- Email: [email protected]
500. CD56-Specific T Cells Can Distinguish between Allogeneic and Autologous CD56+ Targets
CANCER - IMMUNOTHERAPY II in these intercellular junctions. In addition to complete virions, penton recombinant dodecahedral particles (PtDds) and dimeric Ad3 fiber domains (Ad3K-K), can trigger DSG2-mediated opening of intercellular junctions. In in vitro studies we show a significant improvement of trastuzumab dependent cell killing of the Her2/neu positive breast cancer cell line BT474M1 subsequent to treatment with the dimeric Ad3K fiber. We also tested whether the application of Ad3K-K would result in the improvement of trastuzumab or cetuximab therapy in vivo. In mouse models with xenograft breast cancer tumors (BT474-M1, HCC 1954) and xenograft lung cancer tumors (A549), Ad3K-K improved the efficiency of the monoclonal antibody used and enabled control of tumor growth in subcutaneous tumor models. We are currently testing a combination of Ad3K-K and cetuximab therapy in an orthotropic lung metastasis model, where we expect to see a benefit in the overall survival and control of tumor growth in the group that received the co-therapy. Our results have potential implication for cancer therapy with T-cells or encapsulated chemotherapy drugs.
498. Genetic Editing of T Lymphocyte Specificity for Safe and Effective Adoptive Immunotherapy
Pietro Genovese,1,2 Elena Provasi,2,3 Angelo Lombardo,1,2 Zulma Magnani,3 Pei-Qi Liu,4 Andreas Reik,4 Victoria Chu,4 David E. Paschon,4 Lei Zhang,4 Jurgen Kuball,5 Attilio Bondanza,3 Giulia Casorati,3 Fabio Ciceri,3 Claudio Bordignon,3 Philip D. Greenberg,5 Michael C. Holmes,4 Philip D. Gregory,4 Luigi Naldini,1,2 Chiara Bonini.2,3 1 HSR-Telethon Institute for Gene Therapy, Milan, Italy; 2Vita Salute San Raffaele University, Milan, Italy; 3San Raffaele Scientific Institute, Milan, Italy; 4Sangamo BioSciences, Richmond; 5 Fred Hutchinson Cancer Research Center, Seattle. Transfer of a T cell receptor (TCR) from a high-avidity tumorspecific T cell (CTL) to polyclonal T cells may overcome the challenges of expanding rare tumor-specific CTLs under conditions that preserve function and prevent exhaustion. Unfortunately, the full potential of this approach is limited by the co-expression in the same lymphocyte of the endogenous and exogenous TCR chains, resulting in competition for surface expression and acquisition of novel unpredicted specificities due to TCR mispairing between the 4 chains, which might lead to dangerous autoreactivity. Thus, we developed two sets of Zinc Finger Nucleases (ZFNs) to target double-strand breaks to the constant regions of the TCR α (TRAC) and β (TRBC1 and TRBC2) genes and disrupt their coding potential by the induced Non Homologous End Joining (NHEJ) repair process. We used a stimulation protocol based on anti-CD3/CD28 antibodyconjugated beads and culture with low doses of IL-7/IL-15 to preserve cells with an early T cell differentiation phenotype. Upon stimulation, delivery of either ZFN set by Adenoviral vectors (Ad5/F35) resulted in functional inactivation of the target genes in primary T cells (>45%), as indicated by the generation of cells that lack surface expression of the CD3/TCR complex (CD3neg). Once sorted, CD3neg cells proved stable in culture for more than 50 days, maintaining an early T cell phenotype (CD62L+ CD28+ CD27+ IL7Ra+), and were permissive to further lentiviral vector (LV) transduction. For complete editing of T cell specificity, we selected a codon-optimized, cystein-modified TCR specific for the Wilm’s Tumor Antigen 1 (WT1), involved in oncogenic transformation in several tumors, and developed a strategy for sequential disruption of each endogenous TCR chain followed by LV transfer of the respective WT1-specific chain. Using this approach we obtained a population of TCR-edited lymphocytes, carrying only the tumor-specific TCR that, in the absence of competition, was robustly expressed at physiological levels. Genetic editing did not affect the proliferative potential and the clonability of engineered cells nor their capacity to differentiate into effector and effector memory T S192
cells. TCR-edited lymphocytes were superior to conventional TCRtransferred cells in WT1 pentamer binding, specific recognition and lysis of WT1pos targets, including primary acute myeloid leukemia blasts. Importantly, these cells showed sharply reduced non-specific reactivity, including alloreactivity, demonstrating the advantage of preventing TCR mispairing. Overall, our results demonstrate that full genetic editing of T cell specificity is feasible, and allows the rapid generation of effective and safe T cells for adoptive immunotherapy.
