Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains

Carpenito, Carmine; Milone, Michael C.; Hassan, Raffit; Simonet, Jacqueline C.; Lakhal, Mehdi; Suhoski, Megan M.; Varela‐Rohena, Angel; Haines, Kathleen M.; Heitjan, Daniel F.; Albelda, Steven Μ.; Carroll, Richard G.; Riley, James L.; Pastan, Ira; June, Carl H.

doi:10.1073/pnas.0813101106

Cited by 754 publications

(716 citation statements)

References 38 publications

(37 reference statements)

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“…The retargeted tumor-specific T cells survived and significantly reduced tumor burden, and, in some cases, resulted in the complete eradication of large pre-established mesothelioma xenografts [136]. It was further shown in this tumor xenograft model that the incorporation of the CD137 signaling domain into the chimeric receptor, significantly enhanced the persistence of the engineered T cells in the tumor-bearing mice following intratumoral or intravenous administration.…”

Section: Mouse/human Xenograft Models To Study In Vivo Dynamic Interamentioning

confidence: 81%

“…The ability of tumor specific T cells to overcome the immunosuppressive effects of the tumor microenvironment was demonstrated in another NOG mouse tumor xenograft model by the direct injection of T cells (engineered to express a chimeric receptor with high affinity for a tumor antigen) into pre-established large tumor xenografts [136].…”

Section: Mouse/human Xenograft Models To Study In Vivo Dynamic Interamentioning

confidence: 99%

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T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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Section: Mouse/human Xenograft Models To Study In Vivo Dynamic Interamentioning

confidence: 81%

Section: Mouse/human Xenograft Models To Study In Vivo Dynamic Interamentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

View full text Add to dashboard Cite

show abstract

“…DNA was synthesized by BlueHeron (Bothell, WA), using an optimization algorithm for codon usage in humans, and cloned into NcoI and XhoI sites of pMSGV1-28Z and pMSGV1-28-BBZ vectors. A CD28-containing second-generation CAR against MSLN was generated based on previously published sequences (Li et al, 2004;Carpenito et al, 2009) and cloned into MSGV1 retroviral vector. Evaluation of interferon-gamma (IFNg) secretion by CAR-transduced T cells was performed as described.…”

Section: Retroviral Constructs and Analysismentioning

confidence: 99%

A Novel Chimeric Antigen Receptor Against Prostate Stem Cell Antigen Mediates Tumor Destruction in a Humanized Mouse Model of Pancreatic Cancer

et al. 2014

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Despite advances in the understanding of its molecular pathophysiology, pancreatic cancer remains largely incurable, highlighting the need for novel therapies. We developed a chimeric antigen receptor (CAR) specific for prostate stem cell antigen (PSCA), a glycoprotein that is overexpressed in pancreatic cancer starting at early stages of malignant transformation. To optimize the CAR design, we used antigen-recognition domains derived from mouse or human antibodies, and intracellular signaling domains containing one or two T cell costimulatory elements, in addition to CD3zeta. Comparing multiple constructs established that the CAR based on human monoclonal antibody Ha1-4.117 had the greatest reactivity in vitro. To further analyze this CAR, we developed a human pancreatic cancer xenograft model and adoptively transferred CAR-engineered T cells into animals with established tumors. CAR-engineered human lymphocytes induced significant antitumor activity, and unlike what has been described for other CARs, a second-generation CAR (containing CD28 cosignaling domain) induced a more potent antitumor effect than a third-generation CAR (containing CD28 and 41BB cosignaling domains). While our results provide evidence to support PSCA as a target antigen for CAR-based immunotherapy of pancreatic cancer, the expression of PSCA on selected normal tissues could be a source of limiting toxicity.

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“…Greater in vivo T cell proliferation and persistence was seen after infusion of T cells modified with the second-generation CAR incorporating CD3f and a CD28 costimulatory domain compared with those modifed with the first-generation CD3f CAR without costimulation. While there is general agreement that T cells modified to express secondgeneration CARs are more effective than those engineered to express their first-generation counterparts, there is no consensus about the selection of costimulatory molecule domain to incorporate into second-generation CARs or whether third-generation CARs are superior to secondgeneration CARs [36,37]. One clinical trial has investigated infusion of T cells modified to express a third-generation CD20-specific CAR that incorporated costimulatory domains derived from both CD28 and 41BB [15]; however, clinical efficacy and T cell persistence were modest.…”

Section: Design Of Chimeric Antigen Receptorsmentioning

confidence: 99%

Chimeric antigen receptor modified T cell therapy for B cell malignancies

Turtle

2013

Int J Hematol

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Adoptive transfer of tumor-reactive T cells into cancer patients with the intent of inducing a cytotoxic antitumor effector response and durable immunity has long been proposed as a novel therapy for a broad range of malignancies; however, local and systemic tolerance mechanisms have hindered the generation of effective T cell therapies and limited the clinical efficacy of this approach in cancer patients. Chimeric antigen receptors (CARs) are recombinant receptors that comprise an extracellular antigen-targeting domain in conjunction with one or more intracellular T cell signaling domains that can be introduced into T cells by genetic modification to redirect their specificity to the CAR-targeted antigen. Administration of CD19-specific CAR-modified T cells that target B cell non-Hodgkin lymphomas and leukemia has been remarkably effective in recent clinical trials, energizing the field and stimulating new efforts to identify the critical parameters of CAR design and T cell engineering that are necessary for effective cancer therapy.

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Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains

Cited by 754 publications

References 38 publications

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

A Novel Chimeric Antigen Receptor Against Prostate Stem Cell Antigen Mediates Tumor Destruction in a Humanized Mouse Model of Pancreatic Cancer

Chimeric antigen receptor modified T cell therapy for B cell malignancies

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