10508 Background: Outcome for patients with advanced sarcoma is extremely poor and treatment opti... more 10508 Background: Outcome for patients with advanced sarcoma is extremely poor and treatment options are limited. Encouragingly, in our phase 1 dose-escalation trial (Ahmed et al, JCO 2015), systemic administration of up to 1x108/m2 autologous HER2-CAR T cells in patient with HER2+ sarcoma was safe. While T cells did not expand, 4/19 evaluable patients are alive 37-61 months post infusion without evidence of disease. The goal of this study was to evaluate if lympohodepleting chemotherapy can safely induce the expansion of HER2-CAR T cells. Methods: In a phase 1 clinical study, NCT00902044, we administered 1x108/m2 autologous HER2-CAR (with a CD28.zeta signaling domain) T cells to patients with refractory/metastatic HER2+ sarcoma after lymphodepletion. Results: Six patients with refractory/metastatic HER2+ sarcoma (4 osteosarcoma, 1 rhabdomyosarcoma, 1 synovial sarcoma) with a median age of 16 (range: 4 to 55) received up to 3 infusions of 1x108 cells/m2 CAR T cells after lymphodeple...
Astrocytes are the most abundant cell type in the brain, where they perform a wide array of funct... more Astrocytes are the most abundant cell type in the brain, where they perform a wide array of functions, yet the nature of their cellular heterogeneity and how it oversees these diverse roles remains shrouded in mystery. Using an intersectional fluorescence-activated cell sorting-based strategy, we identified five distinct astrocyte subpopulations present across three brain regions that show extensive molecular diversity. Application of this molecular insight toward function revealed that these populations differentially support synaptogenesis between neurons. We identified correlative populations in mouse and human glioma and found that the emergence of specific subpopulations during tumor progression corresponded with the onset of seizures and tumor invasion. In sum, we have identified subpopulations of astrocytes in the adult brain and their correlates in glioma that are endowed with diverse cellular, molecular and functional properties. These populations selectively contribute to ...
CanCer-Immunotherapy, CanCer VaCCInes II a significant decline in the tumor growth of vascularize... more CanCer-Immunotherapy, CanCer VaCCInes II a significant decline in the tumor growth of vascularized orthotopic breast cancer xenografts in a murine model, compared to nontransduced T cells (p=0.03). Conclusion: We conclude that TEM8 specific CAR T cells could serve as a tumor and vascular targeted therapy for TNBC.
Background: Glioblastoma (GBM) is the most malignant and aggressive brain tumor, and survival of ... more Background: Glioblastoma (GBM) is the most malignant and aggressive brain tumor, and survival of patients affected by GBM has remained virtually unchanged over numerous years. GBM is only minimally responsive to aggressive standard therapies including radical surgery and concurrent chemo-radiation treatment with temozolomide (TMZ). Seneca Valley virus (SVV-001) is a non-pathogenic oncolytic virus that can be systemically administered and can pass through the blood-brain barrier. In this study, we developed a new panel of patient derived orthotopic xenograft (PDOX) models to examine the therapeutic efficacy of SVV-001 combined with irradiation. In addition, we explored the mechanism of tumor cell infection with SVV-001 in malignant gliomas. Material and Methods: Surgical GBM tumor samples were obtained from 17 patients and directly implanted into the right cerebrum of NOD/SCID mice (1×105 cells suspended in 2 uL growth medium). Once tumor formation was confirmed, we performed H&E sta...
New discoveries concerning genetic alterations or cell surface immunophenotypes may allow previou... more New discoveries concerning genetic alterations or cell surface immunophenotypes may allow previously undefined subsets of poor responders to have improved outcomes with chemotherapy plus targeted agents or novel immunotherapeutics. However, for patients without targetable lesions or cell surface markers who respond poorly to current-era therapy, our data demonstrate that allogeneic HSCT may be performed with acceptable safety and efficacy for patients with ALL and high risk features in CR1 with excellent 3-year EFS and OS.