499. Primary Human CD8+ T Cells Engineered To Express a PD1-CD28 Chimeric Receptor Are Co-Stimulated through the Exploitation of Tumor Expressed PD-L1
Megan E. Prosser,1 Christine E. Brown,1 Michael C. Jensen.2 Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute of the City of Hope, Duarte, CA; 2Center for Immunity and Immunotherapies, Seattle Childrens Research Institute, Seattle, WA.
1
Adoptive immunotherapy is a promising therapeutic approach for the treatment of malignancies. However, several challenges must be addressed to enhance therapeutic efficacy, including the loss of effector function of adoptively transferred cells in the tumor microenvironment. Tumors elicit multiple mechanisms for immunosuppression of transferred cells including deficiency of costimulation and expression of inhibitory ligands. T cell activation requires both antigenic stimulation through the T cell receptor as well as a costimulatory second signal. This secondary costimulatory signal is commonly deficient within the tumor microenvironment resulting in T cell anergy. In addition, tumors often express the inhibitory ligand Programmed Death Ligand 1 (PD-L1) which interacts with Programmed Death 1 (PD-1) expressed on the T cell surface, resulting in T cell exhaustion, characterized inhibition of TcR signaling, and enhanced apoptosis. We hypothesize that the development of a PD1-CD28 chimera could exploit the PD-L1 tumor derived inhibitory mechanism to result in tumor-induced costimulation and maintenance of effector function of adoptively transferred CD8+ T cells, thereby addressing the two aforementioned immunosuppressive mechanisms. Preliminary assessment of this PD1-CD28 chimera in transformed cells reveals that fusion of the PD1 extracellular domain to the intracellular signaling domain of CD28 does not alter PD-L1 binding to the extracellular PD-1 moiety. Furthermore, the chimera results in increased phosphorylation of ERK and AKT suggesting increased signaling through CD28- and TCR- signaling pathways in transformed cells upon ligand binding. In addition, this PD1-CD28 chimera results in increased costimulatory cytokine production in both transformed T cell lines as well as primary human CD8+ T cells. The PD1-CD28 chimera also provides a proliferative advantage, as well as increased accumulation of cytotoxic granules for CD8+ T cells. This work suggests that genetically engineering T cells to express the PD1CD28 chimera may exploit an intrinsic tumor immunosuppressive mechanism to result in costimulation and maintenance of effector function of adoptively transferred cells.
500. CD56-Specific T Cells Can Distinguish between Allogeneic and Autologous CD56+ Targets
Denise L. Kellar,1 Sonny Ang,1 Simon Olivares,1 Helen Huls,1 Laurence J. N. Cooper.1 1 Division of Pediatrics, UT MD Anderson Cancer Center, Houston, TX. Some candidate tumor-associated antigens (TAAs) are also expressed on T cells limiting the use of targeted T-cell therapy. CD56 is an attractive TAA with expression on many malignancies, yet CD56 upregulation on a subset of activated T cells could lead to Molecular Therapy Volume 19, Supplement 1, May 2011 Copyright © The American Society of Gene & Cell Therapy
CANCER - IMMUNOTHERAPY II self targeting, i.e. autolysis. We show here that a chimeric antigen receptor (CAR) can be generated with specificity for CD56. Primary human T cells were electrotransfered with a CD56-specific CAR (CD56RCD28) and CAR+ T cells were selectively propagated on γ-irradiated CD56+ artificial antigen presenting cells (aAPC) in the presence of exogenous recombinant IL-2 and IL-21. Surprisingly, a subset of CD56RCD28+ T cells co-expressed the CD56 antigen. With these data, we tested if CD56+CD56RCD28+ T cells could evade autolysis. A CD19-specific CAR (CD19RCD28) was expressed on control T cells, representing a CAR without self-targeting capacity. There were no significant differences between percent CD56 expression on, nor the expansion rate of, CD19RCD28+ T cells compared with CD56RCD28+ T cells over 28 days inferring that CD56-specific T cells are not lysing themselves. CD56RCD28+ T cells are functional as demonstrated by CD56-specific redirected cytotoxicity against a panel of allogeneic CD56+ tumor cells including neuroblastoma, small cell lung carcinoma, and glioma. To investigate the origin and proliferative capacity of CD56+ T cells, we sorted the CD56RCD28+ T cells into CD56neg and CD56+ fractions. The population of CD56+CD56RCD28+ T cells maintained CD56 expression and expanded over 14 days in a CAR-dependent manner implying that the CD56+CD56RCD28+ T cells did not predominately arise from CD56negCD56RCD28+ T cells gaining CD56 expression. Next, we determined if CD56RCD28+ T cells