armed with mAb. Trastuzumab-armed FcIR T cells specifically recognized HER2+ cancer cells, as did unarmed FcIRs but only when the cancer cells were first pre-bound with Trastuzumab. Addition of a CD28 cytoplasmic domain juxtaposed to the TCR CD3z signaling moiety increased IFN-g secretion by FcIR-28z transduced T cells following encounter with antigen-bound mAb on the cancer cell surface. Notably, T cells expressing a high affinity FcIRI (CD64) demonstrated the greatest specific anti-tumor reactivity in comparison to cells expressing FcγRIIA (CD32) or FcγRIIIA (CD16) FcIRs. In addition, FcIRI (CD64) T cells exhibited stronger specific lytic activity than NK cells, even at low antibody concentrations. Further, co-administration of FcIRI (CD64) FcIR-28z T cells with immunotherapeutic mAb, Trastuzumab, exerted strong antitumor activity in vivo, completely eliminating HER2+ tumor. In summary, our results show that ADCC can be enhanced by human T cells engineered to express an FcIR and that this novel approach may overcome issues of resistance to mAb-targeted therapies including those utilizing Trastuzumab. Citation Format: Katarzyna Urbanska, Mathilde Poussin, Caitlin Stashwick, Jenessa B. Smith, Daniel J. Powell Jr. Overcoming resistance to antibody targeted therapy in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1433.