respiratory tract infections (LRI) in immunocompetent young children and older adults. Data on th... more respiratory tract infections (LRI) in immunocompetent young children and older adults. Data on the impact of hMPV infections in HCT recipients has been scarce. In this study, we aimed to determine the morbidity and mortality of hMPV infections in HCT recipients. Methods: We reviewed the medical records of all 83 HCT recipients with positive hMPV testing from April 2012 to April 2015. We collected the demographics, clinical characteristics and outcomes of hMPV infections from medical records. Results: Most of patients were allogeneic HCT recipients (60%) including matched related and unrelated donor (27% each), haploidentical (5%) and mismatched (2%), and the rest were autologous HCT recipients (40%). The cell source of the donor was peripheral (72%), marrow (8%), and cord (5%). Majority of patients were Caucasians (63%), males (57%) with a median age of 58 years (range: 4 to 80 years). Corticosteroid use in the past 30 days was identified in 34%, lymphocytopenia in 8% and neutropenia in 5% of hMPV patients. Three patients (3%) had acute GvHD, 9 patients (11%) had chronic GvHD, and 1 patient had acute on chronic GvHD at the time of hMPV diagnosis. Majority of infections were community-acquired (88%), presented at the URI stage (72%) and overall LRI rate was 39% (28% presented with LRI). Rates of LRI were higher for patients undergoing mismatched/ haploidentical/cord blood HCT compared to autologous HCT (P ¼ 0.08) (Figure). Hospital admission secondary to infection (39%), mechanical ventilation (5%), and oxygen requirements (25%) were observed. At day 30, all-cause and hMPV associated mortality was low (2%). Conclusions: hMPV infections are common in HCT recipients with the potential for nosocomial transmission and can cause significant morbidity leading to high rates of hospital admissions.
Medulloblastoma (MB) is a cancer of the cerebellum and the most common primary pediatric malignan... more Medulloblastoma (MB) is a cancer of the cerebellum and the most common primary pediatric malignancy of the central nervous system. Classified as a primitive neural ectoderm tumor; it is thought to arise from granule cell precursors in the cerebellum. The standard of care consists of surgery, chemotherapy and age-dependent radiation therapy. Despite aggressive multimodality therapy; approximately 30% of MB patients remain incurable. Moreover, for long-term survivors, the treatment related sequelae are often debilitating. Side effects include cerebellar mutism, sterility, neurocognitive deficits, and a substantial risk of developing secondary cancers. In a quest for more effective and targeted therapies, scientists have begun to investigate the biological events that not only initiate but also sustain the malignant phenotype in MB. Of particular interest is, the role of the tumor microenvironment in tumor pathogenesis. This review seeks to highlight several key processes observed in cancer biology, particularly the involvement of the tumor microenvironment, with relevant examples from MB.
One major advance in T cell based immunotherapy in the last twenty years has been the molecular d... more One major advance in T cell based immunotherapy in the last twenty years has been the molecular definition of numerous viral and tumor antigens. Adoptive T-cell transfer has shown definite clinical benefit in the prophylaxis and treatment of viral infections that develop in pediatric patients after allogeneic transplant and in Epstein-Barr virus-associated post-transplant lymphoproliferative disease. Developing adoptive T cell therapies for other malignancies presents additional challenges. This article describes the recent advances in T cell based therapies for malignancy and infection in childhood and strategies to enhance the effector functions of T cells and optimize the cellular product, including gene modification and modulation of the host environment.
Preclinical and early clinical studies have demonstrated that chimeric antigen receptor (CAR)-red... more Preclinical and early clinical studies have demonstrated that chimeric antigen receptor (CAR)-redirected T cells are highly promising in cancer therapy. We observed that targeting HER2 in a glioblastoma (GBM) cell line results in the emergence of HER2-null tumor cells that maintain the expression of nontargeted tumor-associated antigens. Combinational targeting of these tumorassociated antigens could therefore offset this escape mechanism. We studied the single-cell coexpression patterns of HER2, IL-13Rα2, and EphA2 in primary GBM samples using multicolor flow cytometry and immunofluorescence, and applied a binomial routine to the permutations of antigen expression and the related odds of complete tumor elimination. This mathematical model demonstrated that cotargeting HER2 and IL-13Rα2 could maximally expand the therapeutic reach of the T cell product in all primary tumors studied. Targeting a third antigen did not predict an added advantage in the tumor cohort studied. We therefore generated bispecific T cell products from healthy donors and from GBM patients by pooling T cells individually expressing HER2 and IL-13Rα2-specific CARs and by making individual T cells to coexpress both molecules. Both HER2/ IL-13Rα2-bispecific T cell products offset antigen escape, producing enhanced effector activity in vitro immunoassays (against autologous glioma cells in the case of GBM patient products) and in an orthotopic xenogeneic murine model. Further, T cells coexpressing HER2 and IL-13Rα2-CARs exhibited accentuated yet antigendependent downstream signaling and a particularly enhanced antitumor activity.