were capable of lysing autologous CD56+ lymphocytes with and without CAR. Significantly, the CD56+CD56RCD28+ T cells were resistant to autolysis by CD56RCD28+ T cells while autologous CD56+CARneg T cells, CD56+CD19RCD28+ T cells, and NK cells were lysed, confirming that CD56RCD28+ T cells cannot lyse CD56+ T cells co-expressing this CAR. CD56RCD28+ T cells did not upregulate expression of CD69, express CD107a or produce IFN-γ in the presence of autologous CD56+CD56RCD28+ T cells, but did exhibit all three characteristics of activation in the presence of autologous CD56+CARneg T cells, CD56+CD19RCD28+ T cells, and NK cells. This lack of activation in response to CD56 on CD56RCD28+ T cells infers that these T cells can avoid autolysis. To conclude, our data demonstrate that we can express a CD56-specific CAR on T cells despite the co-expression of CD56 and these genetically modified T cells can target tumor cells while evading autolysis. These data show clinical potential for CD56RCD28+ T cells against a multitude of CD56+ tumors and shed light on a unique phenomenom of evasion of CAR-mediated lysis which could impact T-cell based therapies.
501. Chimeric γc-Cytokine Receptors That Support Engraftment of Human CD8+ Cytolytic T Lymphocytes
Michelle R. Hunter,1 Vaidehi Mahadev,1 Christine E. Brown,1 Michael C. Jensen.2 1 Beckman Research Institute City of Hope National Medical Center, Duarte, CA; 2Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, WA. Therapeutic responses following adoptive transfer of cytotoxic T lymphocytes (CTLs) correlates with the duration and magnitude of their persistence. Iatrogenic lymphodepletion and exogenous IL-2 administration can improve CTL persistence following adoptive transfer, but their effects are not uniformly achieved and toxicities are significant. We hypothesized that the engineering of a cell intrinsic constitutive γc cytokine receptor signaling could overcome these limitations. Here we describe chimeric human γc cytokine receptors (CγCRs) composed of an Interleukin-7 (IL-7) tethered to IL-7Rα (CD127) extracellular/Tm domain and cytoplasmic domains capable of heterodimerization with γc to induce STAT5 phosphorylation. We show that this design is modular in that the IL-2Rβ (CD122) cytoplasmic chain can be swapped for IL-7Rα, enhancing the CγCRs Shc activity. When expressed in primary human CD8+ CTLs by lentiviral transduction, these CγCRs support cytokine independent viability and proliferation over prolonged periods of time in vitro. CγCR+ CD8+ CTLs retain effector function as measured by TCR/ CD3 complex-dependent cytolytic activity and cytokine secretion. Importantly, CγCR+ effector CTLs exhibit cytokine-independent engraftment in NOG mice for a period of approximately 3 weeks after which time cell attrition occurred, and persistence of dysregulated/ transformed cells was not observed. On going studies in the laboratory are focused on regulating the expression of CγCRs with clinical compatible small molecule transgene expression regulatory elements.
502. Novel Immunotherapy of Spontaneous Canine Malignant Melanoma: Intra Tumor Immune Stimulation and Long Term Survival with Adenovector CD40 Ligand Therapy
Sara Westberg,1 Arian Sadeghi,2 Angelika Loskog,2 Thomas Segall,3 Olle Korsgren,2 Thomas Tötterman,2 Henrik von Euler.4 1 University Animal Hospital, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden; 2Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; 3 Department of Pathology and Wildlife Diseases, National Veterinary Institute, Uppsala, Sweden; 4Center of Clinical Comparative Oncology, Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden. Introduction: Skin-derived Canine melanomas (CM) are usually benign, in contrast to the human equivalent. Most canine oropharyngeal, uveal, and mucocutaneous melanomas are aggressive with a high metastatic potential. Melanomas represent about 4% of all canine tumors, and are the most common malignant oral tumors. Surgery, radiotherapy and chemotherapy are widely used but seldom curative in advanced stages in both humans and dogs. It is proposed that malignant human melanomas and malignant CM share the same genetic factors leading to tumor development and metastatic spread. CM is a more accurate model for human malignant melanoma than traditional murine models since dogs are outbread, immune competent and share the same environment as humans. The homology of the human and the canine CD40L molecule is 85%. The similarities between human and canine melanoma thus make spontaneous canine melanoma an excellent disease model for exploring novel therapies. Herein, we report a pilot study of local Adenovector huCD40L immunogene (AdCD40L) treatment in 13 cases of malignant CM.