Glioblastoma (GBM) is the most common primary brain cancer in adults and is virtually incurable. ... more Glioblastoma (GBM) is the most common primary brain cancer in adults and is virtually incurable. Recent studies have shown that CMV is present in the majority of GBMs. To evaluate if the CMV antigens pp65 and IE1, which are expressed in GBMs, can be targeted with CMVspecific T cells, we measured the frequency of T cells targeting pp65 and IE1 in the peripheral blood of a cohort of 11 sequentially-diagnosed CMV-seropositive GBM patients, and evaluated whether it was feasible to expand autologous CMV-specific T cells for future clinical studies. All 11 CMV-seropositive GBM patients had T cells specific for pp65 and IE1 in their peripheral blood assessed by IFNγ ELIspot assay. However, the precursor frequency of pp65-specific T cells was decreased in comparison to healthy donors (p=0.001). We successfully reactivated and expanded CMV-specific T cells from 6 out of 6 GBM patients using antigen presenting cells transduced with an adenoviral vector encoding pp65 and IE1. CMV-specific T-cell lines contained CD4-positive as well as CD8-positive T cells, recognized pp65-and IE1-positive targets and killed CMV-infected autologous GBM cells. Infusion of such CMV-specific T-cell lines may extend the benefits of Tcell therapy to patients with CMV-positive GBMs.
Despite the successful development of vaccines that are able to elicit potent and protective immu... more Despite the successful development of vaccines that are able to elicit potent and protective immune responses, the majority of vaccines were developed empirically and the mechanistic events leading to protective immune responses are often poorly understood. This impedes the development of new prophylactic as well as therapeutic vaccines for infectious diseases and cancer. Gaucher et al. took advantage of the effective yellow fever (YF) vaccine 17D (YF17D) to prospectively identify key immunological responses elicited by the vaccine using functional genomics and flow cytometric analysis. The results of the study clearly indicate 'that the immune response to a strong vaccine is preceded by the coordinated induction of master transcription factors that lead to the development of a broad, polyfunctional and persistent immune response integrating all effector cells of the immune system'.
Medulloblastoma is a common malignant brain tumor of childhood. Human epidermal growth factor rec... more Medulloblastoma is a common malignant brain tumor of childhood. Human epidermal growth factor receptor 2 (HER2) is expressed by 40% of medulloblastomas and is a risk factor for poor outcome with current aggressive multimodal therapy. In contrast to breast cancer, HER2 is expressed only at low levels in medulloblastomas, rendering monoclonal antibodies ineffective. We determined if T cells grafted with a HER2-specific chimeric antigen receptor (CAR; HER2-specific T cells) recognized and killed HER2-positive medulloblastomas. Ex vivo, stimulation of HER2-specific T cells with HER2-positive medulloblastomas resulted in T-cell proliferation and secretion of IFN-γ and interleukin 2 (IL-2) in a HER2-dependent manner. HER2-specific T cells killed autologous HER2-positive primary medulloblastoma cells and medulloblastoma cell lines in cytotoxicity assays, whereas HER2-negative tumor cells were not killed. No functional difference was observed between HER2-specific T cells generated from med...
... Co-Investigators Robert Krance, MD George Carrum, MD Catherine Bollard MD Stephen Gottschalk ... more ... Co-Investigators Robert Krance, MD George Carrum, MD Catherine Bollard MD Stephen Gottschalk MD Kathryn Leung MD G Douglas Myers MD Rammurti Kamble MD Nabil Ahmed MD Alana Kennedy-Nasser MD Jessica Shafer MD Adrian Gee MI Biol, PhD Cliona Rooney ...
Outcomes for patients with glioblastoma remain poor despite aggressive multimodal therapy. Immuno... more Outcomes for patients with glioblastoma remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL) 13Rα2, human epidermal growth factor receptor 2, epidermal growth factor variant III or erythropoietin-producing hepatocellular carcinoma A2 has shown promise for the treatment of glioma in preclinical models. On the basis of IL13Rα2 immunotoxins that contain IL13 molecules with one or two amino acid substitutions (IL13 muteins) to confer specificity to IL13Rα2, investigators have constructed CARS with IL13 muteins as antigen-binding domains. Whereas the specificity of IL13 muteins in the context of immunotoxins is well characterized, limited information is available for CAR T cells. We constructed four second-generation CARs with IL13 muteins with one or two amino acid substitutions, and evaluated the effector function of IL13-mutein CAR T cells in vitro and in vivo. T cells...
10508 Background: Outcome for patients with advanced sarcoma is extremely poor and treatment opti... more 10508 Background: Outcome for patients with advanced sarcoma is extremely poor and treatment options are limited. Encouragingly, in our phase 1 dose-escalation trial (Ahmed et al, JCO 2015), systemic administration of up to 1x108/m2 autologous HER2-CAR T cells in patient with HER2+ sarcoma was safe. While T cells did not expand, 4/19 evaluable patients are alive 37-61 months post infusion without evidence of disease. The goal of this study was to evaluate if lympohodepleting chemotherapy can safely induce the expansion of HER2-CAR T cells. Methods: In a phase 1 clinical study, NCT00902044, we administered 1x108/m2 autologous HER2-CAR (with a CD28.zeta signaling domain) T cells to patients with refractory/metastatic HER2+ sarcoma after lymphodepletion. Results: Six patients with refractory/metastatic HER2+ sarcoma (4 osteosarcoma, 1 rhabdomyosarcoma, 1 synovial sarcoma) with a median age of 16 (range: 4 to 55) received up to 3 infusions of 1x108 cells/m2 CAR T cells after lymphodeple...
Astrocytes are the most abundant cell type in the brain, where they perform a wide array of funct... more Astrocytes are the most abundant cell type in the brain, where they perform a wide array of functions, yet the nature of their cellular heterogeneity and how it oversees these diverse roles remains shrouded in mystery. Using an intersectional fluorescence-activated cell sorting-based strategy, we identified five distinct astrocyte subpopulations present across three brain regions that show extensive molecular diversity. Application of this molecular insight toward function revealed that these populations differentially support synaptogenesis between neurons. We identified correlative populations in mouse and human glioma and found that the emergence of specific subpopulations during tumor progression corresponded with the onset of seizures and tumor invasion. In sum, we have identified subpopulations of astrocytes in the adult brain and their correlates in glioma that are endowed with diverse cellular, molecular and functional properties. These populations selectively contribute to ...
CanCer-Immunotherapy, CanCer VaCCInes II a significant decline in the tumor growth of vascularize... more CanCer-Immunotherapy, CanCer VaCCInes II a significant decline in the tumor growth of vascularized orthotopic breast cancer xenografts in a murine model, compared to nontransduced T cells (p=0.03). Conclusion: We conclude that TEM8 specific CAR T cells could serve as a tumor and vascular targeted therapy for TNBC.
Background: Glioblastoma (GBM) is the most malignant and aggressive brain tumor, and survival of ... more Background: Glioblastoma (GBM) is the most malignant and aggressive brain tumor, and survival of patients affected by GBM has remained virtually unchanged over numerous years. GBM is only minimally responsive to aggressive standard therapies including radical surgery and concurrent chemo-radiation treatment with temozolomide (TMZ). Seneca Valley virus (SVV-001) is a non-pathogenic oncolytic virus that can be systemically administered and can pass through the blood-brain barrier. In this study, we developed a new panel of patient derived orthotopic xenograft (PDOX) models to examine the therapeutic efficacy of SVV-001 combined with irradiation. In addition, we explored the mechanism of tumor cell infection with SVV-001 in malignant gliomas. Material and Methods: Surgical GBM tumor samples were obtained from 17 patients and directly implanted into the right cerebrum of NOD/SCID mice (1×105 cells suspended in 2 uL growth medium). Once tumor formation was confirmed, we performed H&E sta...
New discoveries concerning genetic alterations or cell surface immunophenotypes may allow previou... more New discoveries concerning genetic alterations or cell surface immunophenotypes may allow previously undefined subsets of poor responders to have improved outcomes with chemotherapy plus targeted agents or novel immunotherapeutics. However, for patients without targetable lesions or cell surface markers who respond poorly to current-era therapy, our data demonstrate that allogeneic HSCT may be performed with acceptable safety and efficacy for patients with ALL and high risk features in CR1 with excellent 3-year EFS and OS.