Molecular Therapy Volume 19, Supplement 1, May 2011 Copyright © The American Society of Gene & Cell Therapy
S193
498. Genetic Editing of T Lymphocyte Specificity for Safe and Effective Adoptive Immunotherapy
Pietro Genovese,1,2 Elena Provasi,2,3 Angelo Lombardo,1,2 Zulma Magnani,3 Pei-Qi Liu,4 Andreas Reik,4 Victoria Chu,4 David E. Paschon,4 Lei Zhang,4 Jurgen Kuball,5 Attilio Bondanza,3 Giulia Casorati,3 Fabio Ciceri,3 Claudio Bordignon,3 Philip D. Greenberg,5 Michael C. Holmes,4 Philip D. Gregory,4 Luigi Naldini,1,2 Chiara Bonini.2,3 1 HSR-Telethon Institute for Gene Therapy, Milan, Italy; 2Vita Salute San Raffaele University, Milan, Italy; 3San Raffaele Scientific Institute, Milan, Italy; 4Sangamo BioSciences, Richmond; 5 Fred Hutchinson Cancer Research Center, Seattle. Transfer of a T cell receptor (TCR) from a high-avidity tumorspecific T cell (CTL) to polyclonal T cells may overcome the challenges of expanding rare tumor-specific CTLs under conditions that preserve function and prevent exhaustion. Unfortunately, the full potential of this approach is limited by the co-expression in the same lymphocyte of the endogenous and exogenous TCR chains, resulting in competition for surface expression and acquisition of novel unpredicted specificities due to TCR mispairing between the 4 chains, which might lead to dangerous autoreactivity. Thus, we developed two sets of Zinc Finger Nucleases (ZFNs) to target double-strand breaks to the constant regions of the TCR α (TRAC) and β (TRBC1 and TRBC2) genes and disrupt their coding potential by the induced Non Homologous End Joining (NHEJ) repair process. We used a stimulation protocol based on anti-CD3/CD28 antibodyconjugated beads and culture with low doses of IL-7/IL-15 to preserve cells with an early T cell differentiation phenotype. Upon stimulation, delivery of either ZFN set by Adenoviral vectors (Ad5/F35) resulted in functional inactivation of the target genes in primary T cells (>45%), as indicated by the generation of cells that lack surface expression of the CD3/TCR complex (CD3neg). Once sorted, CD3neg cells proved stable in culture for more than 50 days, maintaining an early T cell phenotype (CD62L+ CD28+ CD27+ IL7Ra+), and were permissive to further lentiviral vector (LV) transduction. For complete editing of T cell specificity, we selected a codon-optimized, cystein-modified TCR specific for the Wilm’s Tumor Antigen 1 (WT1), involved in oncogenic transformation in several tumors, and developed a strategy for sequential disruption of each endogenous TCR chain followed by LV transfer of the respective WT1-specific chain. Using this approach we obtained a population of TCR-edited lymphocytes, carrying only the tumor-specific TCR that, in the absence of competition, was robustly expressed at physiological levels. Genetic editing did not affect the proliferative potential and the clonability of engineered cells nor their capacity to differentiate into effector and effector memory T S192
cells. TCR-edited lymphocytes were superior to conventional TCRtransferred cells in WT1 pentamer binding, specific recognition and lysis of WT1pos targets, including primary acute myeloid leukemia blasts. Importantly, these cells showed sharply reduced non-specific reactivity, including alloreactivity, demonstrating the advantage of preventing TCR mispairing. Overall, our results demonstrate that full genetic editing of T cell specificity is feasible, and allows the rapid generation of effective and safe T cells for adoptive immunotherapy.
499. Primary Human CD8+ T Cells Engineered To Express a PD1-CD28 Chimeric Receptor Are Co-Stimulated through the Exploitation of Tumor Expressed PD-L1
Megan E. Prosser,1 Christine E. Brown,1 Michael C. Jensen.2 Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute of the City of Hope, Duarte, CA; 2Center for Immunity and Immunotherapies, Seattle Childrens Research Institute, Seattle, WA.