respiratory tract infections (LRI) in immunocompetent young children and older adults. Data on th... more respiratory tract infections (LRI) in immunocompetent young children and older adults. Data on the impact of hMPV infections in HCT recipients has been scarce. In this study, we aimed to determine the morbidity and mortality of hMPV infections in HCT recipients. Methods: We reviewed the medical records of all 83 HCT recipients with positive hMPV testing from April 2012 to April 2015. We collected the demographics, clinical characteristics and outcomes of hMPV infections from medical records. Results: Most of patients were allogeneic HCT recipients (60%) including matched related and unrelated donor (27% each), haploidentical (5%) and mismatched (2%), and the rest were autologous HCT recipients (40%). The cell source of the donor was peripheral (72%), marrow (8%), and cord (5%). Majority of patients were Caucasians (63%), males (57%) with a median age of 58 years (range: 4 to 80 years). Corticosteroid use in the past 30 days was identified in 34%, lymphocytopenia in 8% and neutropenia in 5% of hMPV patients. Three patients (3%) had acute GvHD, 9 patients (11%) had chronic GvHD, and 1 patient had acute on chronic GvHD at the time of hMPV diagnosis. Majority of infections were community-acquired (88%), presented at the URI stage (72%) and overall LRI rate was 39% (28% presented with LRI). Rates of LRI were higher for patients undergoing mismatched/ haploidentical/cord blood HCT compared to autologous HCT (P ¼ 0.08) (Figure). Hospital admission secondary to infection (39%), mechanical ventilation (5%), and oxygen requirements (25%) were observed. At day 30, all-cause and hMPV associated mortality was low (2%). Conclusions: hMPV infections are common in HCT recipients with the potential for nosocomial transmission and can cause significant morbidity leading to high rates of hospital admissions.
Medulloblastoma (MB) is a cancer of the cerebellum and the most common primary pediatric malignan... more Medulloblastoma (MB) is a cancer of the cerebellum and the most common primary pediatric malignancy of the central nervous system. Classified as a primitive neural ectoderm tumor; it is thought to arise from granule cell precursors in the cerebellum. The standard of care consists of surgery, chemotherapy and age-dependent radiation therapy. Despite aggressive multimodality therapy; approximately 30% of MB patients remain incurable. Moreover, for long-term survivors, the treatment related sequelae are often debilitating. Side effects include cerebellar mutism, sterility, neurocognitive deficits, and a substantial risk of developing secondary cancers. In a quest for more effective and targeted therapies, scientists have begun to investigate the biological events that not only initiate but also sustain the malignant phenotype in MB. Of particular interest is, the role of the tumor microenvironment in tumor pathogenesis. This review seeks to highlight several key processes observed in cancer biology, particularly the involvement of the tumor microenvironment, with relevant examples from MB.
One major advance in T cell based immunotherapy in the last twenty years has been the molecular d... more One major advance in T cell based immunotherapy in the last twenty years has been the molecular definition of numerous viral and tumor antigens. Adoptive T-cell transfer has shown definite clinical benefit in the prophylaxis and treatment of viral infections that develop in pediatric patients after allogeneic transplant and in Epstein-Barr virus-associated post-transplant lymphoproliferative disease. Developing adoptive T cell therapies for other malignancies presents additional challenges. This article describes the recent advances in T cell based therapies for malignancy and infection in childhood and strategies to enhance the effector functions of T cells and optimize the cellular product, including gene modification and modulation of the host environment.
Preclinical and early clinical studies have demonstrated that chimeric antigen receptor (CAR)-red... more Preclinical and early clinical studies have demonstrated that chimeric antigen receptor (CAR)-redirected T cells are highly promising in cancer therapy. We observed that targeting HER2 in a glioblastoma (GBM) cell line results in the emergence of HER2-null tumor cells that maintain the expression of nontargeted tumor-associated antigens. Combinational targeting of these tumorassociated antigens could therefore offset this escape mechanism. We studied the single-cell coexpression patterns of HER2, IL-13Rα2, and EphA2 in primary GBM samples using multicolor flow cytometry and immunofluorescence, and applied a binomial routine to the permutations of antigen expression and the related odds of complete tumor elimination. This mathematical model demonstrated that cotargeting HER2 and IL-13Rα2 could maximally expand the therapeutic reach of the T cell product in all primary tumors studied. Targeting a third antigen did not predict an added advantage in the tumor cohort studied. We therefore generated bispecific T cell products from healthy donors and from GBM patients by pooling T cells individually expressing HER2 and IL-13Rα2-specific CARs and by making individual T cells to coexpress both molecules. Both HER2/ IL-13Rα2-bispecific T cell products offset antigen escape, producing enhanced effector activity in vitro immunoassays (against autologous glioma cells in the case of GBM patient products) and in an orthotopic xenogeneic murine model. Further, T cells coexpressing HER2 and IL-13Rα2-CARs exhibited accentuated yet antigendependent downstream signaling and a particularly enhanced antitumor activity.