1
Adoptive immunotherapy is a promising therapeutic approach for the treatment of malignancies. However, several challenges must be addressed to enhance therapeutic efficacy, including the loss of effector function of adoptively transferred cells in the tumor microenvironment. Tumors elicit multiple mechanisms for immunosuppression of transferred cells including deficiency of costimulation and expression of inhibitory ligands. T cell activation requires both antigenic stimulation through the T cell receptor as well as a costimulatory second signal. This secondary costimulatory signal is commonly deficient within the tumor microenvironment resulting in T cell anergy. In addition, tumors often express the inhibitory ligand Programmed Death Ligand 1 (PD-L1) which interacts with Programmed Death 1 (PD-1) expressed on the T cell surface, resulting in T cell exhaustion, characterized inhibition of TcR signaling, and enhanced apoptosis. We hypothesize that the development of a PD1-CD28 chimera could exploit the PD-L1 tumor derived inhibitory mechanism to result in tumor-induced costimulation and maintenance of effector function of adoptively transferred CD8+ T cells, thereby addressing the two aforementioned immunosuppressive mechanisms. Preliminary assessment of this PD1-CD28 chimera in transformed cells reveals that fusion of the PD1 extracellular domain to the intracellular signaling domain of CD28 does not alter PD-L1 binding to the extracellular PD-1 moiety. Furthermore, the chimera results in increased phosphorylation of ERK and AKT suggesting increased signaling through CD28- and TCR- signaling pathways in transformed cells upon ligand binding. In addition, this PD1-CD28 chimera results in increased costimulatory cytokine production in both transformed T cell lines as well as primary human CD8+ T cells. The PD1-CD28 chimera also provides a proliferative advantage, as well as increased accumulation of cytotoxic granules for CD8+ T cells. This work suggests that genetically engineering T cells to express the PD1CD28 chimera may exploit an intrinsic tumor immunosuppressive mechanism to result in costimulation and maintenance of effector function of adoptively transferred cells.
500. CD56-Specific T Cells Can Distinguish between Allogeneic and Autologous CD56+ Targets
Denise L. Kellar,1 Sonny Ang,1 Simon Olivares,1 Helen Huls,1 Laurence J. N. Cooper.1 1 Division of Pediatrics, UT MD Anderson Cancer Center, Houston, TX. Some candidate tumor-associated antigens (TAAs) are also expressed on T cells limiting the use of targeted T-cell therapy. CD56 is an attractive TAA with expression on many malignancies, yet CD56 upregulation on a subset of activated T cells could lead to Molecular Therapy Volume 19, Supplement 1, May 2011 Copyright © The American Society of Gene & Cell Therapy
CANCER - IMMUNOTHERAPY II self targeting, i.e. autolysis. We show here that a chimeric antigen receptor (CAR) can be generated with specificity for CD56. Primary human T cells were electrotransfered with a CD56-specific CAR (CD56RCD28) and CAR+ T cells were selectively propagated on γ-irradiated CD56+ artificial antigen presenting cells (aAPC) in the presence of exogenous recombinant IL-2 and IL-21. Surprisingly, a subset of CD56RCD28+ T cells co-expressed the CD56 antigen. With these data, we tested if CD56+CD56RCD28+ T cells could evade autolysis. A CD19-specific CAR (CD19RCD28) was expressed on control T cells, representing a CAR without self-targeting capacity. There were no significant differences between percent CD56 expression on, nor the expansion rate of, CD19RCD28+ T cells compared with CD56RCD28+ T cells over 28 days inferring that CD56-specific T cells are not lysing themselves. CD56RCD28+ T cells are functional as demonstrated by CD56-specific redirected cytotoxicity against a panel of allogeneic CD56+ tumor cells including neuroblastoma, small cell lung carcinoma, and glioma. To investigate the origin and proliferative capacity of CD56+ T cells, we sorted the CD56RCD28+ T cells into CD56neg and CD56+ fractions. The population of CD56+CD56RCD28+ T cells maintained CD56 expression and expanded over 14 days in a CAR-dependent manner implying that the CD56+CD56RCD28+ T cells did not predominately arise from CD56negCD56RCD28+ T cells gaining CD56 expression. Next, we determined if CD56RCD28+ T cells were capable of lysing autologous CD56+ lymphocytes with and without CAR. Significantly, the CD56+CD56RCD28+ T cells were resistant to autolysis by CD56RCD28+ T cells while autologous CD56+CARneg T cells, CD56+CD19RCD28+ T cells, and NK cells were lysed, confirming that CD56RCD28+ T cells cannot lyse CD56+ T cells co-expressing this CAR. CD56RCD28+ T cells did not upregulate expression of CD69, express CD107a or produce IFN-γ in the presence of autologous CD56+CD56RCD28+ T cells, but did exhibit all three characteristics of activation in the presence of autologous CD56+CARneg T cells, CD56+CD19RCD28+ T cells, and NK cells. This lack of activation in response to CD56 on CD56RCD28+ T cells infers that these T cells can avoid autolysis. To conclude, our data demonstrate that we can express a CD56-specific CAR on T cells despite the co-expression of CD56 and these genetically modified T cells can target tumor cells while evading autolysis. These data show clinical potential for CD56RCD28+ T cells against a multitude of CD56+ tumors and shed light on a unique phenomenom of evasion of CAR-mediated lysis which could impact T-cell based therapies.
501. Chimeric γc-Cytokine Receptors That Support Engraftment of Human CD8+ Cytolytic T Lymphocytes
Michelle R. Hunter,1 Vaidehi Mahadev,1 Christine E. Brown,1 Michael C. Jensen.2 1 Beckman Research Institute City of Hope National Medical Center, Duarte, CA; 2Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, WA. Therapeutic responses following adoptive transfer of cytotoxic T lymphocytes (CTLs) correlates with the duration and magnitude of their persistence. Iatrogenic lymphodepletion and exogenous IL-2 administration can improve CTL persistence following adoptive transfer, but their effects are not uniformly achieved and toxicities are significant. We hypothesized that the engineering of a cell intrinsic constitutive γc cytokine receptor signaling could overcome these limitations. Here we describe chimeric human γc cytokine receptors (CγCRs) composed of an Interleukin-7 (IL-7) tethered to IL-7Rα (CD127) extracellular/Tm domain and cytoplasmic domains capable of heterodimerization with γc to induce STAT5 phosphorylation. We show that this design is modular in that the IL-2Rβ (CD122) cytoplasmic chain can be swapped for IL-7Rα, enhancing the CγCRs Shc activity. When expressed in primary human CD8+ CTLs by lentiviral transduction, these CγCRs support cytokine independent viability and proliferation over prolonged periods of time in vitro. CγCR+ CD8+ CTLs retain effector function as measured by TCR/ CD3 complex-dependent cytolytic activity and cytokine secretion. Importantly, CγCR+ effector CTLs exhibit cytokine-independent engraftment in NOG mice for a period of approximately 3 weeks after which time cell attrition occurred, and persistence of dysregulated/ transformed cells was not observed. On going studies in the laboratory are focused on regulating the expression of CγCRs with clinical compatible small molecule transgene expression regulatory elements.
502. Novel Immunotherapy of Spontaneous Canine Malignant Melanoma: Intra Tumor Immune Stimulation and Long Term Survival with Adenovector CD40 Ligand Therapy
Sara Westberg,1 Arian Sadeghi,2 Angelika Loskog,2 Thomas Segall,3 Olle Korsgren,2 Thomas Tötterman,2 Henrik von Euler.4 1 University Animal Hospital, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden; 2Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; 3 Department of Pathology and Wildlife Diseases, National Veterinary Institute, Uppsala, Sweden; 4Center of Clinical Comparative Oncology, Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden. Introduction: Skin-derived Canine melanomas (CM) are usually benign, in contrast to the human equivalent. Most canine oropharyngeal, uveal, and mucocutaneous melanomas are aggressive with a high metastatic potential. Melanomas represent about 4% of all canine tumors, and are the most common malignant oral tumors. Surgery, radiotherapy and chemotherapy are widely used but seldom curative in advanced stages in both humans and dogs. It is proposed that malignant human melanomas and malignant CM share the same genetic factors leading to tumor development and metastatic spread. CM is a more accurate model for human malignant melanoma than traditional murine models since dogs are outbread, immune competent and share the same environment as humans. The homology of the human and the canine CD40L molecule is 85%. The similarities between human and canine melanoma thus make spontaneous canine melanoma an excellent disease model for exploring novel therapies. Herein, we report a pilot study of local Adenovector huCD40L immunogene (AdCD40L) treatment in 13 cases of malignant CM.
Molecular Therapy Volume 19, Supplement 1, May 2011 Copyright © The American Society of Gene & Cell Therapy
S193