Glioblastoma (GBM) is the most common primary brain cancer in adults and is virtually incurable. ... more Glioblastoma (GBM) is the most common primary brain cancer in adults and is virtually incurable. Recent studies have shown that CMV is present in the majority of GBMs. To evaluate if the CMV antigens pp65 and IE1, which are expressed in GBMs, can be targeted with CMVspecific T cells, we measured the frequency of T cells targeting pp65 and IE1 in the peripheral blood of a cohort of 11 sequentially-diagnosed CMV-seropositive GBM patients, and evaluated whether it was feasible to expand autologous CMV-specific T cells for future clinical studies. All 11 CMV-seropositive GBM patients had T cells specific for pp65 and IE1 in their peripheral blood assessed by IFNγ ELIspot assay. However, the precursor frequency of pp65-specific T cells was decreased in comparison to healthy donors (p=0.001). We successfully reactivated and expanded CMV-specific T cells from 6 out of 6 GBM patients using antigen presenting cells transduced with an adenoviral vector encoding pp65 and IE1. CMV-specific T-cell lines contained CD4-positive as well as CD8-positive T cells, recognized pp65-and IE1-positive targets and killed CMV-infected autologous GBM cells. Infusion of such CMV-specific T-cell lines may extend the benefits of Tcell therapy to patients with CMV-positive GBMs.
Despite the successful development of vaccines that are able to elicit potent and protective immu... more Despite the successful development of vaccines that are able to elicit potent and protective immune responses, the majority of vaccines were developed empirically and the mechanistic events leading to protective immune responses are often poorly understood. This impedes the development of new prophylactic as well as therapeutic vaccines for infectious diseases and cancer. Gaucher et al. took advantage of the effective yellow fever (YF) vaccine 17D (YF17D) to prospectively identify key immunological responses elicited by the vaccine using functional genomics and flow cytometric analysis. The results of the study clearly indicate 'that the immune response to a strong vaccine is preceded by the coordinated induction of master transcription factors that lead to the development of a broad, polyfunctional and persistent immune response integrating all effector cells of the immune system'.
Medulloblastoma is a common malignant brain tumor of childhood. Human epidermal growth factor rec... more Medulloblastoma is a common malignant brain tumor of childhood. Human epidermal growth factor receptor 2 (HER2) is expressed by 40% of medulloblastomas and is a risk factor for poor outcome with current aggressive multimodal therapy. In contrast to breast cancer, HER2 is expressed only at low levels in medulloblastomas, rendering monoclonal antibodies ineffective. We determined if T cells grafted with a HER2-specific chimeric antigen receptor (CAR; HER2-specific T cells) recognized and killed HER2-positive medulloblastomas. Ex vivo, stimulation of HER2-specific T cells with HER2-positive medulloblastomas resulted in T-cell proliferation and secretion of IFN-γ and interleukin 2 (IL-2) in a HER2-dependent manner. HER2-specific T cells killed autologous HER2-positive primary medulloblastoma cells and medulloblastoma cell lines in cytotoxicity assays, whereas HER2-negative tumor cells were not killed. No functional difference was observed between HER2-specific T cells generated from med...
... Co-Investigators Robert Krance, MD George Carrum, MD Catherine Bollard MD Stephen Gottschalk ... more ... Co-Investigators Robert Krance, MD George Carrum, MD Catherine Bollard MD Stephen Gottschalk MD Kathryn Leung MD G Douglas Myers MD Rammurti Kamble MD Nabil Ahmed MD Alana Kennedy-Nasser MD Jessica Shafer MD Adrian Gee MI Biol, PhD Cliona Rooney ...
Outcomes for patients with glioblastoma remain poor despite aggressive multimodal therapy. Immuno... more Outcomes for patients with glioblastoma remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL) 13Rα2, human epidermal growth factor receptor 2, epidermal growth factor variant III or erythropoietin-producing hepatocellular carcinoma A2 has shown promise for the treatment of glioma in preclinical models. On the basis of IL13Rα2 immunotoxins that contain IL13 molecules with one or two amino acid substitutions (IL13 muteins) to confer specificity to IL13Rα2, investigators have constructed CARS with IL13 muteins as antigen-binding domains. Whereas the specificity of IL13 muteins in the context of immunotoxins is well characterized, limited information is available for CAR T cells. We constructed four second-generation CARs with IL13 muteins with one or two amino acid substitutions, and evaluated the effector function of IL13-mutein CAR T cells in vitro and in vivo. T cells...
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